Skip to content
naulon
Get started

No retraction, correction or concern found when last checked on Oct 26, 2026.

Plasma Cell Differentiation Pathways in Systemic Lupus Erythematosus

Susan Malkiel, Ashley N. Barlev, Yemil Atisha-Fregoso and 2 more

Frontiers in Immunology · 2018 · Review

doi:10.3389/fimmu.2018.00427

Abstract

Plasma cells (PCs) are responsible for the production of protective antibodies against infectious agents but they also produce pathogenic antibodies in autoimmune diseases, such as systemic lupus erythematosus (SLE). Traditionally, high affinity IgG autoantibodies are thought to arise through germinal center (GC) responses. However, class switching and somatic hypermutation can occur in extrafollicular (EF) locations, and this pathway has also been implicated in SLE. The pathway from which PCs originate may determine several characteristics, such as PC lifespan and sensitivity to therapeutics. Although both GC and EF responses have been implicated in SLE, we hypothesize that one of these pathways dominates in each individual patient and genetic risk factors may drive this predominance. While it will be important to distinguish polymorphisms that contribute to a GC-driven or EF B cell response to develop targeted treatments, the challenge will be not only to identify the differentiation pathway but the molecular mechanisms involved. In B cells, this task is complicated by the cross-talk between the B cell receptor, toll-like receptors (TLR), and cytokine signaling molecules, which contribute to both GC and EF responses. While risk variants that affect the function of dendritic cells and T follicular helper cells are likely to primarily influence GC responses, it will be important to discover whether some risk variants in the interferon and TLR pathways preferentially influence EF responses. Identifying the pathways of autoreactive PC differentiation in SLE may help us to understand patient heterogeneity and thereby guide precision therapy.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 26, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the production of pathogenic autoantibodies that target a variety of nuclear self-antigens, some of which cross-react with tissue antigens. These autoantibodies cause tissue inflammation and lead to organ damage in the kidneys, skin, and more. Presence of IgG ANA is a diagnostic feature for SLE and other systemic autoimmune diseases, and these antibodies have an important role in disease pathogenesis. In contrast, IgM ANA are considered to be protective against autoimmunity. They can be present in healthy individuals and assist in the non-inflammatory clearance of cellular debris and inhibit responses induced by IgG ANA. Other isotypes include IgA and IgE, but the pathogenicity of these isotypes has been less well studied.

Antibodies are secreted by plasma cells (PCs), which arise as a terminal differentiation step from B cells. Most of our knowledge of immune tolerance to nuclear antigens, and the break of tolerance in SLE patients, is derived from studies with B cell receptor (BCR)-transgenic mice and single cell studies in humans, where self-reactivity is usually censored in developing B cells prior to their achieving immunocompetence. Autoreactive cells that escape these mechanisms often become anergic, a process that mitigates against these cells giving rise to high affinity IgG autoantibody-producing PCs.

Plasma cells can arise through two pathways: through activation of B cells and direct differentiation in extrafollicular (EF) foci or through a germinal center (GC) response. Although traditionally pathogenic high affinity autoantibodies have been associated with the GC response, recent insights have implicated the EF pathway in SLE as well. We hypothesize that both pathways can contribute to production of SLE autoantibodies. Understanding the regulation of each pathway and how genetic risk alleles may preferentially target one or the other of these pathways will be the focus of this review.

Different subtypes of PCs have been described, including plasmablasts (PB), pre-PC, early PC, short-lived PC, and long-lived PC. These terms are sometimes used interchangeably or not clearly defined. The confusion in part derives from the original paradigm that the EF pathway only results in short-lived proliferating PBs, whereas the GC pathway was thought to result only in long-lived quiescent PCs. However, lifespan and proliferation can operate independently from each other, such that there are short-lived PCs which are not proliferating, and long-lived PCs from GC origin can proliferate prior to becoming quiescent. In addition, PC differentiation is a continuum where expression of canonical B cell markers [B220, CD19, major histocompatibility complex (MHC) class II] is gradually lost and PC markers (such as Blimp-1, CD138, secreted Ig) are gradually upregulated. It is therefore difficult to define specific PC subsets based on the expression of these markers. Here, we define PCs as antibody secreting cells and we will only mention specific PC subsets if these have been clearly verified. Definitions used in this review are PBs, if proliferation has been verified; short-lived plasma cells, if a short lifespan of <7 days has been shown; or long-lived PC, if a long lifespan of >28 days has been demonstrated.

T-Independent B Cell Activation and PC Differentiation

The B cell lineage consists of several subsets and cells diverge early in development. Each of these naive cell subsets can give rise to PCs, but they each preferentially respond to specific types of antigen. Antigens can activate B cells in a T-independent or T-dependent manner. T-independent responses do not require cognate T cell help. T-independent activation therefore leads to plasma cell differentiation in the absence of GCs. There are two types of T-independent antigens that can induce activation of B cells; TI-1 antigens can activate B cells through coengagement of Toll-like receptors (TLR), such as LPS or other bacterial polysaccharides, whereas TI-2 antigens lead to extensive crosslinking of the BCR, such as polymeric protein antigens or repeated structural motifs. In TI-2 responses, competition for antigen enhances the activation and expansion of high-affinity cells, while antigen affinity is less important in TI-1 responses.

Although TI-1 and TI-2 antigens have been considered to induce T cell-independent responses, it is now clear that this distinction is not absolute: TI-2 and possibly TI-1 antigens can induce a transient GC, and the TI-2 serum antibody responses, in particular IgG, can still be T cell-dependent, even if the antigen cannot directly trigger T cells through MHC class II. It has therefore been proposed that the characteristics of the antigen is not the leading determinant of the response, but rather the B cell subset and the ancillary cell types involved determine the nature of the response.

In addition to the strength of the initial stimulus through the BCR and cognate and non-cognate T cell interactions, B cell activation is also modified by the presence of other potent stimuli. Pattern recognition receptors, such as TLRs, interact with damage-associated molecular patterns or highly conserved microbial structures present in bacteria or virus. Included among these are both dsDNA (CpG enriched) and RNA. Many TLRs signal through MyD88, and MyD88-deficient mice have diminished antibody responses, both early and late after immunization. Simultaneous engagement of the BCR and TLRs has a synergistic effect on signaling and subsequent B cell activation.

Cytokines, such as type I interferon (IFN), IL-6, and BAFF, can activate B cells and enhance both T-independent and T-dependent activation. BAFF has three recognized receptors, and one of them, TACI, signals through MyD88, the same adaptor used by TLR7 and TLR9. Antigen-presenting cells, such as dendritic cell (DC) and macrophages, induce CD40-independent PC differentiation through secretion of cytokines such as BAFF and APRIL.

Two processes that alter the antibody response are somatic hypermutation (SHM) and class switch recombination (CSR), both of which are mediated by the enzyme activation-induced cytidine deaminase (AID). These processes can change antigen recognition by the BCR (SHM) or change the isotype that is expressed (CSR), and are usually associated with GC responses (discussed below). Although T-independent responses are usually associated with the IgM isotype, CSR can occur in certain infections and does not require cognate T–B interactions. CSR can be driven by MyD88 signaling or cytokines such as BAFF, APRIL, IFN-gamma, and IL-21.

B-1 Cells

B-1 cells represent a distinct population of B cells that arises during fetal development. They are mainly found in the peritoneal and pleural cavities of mice and are rare in lymphoid organs and blood (Figure 1). B-1 cells generally express germline-encoded, polyreactive IgM and IgA antibodies with limited V-gene segment usage, and are activated by T-independent antigens, such as LPS (TI-1) or multivalent antigens (TI-2). In mice, B-1 cells can be further divided into B-1a and B-1b according to the expression of CD5 (CD5+ or CD5−, respectively). B-1a cells have been proposed as a major source of natural autoantibodies. These low-affinity polyreactive antibodies can be secreted spontaneously and are important in the clearance of apoptotic debris. They also contribute to protection against pathogens such as Streptococcus pneumoniae and influenza. B-1b cells respond primarily to T-independent antigens (TI-1 and TI-2) and generate IgM memory cells, which contribute to protection against reinfection with Borrelia hermsii, S. pneumoniae, and Salmonella.

B-1 cells are poor at forming GCs; however, class-switched, somatically mutated B-1 antibodies showing evidence of antigen selection have been isolated from humans. Although elevated numbers of B-1 cells are present in some lupus-prone mouse strains, there is not a clear association with SLE.

Marginal Zone (MZ) B Cells

Marginal zone and follicular (FO) B cells differentiate from transitional B cells and both can participate in T-dependent and T-independent immune responses. MZ B cells are located in the MZ of the spleen, where they can serve as a first line of defense to T-independent and blood-borne antigens, such as lipopolysaccharide from bacteria. They are characterized by high responsiveness to TLR activation, as well as a preactivated state with high expression of complement receptors and costimulatory molecules. Due to these characteristics, they are known for their ability to quickly differentiate into PCs in response to T-independent antigens. MZ B cells do not require cognate T cell help, as soluble factors such as cytokines and costimulation derived from DCs, neutrophils, iNKT cells, and T cells, can also lead to their activation, CSR, and differentiation into PCs.

FO B Cells

Follicular B cells are migratory cells that move between lymph nodes, splenic follicles and the circulation until they interact with antigen. While MZ B cells are specialized in the response to T-independent antigen, they can also transport these antigens to the follicles and transfer such antigens to FO B cells. However, compared to MZ B cells which become blasts within 24 h of mitogen activation, FO B cells do not show blast formation in response to mitogen, due to their requirement for cognate T cell help, and therefore the contribution of FO B cells in T-independent responses is probably limited.

T-Cell-Dependent Activation of B Cells

Although there are models where T-independent responses can contribute to lupus in mice, the majority of studies in lupus-prone mice and SLE patients suggest that T-dependent responses are the main driver of the disease. Therefore, we will focus on T cell-dependent responses for the remainder of this review. Here, we will first discuss the initial activation of B cells in a T-dependent response, including the cell fate decisions into either the EF or the GC pathway, followed by a discussion of the PC differentiation pathways after they diverge.

T-dependent responses are thought to be dominated by FO B cells, although MZ B cells can migrate to the T–B border, activate T cells, and enter a GC. Although it is unclear how much they contribute to class-switched GC-derived antibody responses, MZ B cells can certainly contribute to T-dependent EF responses (Figure 2). MZ B cells can also capture and deliver blood borne antigens to the follicles, thereby enhancing T-dependent FO responses. This indicates that although MZ B cells do not require cognate T cell interactions for their differentiation into PCs, they can still participate in T-dependent responses (Figure 2).

Recirculating FO B cells are activated by antigen in peripheral tissues or in lymphoid tissue where they encounter soluble antigen or antigen arrayed on follicular dendritic cells (FDCs). Activated B cells upregulate chemotactic factors (CCR7, EBI2) that favor their migration to the B–T border in the lymph nodes or spleen. At the same time, CD4+ T cells are activated by DCs in the T cell zone, and these activated T cells will also migrate to the B–T cell border. The differentiation of Th cells [Th1, Th2, Th17, T follicular helper cells (Tfh)] is determined by T cell–DC interactions and is driven by the engagement of pattern recognition receptors by pathogens- or damage-associated molecules. At the T–B border, cognate interactions between antigen-specific B and T cells drives initial proliferation, and some B cells will undergo immunoglobulin CSR under the influence of T cell-derived cytokines.

After activation, B cells can diverge into EF PCs and GC B cells. While it is well known which transcription factors drive the differentiation into GC B cells versus EF PCs, whether there is direct competition between EF and GC differentiation has not been fully demonstrated. Since B cells can proliferate at the T–B border prior to making cell-fate decisions, it is possible that the distinction between cells with the same high affinity that enter an EF or a GC pathway is partly stochastic and that the same B cell clone can be found in both pathways.

Under non-competitive conditions, low-, medium-, or high-affinity B cells can all seed a GC, whereas the low-affinity cells are unable to generate an EF antibody response, due to failure to expand low-affinity EF PCs rather than a lack of initiation of PC differentiation. In contrast, under competitive conditions, low-affinity cells compete with high affinity cells and are unable to expand or enter a GC response. The advantage of high affinity B cells in each response can be at least partly explained by the degree of T cell help that is received, as high affinity B cells stimulated with antigen express higher amounts of MHC class II in the membrane, and are able to present more peptide to T cells, establishing a more effective immunological synapse, which can affect both EF and GC responses.

Although TLR activation during T-independent responses clearly increases the magnitude of the EF response, TLR ligation in T-dependent responses can enhance both the GC response and the EF response, in a B cell-extrinsic or -intrinsic manner.

PC Differentiation in EF Responses

As EF PCs can provide an initial wave of secreted antibodies during the first week of an infection, these cells are an important part of the initial antibody response against pathogens. During expansion at the T–B border, those cells destined to become EF PCs will upregulate Blimp-1, CD138, and CXCR4. Differentiation of EF PCs is driven by T–B interactions with a specific subset of Th cells that resembles Tfh cells but is located in EF areas. These Th cells are dependent on Bcl-6 and Stat3, and their interaction with B cells is mediated through CD40-CD40L and inducible T-cell costimulator (ICOS)–ICOSL interactions as well as cytokines, such as IL-21. These interactions lead to heavy chain CSR as well as initiation of PC differentiation (Figure 4).

Under the influence of CXCR4, EF PCs migrate to the red pulp, where they can further proliferate and differentiate in EF foci. Proliferation is driven by BCR signaling, as cells with high affinity BCRs have increased proliferation and decreased apoptosis compared to cells with low affinity BCRs. Cofactors, such as CD19 and other molecules that enhance BCR signaling, can enhance EF proliferation. Lyn, an inhibitory molecule in the BCR signaling pathway, can diminish proliferation while in fact driving terminal PC differentiation. After the proliferative stage, PBs will differentiate further into PCs, characterized by higher expression of Blimp-1, further loss of MHC class II and costimulatory molecules. However, as discussed below, many EF PBs are short-lived and die prior to full differentiation into PCs. Some, however, complete their PC differentiation, after which they can survive in specialized niches in the spleen or bone marrow (BM).

Recent evidence suggests that several characteristics previously attributed to GC responses can also occur in EF responses. This includes the formation of memory B cells, CSR, SHM, and induction of long-lived PCs (discussed below). Whereas the previous understanding was that memory B cells are generated only in the GC, memory cells initially appear in blood before GC formation, and Bcl-6-deficient mice, which are unable to form GCs, generate memory cells. Most of these are non-mutated and IgM + memory cells, suggesting an EF origin at least for some memory cells. Although CSR and a low degree of SHM occur during early B–T interactions at the T–B border, continued AID expression and affinity maturation in EF sites has been observed.

GC Responses

Germinal centers are areas of T-dependent B cell development in spleen, tonsils, lymph nodes, and Peyers’ patches. FDCs are important for normal splenic architecture and B cell development, as well as for maintaining the structure and function of the GC. Importantly, they capture antigen in immune complexes and retain the antigen in native form. Antigens are presented by FDCs on the cell surface. Several sequential events are involved in the formation of the GC. At the T–B border, B cell and T cell encounter with antigen stimulates formation of a GC, and migration from the T–B border into the follicle is mediated by CXCR5. B cells receiving more T-help are more prone to differentiate into GC B cells, and T cells differentiate into Tfh under the influence of B cell costimulatory molecules, including OX40L and CD80, which are essential for the maturation of Tfh cells. The transcription factor Bcl-6 is required for the development of both GC B cells and Tfh cells. Tfh cells are specialized T helper cells that are involved in the selection and survival of B cells in the GC. The canonical costimulatory signal involved in the B–T cell interaction in the GC is CD40–CD40L, but other signals such as ICOS–ICOSL, and IL-21 produced by Tfh cells are also required.

The structure of the GC, with a light zone and a dark zone, aligns with the processes of SHM, affinity maturation, and selection (Figure 5). B cells in the light zone are referred to as centrocytes. They interact with FDCs through antigen and with Tfh cells through MHC–peptide interactions. Those B cells which make stronger interactions with Tfh cells, due to an increased T cell receptor peptide–MHC interaction, are positively selected and enter the dark zone where their proliferation is greater. As more antigen is added, the population of B cells with BCRs that bind antigen sufficiently to induce positive selection increases. Positive selection in the light zone is important as it leads to GC B cells with the greatest affinity for antigen. Interactions between Tfh cells, antigen, and B cells in the light zone determine the extent of proliferation in the dark zone. Fewer cells move from the light zone to the dark zone than from the dark zone to the light zone indicating that selection occurs in the light zone.

The dark zone is the location where the most active proliferation of GC B cells takes place, as all GC B cells that are in G2 or M phase are in the dark zone; however, S phase cells are present in both the light zone and dark zone. Proliferation can occur under the influence of mTORC1 kinase, which activates the metabolic program that permits proliferation of B cells in the dark zone. After positive selection in the light zone and while undergoing proliferation in the dark zone, SHM occurs to effect a process called affinity maturation. During this process, point mutations occur in the BCR which affect its affinity for antigen. When the B cell returns to the light zone, the B cells that have undergone mutations to enhance affinity for the antigen are preferentially selected. A stronger interaction with Tfh cells in the light zone allows the B cell to undergo more rounds of proliferation in the dark zone. Therefore, each time the cell divides and more mutations are acquired, more affinity maturation can occur for B cells that were most positively selected for in the light zone.

Negative selection also occurs in the GC. B cells with weak affinity for antigens in the GC, or autoreactive B cells recognizing ubiquitously expressed self-antigens are eliminated. Proposed mechanisms for the negative selection of these B cells are Fas-mediated apoptosis of cells that fail to bind antigen, failure to receive continuing T cell help, or the activity of T follicular regulatory cells (Tfr). A recent study, however, suggests that negative selection primarily occurs in cells with an unproductive BCR as a consequence of SHM rather than in cells with lower affinity.

PC Differentiation in the GC

Both memory B cells and PCs arise from the GC, and many studies have examined the factors that determine if a given B cell will become a memory B cell or a PC. High affinity GC B cells become PCs, while lower affinity GC B cells become memory B cells. The initiation of PC differentiation in the light zone requires strong affinity for antigen; further differentiation in the dark zone requires help from Tfh cells. Light zone B cells become memory B cells early in the GC reaction, while PCs are formed later. Preventing apoptosis in the GC allows for lower affinity B cells to become memory B cells but does not change the development of PCs, further suggesting that selection of B cells into the PC population is dependent on high affinity for antigen.

Certain cytokines favor the development of PCs. Among them, IL-21 is the most potent inducer of PC differentiation from memory and naive B cells. This cytokine is produced by Tfh cells in the GC and activates the JAK1/3 STAT3 pathway. IL-21-deficient mice are unable to generate fully functional GCs. Without IL-21 or Tfh cells, PC formation is disrupted, affinity maturation does not occur, and the population of memory B cells is expanded.

Toll-like receptor ligands also enhance GC responses through both DCs and B cells. Whereas soluble TLR ligands can enhance GC responses through an effect on DCs, an antigen that can trigger both endosomal TLRs and BCRs can enhance the IgG antibody response in a B cell-intrinsic manner. This probably reflects the requirement for BCR-mediated uptake of ligands for endosomal TLRs in this process, and explains why some studies reported no effect of TLR signaling on GC responses induced with LPS. B cell-intrinsic MyD88 signaling specifically enhances the formation of GC B cells, affinity maturation, and CSR in response to the TLR-9 ligand CpG coupled to the hapten NP, without affecting the number of PCs. In contrast, MyD88 signaling in DCs contributes to PC differentiation without affecting affinity maturation.

Different transcription factors are involved in the differentiation of PCs and memory B cells. Bach2 is reported to be important for selection of GC B cells into memory B cells; in the light zone, B cells with lower affinity for antigen have higher expression of Bach2, probably due to a lower degree of T cell help in those cells. In addition to Bach2, ABF-1 leads to memory B cell differentiation and prevents PC differentiation. The transcription factors Blimp-1, XBP-1, and IRF4 are all involved in PC differentiation. Blimp-1 leads to decreased expression of genes involved in B cell signaling pathways including Pax5, which in turn leads to increased expression of Blimp-1 and XBP-1. This feed-forward mechanism is needed for PC differentiation. Whereas Blimp-1 is required for PC differentiation, XBP-1 is more specifically needed for the unfolded protein response that is required for the production of high amounts of immunoglobulin in PCs.

It has been recently reported that PC differentiation is initiated in light zone B cells after which they migrate to the dark zone to further differentiate. Together with simulation data, this suggests that PCs exit the GC through the dark zone. Similar to the EF response, GC-derived PCs are characterized by a proliferative PB stage. Proliferating PBs have been reported in the dark zone of the GC, as well as the T–B border directly adjacent to the GC, and their proliferation decreases as they migrate further from the GC, and is completely lost as they reach the medulla of the lymph node or the splenic red pulp. This suggests that proliferation of GC-derived PBs occurs during their transit out of the GC, at distinct locations from EF PBs, which proliferate in EF foci mainly in the red pulp of the spleen or the medulla of the LN. Some GC-derived PCs migrate to the red pulp in the spleen or the medullary cords in the lymph nodes, and others migrate through the blood to the BM. Their exit out of the secondary lymphoid organs occurs prior to completion of their differentiation, as circulating PBs that arise in GC responses in humans show signs of recent proliferation such as expression of Ki67.

PC Survival

Two studies in the late 1990s showed the existence of long-lived PCs, disputing previous thinking that PCs were short-lived. A more recent study showed that 10 years after vaccination, long-lived PCs were still present in the BM, despite memory B cell depletion. Another study shows the survival of these long lived PCs despite CD19 directed CAR T cell therapy. These PCs have become a challenge in treatment of SLE, as they are often not eliminated by traditional therapies. Although most evidence suggests that selection of PCs into the long-lived PC pool is dependent on extrinsic factors, there is some evidence that B cell-intrinsic factors are also involved. Identification of intrinsic factors leading to long-lived PC survival could represent therapeutic targets for SLE and other autoimmune diseases.

Plasma cell survival depends on cytokines secreted by stromal cells and eosinophils in the BM, but they can also survive in the spleen or other organs, particularly under inflammatory conditions. PCs can survive anywhere as long as sufficient survival factors are present, but niches have the capacity to support only a limited number of PCs. Two related factors important for survival of PCs are BAFF and APRIL, which act through binding to TACI and BCMA. Both cytokines are anti-apoptotic and increase PC survival. A study in autoimmune thrombocytopenia suggests that an increase in BAFF caused by B cell depletion promotes differentiation of short-lived PCs into long lived PCs in the spleen. Other molecules which can enhance survival of PCs are IL-6, VCAM-1, CXCR4, and CD28.

CD93, a C1q receptor on B cells, is needed for the survival of PCs in the BM and is expressed only by a subset of PCs in mice. Induction of CD93 expression may, therefore, be an example of a B cell-intrinsic factor that contributes to PC survival.

Despite the traditional paradigm mentioned above, there are descriptions of long-lived PCs in T-independent responses, T cell-deficient, and GC-deficient mice, with survival up to at least 100 days. In addition, PCs exit the GC as PBs, and require a survival niche for full differentiation. As many of them fail to find the appropriate niche, not all GC-derived PCs are long-lived. As far as we know now, transcription factors that drive PC differentiation in each response are similar, and it is not clear if all PCs have the potential to become long-lived or whether some are selected, preferentially in the GC, to become long-lived, and whether this is accompanied by altered expression of key survival molecules and transcription factors that drive this distinction.

Tolerance in EF Responses

As autoimmunity has been traditionally thought to arise through the GC, tolerance checkpoints in EF responses have not been extensively studied. Whereas the fast rate of the EF response is needed for adequate responses against pathogens, it also limits the time window for tolerance checkpoints. Therefore, it is likely that autoreactive B cells can be activated during EF responses, either through direct activation by self-antigen in an inflammatory milieu, cross-reactivity with foreign antigen, or through TLR ligands or cytokines. However, even if autoreactive PCs are generated in EF responses, they are mostly short-lived limiting the inflammation and tissue damage that is induced by autoantibodies. Therefore, the transient nature of the EF response may itself be a tolerance mechanism.

In addition to the short-lived nature of the response, tolerance in EF responses can be maintained through the balance between IgM and other (more pathogenic) isotypes. As most EF PBs secrete IgM, even though some CSR can occur, the balance between IgG and IgM that is generated in EF responses may result in prevention of autoimmunity, through downregulating myeloid cell activation in a LAIR-1 dependent fashion and minimizing local inflammation. In addition, sialylation of IgG antibodies, which occurs in T-independent responses can also contribute to tolerance, as these antibodies have lower pathogenicity, at least in the context of rheumatoid arthritis [, p. 296;, p. 429].

T cell help during initial activation might play a role in tolerance in EF foci, where class-switched EF responses can occur through cytokines secreted by bystander T cells or non-T cells. Since there is no requirement for cognate T cell help, the T cell repertoire is unlikely to restrict autoreactivity in the EF response.

Tolerance in GC Responses

Although the mechanisms of central tolerance preclude many autoreactive B cells from entering GCs, self-reactive B cells developing in the BM can bypass tolerance mechanisms. This may occur if they are reactive to monovalent antigen, if their affinity for antigen is below a certain threshold, or if they are present in an inflammatory milieu. Therefore, it is normal to have circulating autoreactive mature (naive) B cells.

Importantly, however, mechanisms of peripheral tolerance are also in place to further eliminate autoreactivity. Mature self-reactive B cells can be thwarted from entering the follicle and be induced to become anergic. Still, some self-reactive B cells are able to enter the follicle. Evidence also suggests that autoreactive B cells that were initially excluded from the follicle can later be recruited into the GC, at which point these cells undergo SHM which may remove autoreactivity, but can also lead to enhanced self-reactivity. One important tolerance mechanism is the short lifespan of these B cells without mitogenic stimulation. Thus, only in an inflammatory milieu are these cells likely to access a GC response.

B cells that acquire autoreactivity in the GC must be eliminated or prevented from becoming PCs. In the GC itself, several tolerance mechanisms have been described, including apoptosis and receptor editing. However, a recent study showed that autoreactive GC B cells are not strongly selected to undergo apoptosis, perhaps because so many autoreactive B cells are cross-reactive with an eliciting antigen. It is conceivable that these tolerance mechanisms are initiated by lack of cognate T cell help. As described, T-cell help is needed for positive selection of B cells into PCs in the GC, and without this help, self-reactive PCs will not develop. Thus, although self-reactive memory B cells can develop, the requirement for Tfh cells and FDCs that recognize or present the autoantigen makes it more difficult for non-cross-reactive autoreactive PCs to develop. T cells recognizing foreign antigen may be able to stimulate autoreactive GC B cells, if the BCR crossreacts with the eliciting antigen or an antigen present in a multimolecular complex with the eliciting antigen.

As IgG + memory B cells in healthy individuals have a much higher frequency of self-reactivity than IgG + PCs, an additional tolerance checkpoint must exist that prevents the differentiation of autoreactive PCs in addition to a tolerance checkpoint in GC B cells (Figure 3). Interestingly, switched PCs maintain expression of MHC class II and the antigen presentation machinery required for cognate T cell interactions at least until they are no longer proliferating, suggesting that this stage of PC differentiation may represent a T cell-dependent tolerance checkpoint. Although this has not been extensively studied, Th cells are required for the completion of GC-derived PC differentiation, and PCs can undergo cognate T cell interactions after their migration out of the GC at the T–B border. This suggests that a lack of T cell help may prevent the terminal differentiation of autoreactive PCs or that autoreactive B cells committed to becoming PCs are more susceptible to apoptosis or receptor editing than B cells committed to a memory pathway.

EF PC Differentiation in SLE

Because there are no definite markers that discriminate PCs based on their pathway of differentiation, it is hard to establish the pathway through which they were derived, especially in humans where access to lymphoid organs is limited. In addition, most studies discriminating EF responses from GC responses use acute immunization models, and it is not clear if all the paradigms that have been proposed for the distinction between EF and GC responses apply in the chronic immune activation present in autoimmune conditions. Although EF PC differentiation in autoimmunity has not been emphasized, recent studies indicate this pathway may have a specific role in autoimmunity. MRL/lpr mice exhibit EF PC generation, although they have increased formation of spontaneous GCs as well. In humans, recent research supports that a large proportion of the PCs in some SLE patients are clonally related to naive cells, suggesting an EF origin. Here, we propose mechanisms which can lead to enhanced EF responses in SLE (Figure 4).

Expansion of MZ B Cells

Marginal zone B cells are expanded in several lupus-prone mouse strains. In humans, the characterization of MZ B cells is much more complicated [reviewed in Ref.], and it is unclear if SLE patients also have an expansion of this population. However, the high BAFF levels often present in SLE patients would support MZ expansion. Mice overexpressing BAFF develop an SLE-like phenotype that is characterized by a high titer of class-switched autoantibodies and PCs, in a T cell-independent manner. A preference for autoreactive B cells to differentiate into MZ B cells compared to FO B cells has been described in mice, and MZ B cells can differentiate directly into IgG + PCs in EF responses. Therefore, development of serum autoantibodies in some lupus-prone mice has been attributed to MZ expansion and activation, although some studies have challenged this paradigm.

Enhanced TLR Signaling

Another mechanism by which EF PC responses in SLE may be altered is through enhanced TLR signaling. MyD88-deficient MRL/lpr mice develop lower autoantibody titers and are protected from disease, suggesting a role for TLRs in EF responses in MRL/lpr mice. Although TLR-7 or -9 deficiency each diminished the production of specific types of autoantibodies in MRL/lpr mice, only TLR-7 deficiency diminished lymphocyte activation, IgG production, and kidney disease. This suggests that although each receptor can enhance EF responses, only TLR-7 induces the production of pathogenic antibodies, or permits the inflammatory response needed to cause disease.

Besides a B cell-intrinsic role of TLR signaling, B cell extrinsic TLR signaling can also enhance T–B interactions through the increased activation of DCs. Enhanced T–B interactions in this situation have the potential to enhance T-dependent PC differentiation in both EF and GC pathways. B cells as well as myeloid cells from SLE patients have increased expression of TLRs, and SLE patients may have increased proinflammatory responses to TLR ligands, which can contribute to stronger T-independent and T-dependent EF responses.

B Cell Hyperresponsiveness

A well-known feature of SLE is B cell hyperresponsiveness, which causes increased signaling upon BCR ligation by antigen. The increased signaling can derive from increased activity of signaling molecules in the BCR pathway (many of which are genetic risk factors for SLE; discussed below), or through a synergy between BCR triggering and other signaling pathways, such as TLR, BAFF, and type I IFN, which can each lower the threshold for B cell activation through the BCR and contribute to the activation of B cells. Type I IFN is necessary for a complete response after BCR/TLR7 stimulation, and increments in type I IFN can overcome tolerance that normally occurs after repetitive stimulation of TLRs. The fact that high affinity B cells are more prone to expansion at the EF PB stage suggests that the increased BCR signaling that occurs in SLE may preferentially stimulate EF responses.

Increased CSR

Increased CSR in EF responses is another feature of SLE that may contribute to enhanced pathogenicity of EF PCs, in particular if the balance between protective IgM and pathogenic IgG is altered. Increased CSR has been described both in lupus-prone mouse models as well as SLE patients. In particular, a special subset of EF T cells in the MRL/lpr mice has been described to contribute to the expansion of class switched IgG + EF PCs. These EF T cells are dependent on Bcl-6, Stat3, and ICOS, and they mediate IgG CSR through CD40–CD40L interactions and IL-21. A similar subset of T cells has been described in EF responses in non-autoimmune mice, although there they localized at the T–B border, and it is not clear if they migrate to EF foci as well. EF Th cells express CXCR4, as opposed to Tfh cells which express CXCR5 (or both). While the EF Th cell subset is present in MRL/lpr mice which have a dominant EF phenotype, mice with a more pronounced GC pathway, such as NZB/W, have a more mixed T cell phenotype. IgG CSR in MRL/lpr mice, as well as in graft versus host-mediated autoimmunity, is almost completely dependent on ICOS, as ICOS-deficiency leads to lower expression of CXCR4, as well as diminished secretion of IL-21. T-independent factors can also increase EF CSR in SLE. In AM14 rheumatoid factor transgenic MRL/lpr mice, T cells are required for the spontaneous production of rheumatoid factor, but not when B cells are exposed to chromatin immune complexes which will trigger both the BCR and TLR.

Increased CSR has been described in circulating PBs of SLE patients, and at least some of these have low mutation rates, suggestive of an EF origin. However, all EF-derived PBs need not have low mutation rates. Factors that increase CSR in EF PCs in mice, such as IL-21, are increased in SLE patients, and factors that mediate T-independent CSR, such as TLR signaling and the myeloid-derived cytokine BAFF, are also increased in SLE. It is therefore conceivable that SLE patients can exhibit increased CSR in EF responses.

Increased SHM

Besides the increased CSR in EF PCs in MRL/lpr mice, SHM has also been shown to occur in EF foci, probably under the influence of EF Th cells. However, SHM can also occur in response to chromatin immune complexes in a T-independent manner. This SHM potentially leads to affinity maturation (although probably to a lesser extent than in the GC) in autoreactive EF PCs, but no mechanism has been described for antigen selection and affinity maturation in EF responses.

GC Responses in SLE

Germinal center responses are well known to be increased in lupus-prone mice, and SLE patients have increased numbers of circulating pre-GC B cells, switched memory B cells and Tfh cells, suggestive of enhanced GC responses. Given that IgG anti-DNA autoantibodies which are considered to be pathogenic in SLE show evidence of SHM, the production of autoreactive PCs by SHM of nonautoreactive naive B cells within the GC has been considered an important contributor to the development of SLE in both mice and humans. The following mechanisms can contribute to GC-derived autoreactive PCs (Figure 5).

Loss of FO Exclusion

In normal conditions, autoreactive naive B cells undergo anergy that leads to FO exclusion and prevents their recruitment into GC responses. However, in SLE, these B cells are able to enter the GC, and continue their differentiation into PCs.

B Cell Hyperresponsiveness

As discussed above, B cell hyperresponsiveness can enhance EF responses and may also potentiate GC responses. Hyperresponsiveness could lead to increased positive selection in the light zone and subsequent proliferation in the dark zone, thereby amplifying GC responses.

Increased TLR Responses

Toll-like receptors, which are involved in the EF pathway, also have a role in the GC response. Loss of MyD88 causes a loss of GC formation; interestingly, this alteration may be attributed to the function of TLR-7 and not TLR-9. Increased function of TLR-7 causes an increment in spontaneous GC formation and an autoimmunity phenotype. B cell-intrinsic MyD88 signaling specifically enhances GC responses when antigen and TLR ligand are coupled; self-antigen that can trigger both TLRs and the BCR will presumably have the same ability. It was recently demonstrated that FDCs, which are crucial for the maintenance of GCs and FO architecture, express type I IFN through a TLR-7 pathway upon internalizing complement-opsonized self-immune complexes through the complement receptor CD21 in the 564Igi RNP-specific lupus mouse model; this pathway is important for spontaneous GC formation and production of isotype-switched autoantibodies. 564Igi BM chimeras in which the recipient FDCs were TLR-7-deficient exhibited less autoimmunity. As many SLE antigens can activate TLRs, these represent potent pathways to amplify GC responses.

De Novo Autoreactivity

Although loss of FO exclusion can lead to recruitment of autoreactive naive cells into GC reactions, SHM of nonautoreactive B cells can lead to de novo autoreactivity in GC B cells. Whether these cells are able to differentiate into PCs has not been reported, but most pathogenic antibodies in SLE show signs of SHM, and de novo autoreactivity explains a large fraction of the autoreactive IgG + memory cells in SLE patients. These studies suggest that GC B cells retain autoreactivity generated through SHM.

Aberrant Selection and Survival of GC B Cells

Another mechanism for the generation of autoreactive PCs in the GC is increased survival of GC B cells. It has been shown that SLE patients have increased levels of BAFF. While BAFF has a large role in the EF pathway of differentiation of PCs, it also expands the Tfh cell population and promotes formation of GC and survival of B cells. This could be a contributing factor in allowing the breach of B cell tolerance seen in SLE patients. As a result of increased BAFF, naive B cells with moderate affinity that would normally undergo apoptosis, may be rescued and enter a GC response.

Increased Tfh Activity

Another mechanism that leads to the development of autoreactive PCs in the GC is increased Tfh activity. One cytokine important for the development of autoreactive PCs is IL-21, a cytokine produced by Tfh cells. The number of Tfh cells as well as the level of IL-21 has been shown to be increased in lupus-prone mice and SLE patients. IL-21 increases IgG PC number, and Tfh cells can alter selection and allow the differentiation of autoreactive B cells into autoreactive antibody secreting PCs. In lupus-prone mice, OX40L expression by B cells contributes to the autoimmune phenotype, presumably through its effect on Tfh cells.

Increased PC Differentiation

B cell hyperresponsiveness may also increase the generation of PCs in SLE by directing more B cells to undergo PC differentiation. SLE patients often have increased numbers of circulating PBs; in one study this inversely correlates with the number of CD27 + memory cells, suggesting a preferred differentiation pathway. Lupus-prone mice, including the ones that have a GC phenotype, have vast increases in their PC numbers, which exceeds the expansion of the memory compartment. This suggests that there may be preferential output of PCs from the GC in SLE.

Increased Survival of PCs

Another possible mechanism for increased autoantibody titers is increased survival of PCs (Figures 2 and 3), which might occur if excess survival factors are present. Increased expression of the cytokines BAFF, APRIL, and IL-6 is present in lupus-prone mice, suggesting that these cytokines can support enhanced PC survival. Although in healthy mice a limited number of PCs can survive in BM and spleen, these organs in lupus-prone mice gain additional capacity and exhibit an increased number of PCs. Both lupus-prone mice and SLE patients often exhibit hypergammaglobulinemia, which may also be caused by an increased capacity to support PC survival in SLE patients. As both EF and GC-derived PCs can either stay in the spleen or stay in the lymph nodes or migrate to the BM, these factors will probably affect both types of PCs. In addition, several lupus-prone mouse strains have increased levels of CXCL12 in their inflamed kidneys, which may allow recruitment of PCs to this organ.

Genetic Risk Alleles

Whereas both EF and GC pathways can lead to autoantibody production, we propose that genetic factors may cause a dominance of either of these pathways in individual patients. Approximately one hundred risk loci have been associated with SLE, and genes within these loci have been broadly cast into categories involving DNA degradation and clearance of apoptotic/cellular debris, innate immunity, including TLR and IFN signaling, and adaptive immunity. Some overlap or fall outside these categories, and others are undefined. Most variants are in non-coding regions that may alter expression levels that can determine the magnitude of a response in a cell-lineage and stage-specific manner. Several risk genes have been described to alter B cell selection, activation, differentiation and/or survival in a B cell-intrinsic fashion, including LYN, BLK, BANK1, PTPN22, TNFAIP3, TNIP1, CSK, and FCGR2B. Although it is known that these risk alleles alter B cell signaling, their effect on PC differentiation has not been extensively investigated, and most of our understanding of the role of these genes in EF and GC responses derives from mouse models. Other risk alleles are involved in B–T cell interactions, memory or PC differentiation, and IFN/TLR signaling. For many of these, the functional consequence of the risk allele has not been determined. However, it is reasonable to ask whether these risk alleles may alter EF or GC responses.

Table 1 shows risk alleles that can alter B cell responses and subsequently PC differentiation. These risk alleles can function in a B cell-intrinsic or -extrinsic manner. We propose that some risk alleles, such as TLR7, FAS, IRF5, TNFAIP3, and TNIP1, can modify both EF and GC responses.

Certain risk alleles, such as HLA class II genes, FCGR2B, STAT4, CD80, IRF8, and PRDM1, most likely drive GC responses, whereas other risk alleles, such as ETS1, LYN, BACH2, and BLK, may preferentially drive EF responses in SLE, although this pathway has not been extensively explored. Further understanding of the exact role of each risk allele in plasma cell differentiation pathways may enhance our insight into patient heterogeneity.

Conclusion

In this review, we have described the PC differentiation pathways which can contribute to the development of autoantibody production in SLE. Whereas both EF and GC pathways may be active in the same patient, we propose that certain genetic risk alleles contribute to the dominance of one of these pathways. The dominant PC differentiation pathway, determined by the composite of risk alleles, may contribute to patient heterogeneity and to response to therapy. Although it is likely that different therapeutics alter each pathway to a different extent, there is to our knowledge not enough understanding of the molecular pathways in each response nor is there clear evidence which therapeutics target which pathway. These pathways are not as distinct as we thought, nor can the pathway taken by a PC be easily distinguished with current knowledge. A more thorough analysis of these pathways, their role in SLE, and the contribution of genetic risk alleles to each pathway may provide us with distinct targets to allow precision therapy.

Author Contributions

SM, AB, and YA-F contributed to writing the manuscript. JS and BD contributed to the concept, reviewing, and writing of the manuscript.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer RM and handling editor declared their shared affiliation.

References 293

  1. 1.

    Suurmond J Diamond B. Autoantibodies in systemic autoimmune diseases: specificity and pathogenicity. J Clin Invest (2015 ) 125(6):2194–202.

    Not in our library10.1172/jci78084

  2. 2.

    Tan EM Cohen AS Fries JF Masi AT McShane DJ Rothfield NF The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum (1982 ) 25(11):1271–7.

    Not in our library10.1002/art.1780251101

  3. 3.

    Vas J Gronwall C Marshak-Rothstein A Silverman GJ. Natural antibody to apoptotic cell membranes inhibits the proinflammatory properties of lupus autoantibody immune complexes. Arthritis Rheum (2012 ) 64(10):3388–98.

    Not in our library10.1002/art.34537

  4. 4.

    Li QZ Xie C Wu T Mackay M Aranow C Putterman C Identification of autoantibody clusters that best predict lupus disease activity using glomerular proteome arrays. J Clin Invest (2005 ) 115(12):3428–39.

    Not in our library10.1172/jci23587

  5. 5.

    Mannoor K Matejuk A Xu Y Beardall M Chen C. Expression of natural autoantibodies in MRL-lpr mice protects from lupus nephritis and improves survival. J Immunol (2012 ) 188(8):3628–38.

    Not in our library10.4049/jimmunol.1102859

  6. 6.

    Nemazee D Buerki K. Clonal deletion of autoreactive B lymphocytes in bone marrow chimeras. Proc Natl Acad Sci U S A (1989 ) 86(20):8039–43.

    Not in our library10.1073/pnas.86.20.8039

  7. 7.

    Wardemann H Yurasov S Schaefer A Young JW Meffre E Nussenzweig MC. Predominant autoantibody production by early human B cell precursors. Science (2003 ) 301(5638):1374–7.

    Not in our library10.1126/science.1086907

  8. 8.

    Pewzner-Jung Y Friedmann D Sonoda E Jung S Rajewsky K Eilat D B cell deletion, anergy, and receptor editing in “knock in” mice targeted with a germline-encoded or somatically mutated anti-DNA heavy chain. J Immunol (1998 ) 161(9):4634–45.

    Not in our library

  9. 9.

    Mandik-Nayak L Bui A Noorchashm H Eaton A Erikson J. Regulation of anti-double-stranded DNA B cells in nonautoimmune mice: localization to the T-B interface of the splenic follicle. J Exp Med (1997 ) 186(8):1257–67.

    Not in our library10.1084/jem.186.8.1257

  10. 10.

    Pugh-Bernard AE Silverman GJ Cappione AJ Villano ME Ryan DH Insel RA Regulation of inherently autoreactive VH4-34 B cells in the maintenance of human B cell tolerance. J Clin Invest (2001 ) 108(7):1061–70.

    Not in our library10.1172/jci12462

  11. 11.

    Nutt SL Hodgkin PD Tarlinton DM Corcoran LM. The generation of antibody-secreting plasma cells. Nat Rev Immunol (2015 ) 15(3):160–71.

    Not in our library10.1038/nri3795

  12. 12.

    Chernova I Jones DD Wilmore JR Bortnick A Yucel M Hershberg U Lasting antibody responses are mediated by a combination of newly formed and established bone marrow plasma cells drawn from clonally distinct precursors. J Immunol (2014 ) 193(10):4971–9.

    Not in our library10.4049/jimmunol.1401264

  13. 13.

    Sanz I Wei C Lee FE Anolik J. Phenotypic and functional heterogeneity of human memory B cells. Semin Immunol (2008 ) 20(1):67–82.

    Not in our library10.1016/j.smim.2007.12.006

  14. 14.

    Kallies A Hasbold J Tarlinton DM Dietrich W Corcoran LM Hodgkin PD Plasma cell ontogeny defined by quantitative changes in blimp-1 expression. J Exp Med (2004 ) 200(8):967–77.

    Not in our library10.1084/jem.20040973

  15. 15.

    Jeurissen A Ceuppens JL Bossuyt X T lymphocyte dependence of the antibody response to ‘T lymphocyte independent type 2’ antigens. Immunology (2004 ) 111(1):1–7.

    Not in our library10.1111/j.1365-2567.2004.01775.x

  16. 16.

    Shih TA Roederer M Nussenzweig MC. Role of antigen receptor affinity in T cell-independent antibody responses in vivo. Nat Immunol (2002 ) 3(4):399–406.

    Not in our library10.1038/ni776

  17. 17.

    Lentz VM Manser T. Cutting edge: germinal centers can be induced in the absence of T cells. J Immunol (2001 ) 167(1):15–20.

    Not in our library10.4049/jimmunol.167.1.15

  18. 18.

    Mongini PK Stein KE Paul WE. T cell regulation of IgG subclass antibody production in response to T-independent antigens. J Exp Med (1981 ) 153(1):1–12.

    Not in our library10.1084/jem.153.1.1

  19. 19.

    Vinuesa CG Chang PP. Innate B cell helpers reveal novel types of antibody responses. Nat Immunol (2013 ) 14(2):119–26.

    Not in our library10.1038/ni.2511

  20. 20.

    Khan AQ Chen Q Wu ZQ Paton JC Snapper CM. Both innate immunity and type 1 humoral immunity to Streptococcus pneumoniae are mediated by MyD88 but differ in their relative levels of dependence on toll-like receptor 2. Infect Immun (2005 ) 73(1):298–307.

    Not in our library10.1128/iai.73.1.298-307.2005

  21. 21.

    Hou B Saudan P Ott G Wheeler ML Ji M Kuzmich L Selective utilization of toll-like receptor and MyD88 signaling in B cells for enhancement of the antiviral germinal center response. Immunity (2011 ) 34(3):375–84.

    Not in our library10.1016/j.immuni.2011.01.011

  22. 22.

    Guay HM Andreyeva TA Garcea RL Welsh RM Szomolanyi-Tsuda E. MyD88 is required for the formation of long-term humoral immunity to virus infection. J Immunol (2007 ) 178(8):5124–31.

    Not in our library10.4049/jimmunol.178.8.5124

  23. 23.

    Raval FM Mishra R Garcea RL Welsh RM Szomolanyi-Tsuda E. Long-lasting T cell-independent IgG responses require MyD88-mediated pathways and are maintained by high levels of virus persistence. MBio (2013 ) 4(6):e812–3.

    Not in our library10.1128/mbio.00812-13

  24. 24.

    Leadbetter EA Rifkin IR Hohlbaum AM Beaudette BC Shlomchik MJ Marshak-Rothstein A. Chromatin-IgG complexes activate B cells by dual engagement of IgM and toll-like receptors. Nature (2002 ) 416(6881):603–7.

    Not in our library10.1038/416603a

  25. 25.

    Jego G Palucka AK Blanck JP Chalouni C Pascual V Banchereau J. Plasmacytoid dendritic cells induce plasma cell differentiation through type I interferon and interleukin 6. Immunity (2003 ) 19(2):225–34.

    Not in our library10.1016/s1074-7613(03)00208-5

  26. 26.

    Litinskiy MB Nardelli B Hilbert DM He B Schaffer A Casali P DCs induce CD40-independent immunoglobulin class switching through BLyS and APRIL. Nat Immunol (2002 ) 3(9):822–9.

    Not in our library10.1038/ni829

  27. 27.

    Moore PA Belvedere O Orr A Pieri K LaFleur DW Feng P BLyS: member of the tumor necrosis factor family and B lymphocyte stimulator. Science (1999 ) 285(5425):260–3.

    Not in our library10.1126/science.285.5425.260

  28. 28.

    He B Santamaria R Xu W Cols M Chen K Puga I The transmembrane activator TACI triggers immunoglobulin class switching by activating B cells through the adaptor MyD88. Nat Immunol (2010 ) 11(9):836–45.

    Not in our library10.1038/ni.1914

  29. 29.

    Stavnezer J Guikema JE Schrader CE. Mechanism and regulation of class switch recombination. Annu Rev Immunol (2008 ) 26:261–92.

    Not in our library10.1146/annurev.immunol.26.021607.090248

  30. 30.

    Rothaeusler K Baumgarth N. B-cell fate decisions following influenza virus infection. Eur J Immunol (2010 ) 40(2):366–77.

    Not in our library10.1002/eji.200939798

  31. 31.

    Puga I Cols M Barra CM He B Cassis L Gentile M B cell-helper neutrophils stimulate the diversification and production of immunoglobulin in the marginal zone of the spleen. Nat Immunol (2011 ) 13(2):170–80.

    Not in our library10.1038/ni.2194

  32. 32.

    Pone EJ Zhang J Mai T White CA Li G Sakakura JK BCR-signalling synergizes with TLR-signalling for induction of AID and immunoglobulin class-switching through the non-canonical NF-kappaB pathway. Nat Commun (2012 ) 3:767

    Not in our library10.1038/ncomms1769

  33. 33.

    Herzenberg LA Stall AM Lalor PA Sidman C Moore WA Parks DR The Ly-1 B cell lineage. Immunol Rev (1986 ) 93:81–102.

    Not in our library10.1111/j.1600-065x.1986.tb01503.x

  34. 34.

    Hardy RR Carmack CE Li YS Hayakawa K. Distinctive developmental origins and specificities of murine CD5+ B cells. Immunol Rev (1994 ) 137:91–118.

    Not in our library10.1111/j.1600-065x.1994.tb00660.x

  35. 35.

    Baumgarth N. The double life of a B-1 cell: self-reactivity selects for protective effector functions. Nat Rev Immunol (2011 ) 11(1):34–46.

    Not in our library10.1038/nri2901

  36. 36.

    Hardy RR Hayakawa K CD5 B cells, a fetal B cell lineage. Adv Immunol (1994 ) 55:297–339.

    Not in our library10.1016/s0065-2776(08)60512-x

  37. 37.

    Kasaian MT Casali P. Autoimmunity-prone B-1 (CD5 B) cells, natural antibodies and self recognition. Auto immunity (1993 ) 15(4):315–29.

    Not in our library10.3109/08916939309115755

  38. 38.

    Hayakawa K Hardy RR Honda M Herzenberg LA Steinberg AD. Ly-1 B cells: functionally distinct lymphocytes that secrete IgM autoantibodies. Proc Natl Acad Sci U S A (1984 ) 81(8):2494–8.

    Not in our library10.1073/pnas.81.8.2494

  39. 39.

    Griffin DO Holodick NE Rothstein TL Human B1 cells in umbilical cord and adult peripheral blood express the novel phenotype CD20+ CD27+ CD43+ CD70. J Exp Med (2011 ) 208(1):67–80.

    Not in our library10.1084/jem.20101499

  40. 40.

    Conger JD Sage HJ Corley RB. Correlation of antibody multireactivity with variable region primary structure among murine anti-erythrocyte autoantibodies. Eur J Immunol (1992 ) 22(3):783–90.

    Not in our library10.1002/eji.1830220323

  41. 41.

    Sindhava VJ Bondada S. Multiple regulatory mechanisms control B-1 B cell activation. Front Immunol (2012 ) 3:372.

    Not in our library10.3389/fimmu.2012.00372

  42. 42.

    Cole LE Yang Y Elkins KL Fernandez ET Qureshi N Shlomchik MJ Antigen-specific B-1a antibodies induced by Francisella tularensis LPS provide long-term protection against F. tularensis LVS challenge. Proc Natl Acad Sci U S A (2009 ) 106(11):4343–8.

    Not in our library10.1073/pnas.0813411106

  43. 43.

    Berland R Wortis HH. Origins and functions of B-1 cells with notes on the role of CD5. Annu Rev Immunol (2002 ) 20:253–300.

    Not in our library10.1146/annurev.immunol.20.100301.064833

  44. 44.

    Haas KM Poe JC Steeber DA Tedder TF B-1a and B-1b cells exhibit distinct developmental requirements and have unique functional roles in innate and adaptive immunity to S. pneumoniae. Immunity (2005 ) 23(1):7–18.

    Not in our library10.1016/j.immuni.2005.04.011

  45. 45.

    Alugupalli KR Leong JM Woodland RT Muramatsu M Honjo T Gerstein RM. B1b lymphocytes confer T cell-independent long-lasting immunity. Immunity (2004 ) 21(3):379–90.

    Not in our library10.1016/j.immuni.2004.06.019

  46. 46.

    Linton PJ Lo D Lai L Thorbecke GJ Klinman NR. Among naive precursor cell subpopulations only progenitors of memory B cells originate germinal centers. Eur J Immunol (1992 ) 22(5):1293–7.

    Not in our library10.1002/eji.1830220526

  47. 47.

    Mantovani L Wilder RL Casali P. Human rheumatoid B-1a (CD5+ B) cells make somatically hypermutated high affinity IgM rheumatoid factors. J Immunol (1993 ) 151(1):473–88.

    Not in our library

  48. 48.

    Murakami M Yoshioka H Shirai T Tsubata T Honjo T. Prevention of autoimmune symptoms in autoimmune-prone mice by elimination of B-1 cells. Int Immunol (1995 ) 7(5):877–82.

    Not in our library10.1093/intimm/7.5.877

  49. 49.

    Casali P Notkins AL Probing the human B-cell repertoire with EBV: polyreactive antibodies and CD5+ B lymphocytes. Annu Rev Immunol (1989 ) 7:513–35.

    Not in our library10.1146/annurev.iy.07.040189.002501

  50. 50.

    Suzuki N Sakane T Engleman EG. Anti-DNA antibody production by CD5+ and CD5- B cells of patients with systemic lupus erythematosus. J Clin Invest (1990 ) 85(1):238–47.

    Not in our library10.1172/jci114418

  51. 51.

    Martin F Oliver AM Kearney JF. Marginal zone and B1 B cells unite in the early response against T-independent blood-borne particulate antigens. Immunity (2001 ) 14(5):617–29.

    Not in our library10.1016/s1074-7613(01)00129-7

  52. 52.

    Genestier L Taillardet M Mondiere P Gheit H Bella C Defrance T TLR agonists selectively promote terminal plasma cell differentiation of B cell subsets specialized in thymus-independent responses. J Immunol (2007 ) 178(12):7779–86.

    Not in our library10.4049/jimmunol.178.12.7779

  53. 53.

    Oliver AM Martin F Gartland GL Carter RH Kearney JF. Marginal zone B cells exhibit unique activation, proliferative and immunoglobulin secretory responses. Eur J Immunol (1997 ) 27(9):2366–74.

    Not in our library10.1002/eji.1830270935

  54. 54.

    Balazs M Martin F Zhou T Kearney J. Blood dendritic cells interact with splenic marginal zone B cells to initiate T-independent immune responses. Immunity (2002 ) 17(3):341–52.

    Not in our library10.1016/s1074-7613(02)00389-8

  55. 55.

    Bialecki E Paget C Fontaine J Capron M Trottein F Faveeuw C. Role of marginal zone B lymphocytes in invariant NKT cell activation. J Immunol (2009 ) 182(10):6105–13.

    Not in our library10.4049/jimmunol.0802273

  56. 56.

    van den Eertwegh AJ Laman JD Schellekens MM Boersma WJ Claassen E. Complement-mediated follicular localization of T-independent type-2 antigens: the role of marginal zone macrophages revisited. Eur J Immunol (1992 ) 22(3):719–26.

    Not in our library10.1002/eji.1830220315

  57. 57.

    Liu YJ Zhang J Lane PJ Chan EY MacLennan IC. Sites of specific B cell activation in primary and secondary responses to T cell-dependent and T cell-independent antigens. Eur J Immunol (1991 ) 21(12):2951–62.

    Not in our library10.1002/eji.1830211209

  58. 58.

    Pao LI Lam KP Henderson JM Kutok JL Alimzhanov M Nitschke L B cell-specific deletion of protein-tyrosine phosphatase Shp1 promotes B-1a cell development and causes systemic autoimmunity. Immunity (2007 ) 27(1):35–48.

    Not in our library10.1016/j.immuni.2007.04.016

  59. 59.

    Groom JR Fletcher CA Walters SN Grey ST Watt SV Sweet MJ BAFF and MyD88 signals promote a lupuslike disease independent of T cells. J Exp Med (2007 ) 204(8):1959–71.

    Not in our library10.1084/jem.20062567

  60. 60.

    MacLennan IC Toellner KM Cunningham AF Serre K Sze DM Zuniga E Extrafollicular antibody responses. Immunol Rev (2003 ) 194:8–18.

    Not in our library10.1034/j.1600-065x.2003.00058.x

  61. 61.

    Song H Cerny J. Functional heterogeneity of marginal zone B cells revealed by their ability to generate both early antibody-forming cells and germinal centers with hypermutation and memory in response to a T-dependent antigen. J Exp Med (2003 ) 198(12):1923–35.

    Not in our library10.1084/jem.20031498

  62. 62.

    Oliver AM Martin F Kearney JF. IgMhighCD21high lymphocytes enriched in the splenic marginal zone generate effector cells more rapidly than the bulk of follicular B cells. J Immunol (1999 ) 162(12):7198–207.

    Not in our library

  63. 63.

    Attanavanich K Kearney JF Marginal zone, but not follicular B cells, are potent activators of naive CD4 T cells. J Immunol (2004 ) 172(2):803–11.

    Not in our library10.4049/jimmunol.172.2.803

  64. 64.

    Chappell CP Draves KE Giltiay NV Clark EA. Extrafollicular B cell activation by marginal zone dendritic cells drives T cell-dependent antibody responses. J Exp Med (2012 ) 209(10):1825–40.

    Not in our library10.1084/jem.20120774

  65. 65.

    Rubtsov A Strauch P Digiacomo A Hu J Pelanda R Torres RM. Lsc regulates marginal-zone B cell migration and adhesion and is required for the IgM T-dependent antibody response. Immunity (2005 ) 23(5):527–38.

    Not in our library10.1016/j.immuni.2005.09.018

  66. 66.

    Cinamon G Zachariah MA Lam OM Foss FW Jr Cyster JG. Follicular shuttling of marginal zone B cells facilitates antigen transport. Nat Immunol (2008 ) 9(1):54–62.

    Not in our library10.1038/ni1542

  67. 67.

    Reif K Ekland EH Ohl L Nakano H Lipp M Forster R Balanced responsiveness to chemoattractants from adjacent zones determines B-cell position. Nature (2002 ) 416(6876):94–9.

    Not in our library10.1038/416094a

  68. 68.

    Pereira JP Kelly LM Xu Y Cyster JG. EBI2 mediates B cell segregation between the outer and centre follicle. Nature (2009 ) 460(7259):1122–6.

    Not in our library10.1038/nature08226

  69. 69.

    Toellner KM Luther SA Sze DM Choy RK Taylor DR MacLennan IC T helper 1 (Th1) and Th2 characteristics start to develop during T cell priming and are associated with an immediate ability to induce immunoglobulin class switching. J Exp Med (1998 ) 187(8):1193–204.

    Not in our library10.1084/jem.187.8.1193

  70. 70.

    Rousset F Garcia E Defrance T Peronne C Vezzio N Hsu DH Interleukin 10 is a potent growth and differentiation factor for activated human B lymphocytes. Proc Natl Acad Sci U S A (1992 ) 89(5):1890–3.

    Not in our library10.1073/pnas.89.5.1890

  71. 71.

    Lundgren M Persson U Larsson P Magnusson C Smith CI Hammarstrom L Interleukin 4 induces synthesis of IgE and IgG4 in human B cells. Eur J Immunol (1989 ) 19(7):1311–5.

    Not in our library10.1002/eji.1830190724

  72. 72.

    Bryant VL Ma CS Avery DT Li Y Good KL Corcoran LM Cytokine-mediated regulation of human B cell differentiation into Ig-secreting cells: predominant role of IL-21 produced by CXCR5+ T follicular helper cells. J Immunol (2007 ) 179(12):8180–90.

    Not in our library10.4049/jimmunol.179.12.8180

  73. 73.

    Avery DT Deenick EK Ma CS Suryani S Simpson N Chew GY B cell-intrinsic signaling through IL-21 receptor and STAT3 is required for establishing long-lived antibody responses in humans. J Exp Med (2010 ) 207(1):155–71.

    Not in our library10.1084/jem.20091706

  74. 74.

    Jacob J Kelsoe G In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. II. A common clonal origin for periarteriolar lymphoid sheath-associated foci and germinal centers. J Exp Med (1992 ) 176(3):679–87.

    Not in our library10.1084/jem.176.3.679

  75. 75.

    Chan TD Gatto D Wood K Camidge T Basten A Brink R. Antigen affinity controls rapid T-dependent antibody production by driving the expansion rather than the differentiation or extrafollicular migration of early plasmablasts. J Immunol (2009 ) 183(5):3139–49.

    Not in our library10.4049/jimmunol.0901690

  76. 76.

    Phan TG Paus D Chan TD Turner ML Nutt SL Basten A High affinity germinal center B cells are actively selected into the plasma cell compartment. J Exp Med (2006 ) 203(11):2419–24.

    Not in our library10.1084/jem.20061254

  77. 77.

    Schwickert TA Victora GD Fooksman DR Kamphorst AO Mugnier MR Gitlin AD A dynamic T cell-limited checkpoint regulates affinity-dependent B cell entry into the germinal center. J Exp Med (2011 ) 208(6):1243–52.

    Not in our library10.1084/jem.20102477

  78. 78.

    Rookhuizen DC DeFranco AL. Toll-like receptor 9 signaling acts on multiple elements of the germinal center to enhance antibody responses. Proc Natl Acad Sci U S A (2014 ) 111(31):E3224–33.

    Not in our library10.1073/pnas.1323985111

  79. 79.

    Garcia De Vinuesa C Gulbranson-Judge A Khan M O’Leary P Cascalho M Wabl M Dendritic cells associated with plasmablast survival. Eur J Immunol (1999 ) 29(11):3712–21.

    Not in our library10.1002/(sici)1521-4141(199911)29:11<3712::aid-immu3712>3.0.co;2-p

  80. 80.

    Lee SK Rigby RJ Zotos D Tsai LM Kawamoto S Marshall JL B cell priming for extrafollicular antibody responses requires Bcl-6 expression by T cells. J Exp Med (2011 ) 208(7):1377–88.

    Not in our library10.1084/jem.20102065

  81. 81.

    Blink EJ Light A Kallies A Nutt SL Hodgkin PD Tarlinton DM Early appearance of germinal center-derived memory B cells and plasma cells in blood after primary immunization. J Exp Med (2005 ) 201(4):545

    Not in our library10.1084/jem.20042060

  82. 82.

    Toyama H Okada S Hatano M Takahashi Y Takeda N Ichii H Memory B cells without somatic hypermutation are generated from Bcl6-deficient B cells. Immunity (2002 ) 17(3):329–39.

    Not in our library10.1016/s1074-7613(02)00387-4

  83. 83.

    Di Niro R Lee SJ Vander Heiden JA Elsner RA Trivedi N Bannock JM Salmonella infection drives promiscuous B cell activation followed by extrafollicular affinity maturation. Immunity (2015 ) 43(1):120–31.

    Not in our library10.1016/j.immuni.2015.06.013

  84. 84.

    Wang X Cho B Suzuki K Xu Y Green JA An J Follicular dendritic cells help establish follicle identity and promote B cell retention in germinal centers. J Exp Med (2011 ) 208(12):2497–510.

    Not in our library10.1084/jem.20111449

  85. 85.

    Heesters BA Chatterjee P Kim YA Gonzalez SF Kuligowski MP Kirchhausen T Endocytosis and recycling of immune complexes by follicular dendritic cells enhances B cell antigen binding and activation. Immunity (2013 ) 38(6):1164–75.

    Not in our library10.1016/j.immuni.2013.02.023

  86. 86.

    Gatto D Brink R The germinal center reaction. J Allergy Clin Immunol (2010 ) 126(5):898–907.

    Not in our library10.1016/j.jaci.2010.09.007

  87. 87.

    Legler DF Loetscher M Roos RS Clark-Lewis I Baggiolini M Moser B B cell-attracting chemokine 1, a human CXC chemokine expressed in lymphoid tissues, selectively attracts B lymphocytes via BLR1/CXCR5. J Exp Med (1998 ) 187(4):655–60.

    Not in our library10.1084/jem.187.4.655

  88. 88.

    Allen CD Okada T Tang HL Cyster JG. Imaging of germinal center selection events during affinity maturation. Science (2007 ) 315(5811):528–31.

    Not in our library10.1126/science.1136736

  89. 89.

    Qi H Cannons JL Klauschen F Schwartzberg PL Germain RN. SAP-controlled T-B cell interactions underlie germinal centre formation. Nature (2008 ) 455(7214):764–9.

    Not in our library10.1038/nature07345

  90. 90.

    Cortini A Ellinghaus U Malik TH Cunninghame Graham DS Botto M Vyse TJ B cell OX40L supports T follicular helper cell development and contributes to SLE pathogenesis. Ann Rheum Dis (2017 ) 76(12):2095–103.

    Not in our library10.1136/annrheumdis-2017-211499

  91. 91.

    Good-Jacobson KL Song E Anderson S Sharpe AH Shlomchik MJ. CD80 expression on B cells regulates murine T follicular helper development, germinal center B cell survival, and plasma cell generation. J Immunol (2012 ) 188(9):4217–25.

    Not in our library10.4049/jimmunol.1102885

  92. 92.

    Kitano M Moriyama S Ando Y Hikida M Mori Y Kurosaki T Bcl6 protein expression shapes pre-germinal center B cell dynamics and follicular helper T cell heterogeneity. Immunity (2011 ) 34(6):961–72.

    Not in our library10.1016/j.immuni.2011.03.025

  93. 93.

    Noelle RJ Ledbetter JA Aruffo A. CD40 and its ligand, an essential ligand-receptor pair for thymus-dependent B-cell activation. Immunol Today (1992 ) 13(11):431–3.

    Not in our library10.1016/0167-5699(92)90068-i

  94. 94.

    Allen RC Armitage RJ Conley ME Rosenblatt H Jenkins NA Copeland NG CD40 ligand gene defects responsible for X-linked hyper-IgM syndrome. Science (1993 ) 259(5097):990–3.

    Not in our library10.1126/science.7679801

  95. 95.

    Taylor JJ Pape KA Jenkins MK A germinal center-independent pathway generates unswitched memory B cells early in the primary response. J Exp Med (2012 ) 209(3):597–606.

    Not in our library10.1084/jem.20111696

  96. 96.

    Linterman MA Beaton L Yu D Ramiscal RR Srivastava M Hogan JJ IL-21 acts directly on B cells to regulate Bcl-6 expression and germinal center responses. J Exp Med (2010 ) 207(2):353–63.

    Not in our library10.1084/jem.20091738

  97. 97.

    El Shikh ME El Sayed RM Sukumar S Szakal AK Tew JG. Activation of B cells by antigens on follicular dendritic cells. Trends Immunol (2010 ) 31(6):205–11.

    Not in our library10.1016/j.it.2010.03.002

  98. 98.

    Ersching J Efeyan A Mesin L Jacobsen JT Pasqual G Grabiner BC Germinal center selection and affinity maturation require dynamic regulation of mTORC1 kinase. Immunity (2017 ) 46(6):1045–58e6.

    Not in our library10.1016/j.immuni.2017.06.005

  99. 99.

    Gitlin AD Shulman Z Nussenzweig MC. Clonal selection in the germinal centre by regulated proliferation and hypermutation. Nature (2014 ) 509(7502):637–40.

    Not in our library10.1038/nature13300

  100. 100.

    Victora GD Schwickert TA Fooksman DR Kamphorst AO Meyer-Hermann M Dustin ML Germinal center dynamics revealed by multiphoton microscopy with a photoactivatable fluorescent reporter. Cell (2010 ) 143(4):592–605.

    Not in our library10.1016/j.cell.2010.10.032

  101. 101.

    Klein U Dalla-Favera R. Germinal centres: role in B-cell physiology and malignancy. Nat Rev Immunol (2008 ) 8(1):22–33.

    Not in our library10.1038/nri2217

  102. 102.

    Hao Z Duncan GS Seagal J Su YW Hong C Haight J Fas receptor expression in germinal-center B cells is essential for T and B lymphocyte homeostasis. Immunity (2008 ) 29(4):615–27.

    Not in our library10.1016/j.immuni.2008.07.016

  103. 103.

    Chan TD Wood K Hermes JR Butt D Jolly CJ Basten A Elimination of germinal-center-derived self-reactive B cells is governed by the location and concentration of self-antigen. Immunity (2012 ) 37(5):893–904.

    Not in our library10.1016/j.immuni.2012.07.017

  104. 104.

    Mayer CT Gazumyan A Kara EE Gitlin AD Golijanin J Viant C The microanatomic segregation of selection by apoptosis in the germinal center. Science (2017 ) 358(6360):eaao2602

    Not in our library10.1126/science.aao2602

  105. 105.

    Shinnakasu R Inoue T Kometani K Moriyama S Adachi Y Nakayama M Regulated selection of germinal-center cells into the memory B cell compartment. Nat Immunol (2016 ) 17(7):861–9.

    Not in our library10.1038/ni.3460

  106. 106.

    Smith KG Light A O’Reilly LA Ang SM Strasser A Tarlinton D. Bcl-2 transgene expression inhibits apoptosis in the germinal center and reveals differences in the selection of memory B cells and bone marrow antibody-forming cells. J Exp Med (2000 ) 191(3):475–84.

    Not in our library10.1084/jem.191.3.475

  107. 107.

    Smith KG Light A Nossal GJ Tarlinton DM. The extent of affinity maturation differs between the memory and antibody-forming cell compartments in the primary immune response. EMBO J (1997 ) 16(11):2996–3006.

    Not in our library10.1093/emboj/16.11.2996

  108. 108.

    Krautler NJ Suan D Butt D Bourne K Hermes JR Chan TD Differentiation of germinal center B cells into plasma cells is initiated by high-affinity antigen and completed by Tfh cells. J Exp Med (2017 ) 214(5):1259–67.

    Not in our library10.1084/jem.20161533

  109. 109.

    Weisel FJ Zuccarino-Catania GV Chikina M Shlomchik MJ A temporal switch in the germinal center determines differential output of memory B and plasma cells. Immunity (2016 ) 44(1):116–30.

    Not in our library10.1016/j.immuni.2015.12.004

  110. 110.

    Zotos D Coquet JM Zhang Y Light A D’Costa K Kallies A IL-21 regulates germinal center B cell differentiation and proliferation through a B cell-intrinsic mechanism. J Exp Med (2010 ) 207(2):365–78.

    Not in our library10.1084/jem.20091777

  111. 111.
    Cytokine-Mediated Regulation of Plasma Cell Generation: IL-21 Takes Center Stage · 2014
    No notice
  112. 112.

    Kasturi SP Skountzou I Albrecht RA Koutsonanos D Hua T Nakaya HI Programming the magnitude and persistence of antibody responses with innate immunity. Nature (2011 ) 470(7335):543–7.

    Not in our library10.1038/nature09737

  113. 113.

    Gavin AL Hoebe K Duong B Ota T Martin C Beutler B Adjuvant-enhanced antibody responses in the absence of toll-like receptor signaling. Science (2006 ) 314(5807):1936–8.

    Not in our library10.1126/science.1135299

  114. 114.

    Meyer-Bahlburg A Khim S Rawlings DJ B cell intrinsic TLR signals amplify but are not required for humoral immunity. J Exp Med (2007 ) 204(13):3095–101.

    Not in our library10.1084/jem.20071250

  115. 115.

    Suan D Sundling C Brink R. Plasma cell and memory B cell differentiation from the germinal center. Curr Opin Immunol (2017 ) 45:97–102.

    Not in our library10.1016/j.coi.2017.03.006

  116. 116.

    Chiu YK Lin IY Su ST Wang KH Yang SY Tsai DY Transcription factor ABF-1 suppresses plasma cell differentiation but facilitates memory B cell formation. J Immunol (2014 ) 193(5):2207–17.

    Not in our library10.4049/jimmunol.1400411

  117. 117.

    Reimold AM Iwakoshi NN Manis J Vallabhajosyula P Szomolanyi-Tsuda E Gravallese EM Plasma cell differentiation requires the transcription factor XBP-1. Nature (2001 ) 412(6844):300–7.

    Not in our library10.1038/35085509

  118. 118.

    Minnich M Tagoh H Bonelt P Axelsson E Fischer M Cebolla B Multifunctional role of the transcription factor Blimp-1 in coordinating plasma cell differentiation. Nat Immunol (2016 ) 17(3):331–43.

    Not in our library10.1038/ni.3349

  119. 119.

    Sciammas R Shaffer AL Schatz JH Zhao H Staudt LM Singh H. Graded expression of interferon regulatory factor-4 coordinates isotype switching with plasma cell differentiation. Immunity (2006 ) 25(2):225–36.

    Not in our library10.1016/j.immuni.2006.07.009

  120. 120.

    Nera KP Kohonen P Narvi E Peippo A Mustonen L Terho P Loss of Pax5 promotes plasma cell differentiation. Immunity (2006 ) 24(3):283–93.

    Not in our library10.1016/j.immuni.2006.02.003

  121. 121.

    Shaffer AL Lin KI Kuo TC Yu X Hurt EM Rosenwald A Blimp-1 orchestrates plasma cell differentiation by extinguishing the mature B cell gene expression program. Immunity (2002 ) 17(1):51–62.

    Not in our library10.1016/s1074-7613(02)00335-7

  122. 122.

    Shaffer AL Shapiro-Shelef M Iwakoshi NN Lee AH Qian SB Zhao H XBP1, downstream of Blimp-1, expands the secretory apparatus and other organelles, and increases protein synthesis in plasma cell differentiation. Immunity (2004 ) 21(1):81–93.

    Not in our library10.1016/j.immuni.2004.06.010

  123. 123.

    Meyer-Hermann M Mohr E Pelletier N Zhang Y Victora GD Toellner KM A theory of germinal center B cell selection, division, and exit. Cell Rep (2012 ) 2(1):162–74.

    Not in our library10.1016/j.celrep.2012.05.010

  124. 124.

    Mohr E Serre K Manz RA Cunningham AF Khan M Hardie DL Dendritic cells and monocyte/macrophages that create the IL-6/APRIL-rich lymph node microenvironments where plasmablasts mature. J Immunol (2009 ) 182(4):2113–23.

    Not in our library10.4049/jimmunol.0802771

  125. 125.

    Tipton CM Fucile CF Darce J Chida A Ichikawa T Gregoretti I Diversity, cellular origin and autoreactivity of antibody-secreting cell population expansions in acute systemic lupus erythematosus. Nat Immunol (2015 ) 16(7):755–65.

    Not in our library10.1038/ni.3175

  126. 126.

    Slifka MK Antia R Whitmire JK Ahmed R. Humoral immunity due to long-lived plasma cells. Immunity (1998 ) 8(3):363–72.

    Not in our library10.1016/s1074-7613(00)80541-5

  127. 127.

    Manz RA Thiel A Radbruch A Lifetime of plasma cells in the bone marrow. Nature (1997 ) 388(6638):133–4.

    Not in our library10.1038/40540

  128. 128.
    Plasma cell survival in the absence of B cell memory · 2017
    No notice
  129. 129.

    Bhoj VG Arhontoulis D Wertheim G Capobianchi J Callahan CA Ellebrecht CT Persistence of long-lived plasma cells and humoral immunity in individuals responding to CD19-directed CAR T-cell therapy. Blood (2016 ) 128(3):360–70.

    Not in our library10.1182/blood-2016-01-694356

  130. 130.

    Hiepe F Radbruch A. Plasma cells as an innovative target in autoimmune disease with renal manifestations. Nat Rev Nephrol (2016 ) 12(4):232–40.

    Not in our library10.1038/nrneph.2016.20

  131. 131.

    Taddeo A Khodadadi L Voigt C Mumtaz IM Cheng Q Moser K Long-lived plasma cells are early and constantly generated in New Zealand Black/New Zealand White F1 mice and their therapeutic depletion requires a combined targeting of autoreactive plasma cells and their precursors. Arthritis Res Ther (2015 ) 17:39.

    Not in our library10.1186/s13075-015-0551-3

  132. 132.

    Sze DM Toellner KM Garcia de Vinuesa C Taylor DR MacLennan IC Intrinsic constraint on plasmablast growth and extrinsic limits of plasma cell survival. J Exp Med (2000 ) 192(6):813–21.

    Not in our library10.1084/jem.192.6.813

  133. 133.

    Minges Wols HA Ippolito JA Yu Z Palmer JL White FA Le PT The effects of microenvironment and internal programming on plasma cell survival. Int Immunol (2007 ) 19(7):837–46.

    Not in our library10.1093/intimm/dxm051

  134. 134.

    Kometani K Kurosaki T. Differentiation and maintenance of long-lived plasma cells. Curr Opin Immunol (2015 ) 33:64–9.

    Not in our library10.1016/j.coi.2015.01.017

  135. 135.

    Tarte K Zhan F De Vos J Klein B Shaughnessy J Jr. Gene expression profiling of plasma cells and plasmablasts: toward a better understanding of the late stages of B-cell differentiation. Blood (2003 ) 102(2):592–600.

    Not in our library10.1182/blood-2002-10-3161

  136. 136.

    Tokoyoda K Egawa T Sugiyama T Choi BI Nagasawa T. Cellular niches controlling B lymphocyte behavior within bone marrow during development. Immunity (2004 ) 20(6):707–18.

    Not in our library10.1016/j.immuni.2004.05.001

  137. 137.

    Chu VT Frohlich A Steinhauser G Scheel T Roch T Fillatreau S Eosinophils are required for the maintenance of plasma cells in the bone marrow. Nat Immunol (2011 ) 12(2):151–9.

    Not in our library10.1038/ni.1981

  138. 138.

    Wilmore JR Allman D Here, there, and anywhere? Arguments for and against the physical plasma cell survival niche. J Immunol (2017 ) 199(3):839–45.

    Not in our library10.4049/jimmunol.1700461

  139. 139.

    Belnoue E Pihlgren M McGaha TL Tougne C Rochat AF Bossen C APRIL is critical for plasmablast survival in the bone marrow and poorly expressed by early-life bone marrow stromal cells. Blood (2008 ) 111(5):2755–64.

    Not in our library10.1182/blood-2007-09-110858

  140. 140.

    Benson MJ Dillon SR Castigli E Geha RS Xu S Lam KP Cutting edge: the dependence of plasma cells and independence of memory B cells on BAFF and APRIL. J Immunol (2008 ) 180(6):3655–9.

    Not in our library10.4049/jimmunol.180.6.3655

  141. 141.

    O’Connor BP Raman VS Erickson LD Cook WJ Weaver LK Ahonen C BCMA is essential for the survival of long-lived bone marrow plasma cells. J Exp Med (2004 ) 199(1):91–8.

    Not in our library10.1084/jem.20031330

  142. 142.

    Mahevas M Michel M Weill JC Reynaud CA. Long-lived plasma cells in autoimmunity: lessons from B-cell depleting therapy. Front Immunol (2013 ) 4:494.

    Not in our library10.3389/fimmu.2013.00494

  143. 143.

    Mahevas M Patin P Huetz F Descatoire M Cagnard N Bole-Feysot C B cell depletion in immune thrombocytopenia reveals splenic long-lived plasma cells. J Clin Invest (2013 ) 123(1):432–42.

    Not in our library10.1172/jci65689

  144. 144.

    Rozanski CH Arens R Carlson LM Nair J Boise LH Chanan-Khan AA Sustained antibody responses depend on CD28 function in bone marrow-resident plasma cells. J Exp Med (2011 ) 208(7):1435–46.

    Not in our library10.1084/jem.20110040

  145. 145.

    Chevrier S Genton C Kallies A Karnowski A Otten LA Malissen B CD93 is required for maintenance of antibody secretion and persistence of plasma cells in the bone marrow niche. Proc Natl Acad Sci U S A (2009 ) 106(10):3895–900.

    Not in our library10.1073/pnas.0809736106

  146. 146.

    Hsu MC Toellner KM Vinuesa CG Maclennan IC B cell clones that sustain long-term plasmablast growth in T-independent extrafollicular antibody responses. Proc Natl Acad Sci U S A (2006 ) 103(15):5905–10.

    Not in our library10.1073/pnas.0601502103

  147. 147.

    Bortnick A Chernova I Quinn WJ III Mugnier M Cancro MP Allman D. Long-lived bone marrow plasma cells are induced early in response to T cell-independent or T cell-dependent antigens. J Immunol (2012 ) 188(11):5389–96.

    Not in our library10.4049/jimmunol.1102808

  148. 148.

    Sanderson NS Zimmermann M Eilinger L Gubser C Schaeren-Wiemers N Lindberg RL Cocapture of cognate and bystander antigens can activate autoreactive B cells. Proc Natl Acad Sci U S A (2017 ) 114(4):734–9.

    Not in our library10.1073/pnas.1614472114

  149. 149.

    Son M Santiago-Schwarz F Al-Abed Y Diamond B. C1q limits dendritic cell differentiation and activation by engaging LAIR-1. Proc Natl Acad Sci U S A (2012 ) 109(46):E3160–7.

    Not in our library10.1073/pnas.1212753109

  150. 150.

    Hess C Winkler A Lorenz AK Holecska V Blanchard V Eiglmeier S T cell-independent B cell activation induces immunosuppressive sialylated IgG antibodies. J Clin Invest (2013 ) 123(9):3788–96.

    Not in our library10.1172/jci65938

  151. 151.

    Pfeifle R Rothe T Ipseiz N Scherer HU Culemann S Harre U Regulation of autoantibody activity by the IL-23-TH17 axis determines the onset of autoimmune disease. Nat Immunol (2017 ) 18(1):104–13.

    Not in our library10.1038/ni.3579

  152. 152.

    Klinman NR The “clonal selection hypothesis” and current concepts of B cell tolerance. Immunity (1996 ) 5(3):189–95.

    Not in our library10.1016/s1074-7613(00)80314-3

  153. 153.

    Linton PJ Rudie A Klinman NR. Tolerance susceptibility of newly generating memory B cells. J Immunol (1991 ) 146(12):4099–104.

    Not in our library

  154. 154.

    Malkiel S Jeganathan V Wolfson S Manjarrez Orduno N Marasco E Aranow C Checkpoints for autoreactive B cells in the peripheral blood of lupus patients assessed by flow cytometry. Arthritis Rheumatol (2016 ) 68(9):2210–20.

    Not in our library10.1002/art.39710

  155. 155.

    Cappione A III Anolik JH Pugh-Bernard A Barnard J Dutcher P Silverman G Germinal center exclusion of autoreactive B cells is defective in human systemic lupus erythematosus. J Clin Invest (2005 ) 115(11):3205–16.

    Not in our library10.1172/jci24179

  156. 156.

    Sabouri Z Schofield P Horikawa K Spierings E Kipling D Randall KL Redemption of autoantibodies on anergic B cells by variable-region glycosylation and mutation away from self-reactivity. Proc Natl Acad Sci U S A (2014 ) 111(25):E2567–75.

    Not in our library10.1073/pnas.1406974111

  157. 157.

    Reed JH Jackson J Christ D Goodnow CC. Clonal redemption of autoantibodies by somatic hypermutation away from self-reactivity during human immunization. J Exp Med (2016 ) 213(7):1255–65.

    Not in our library10.1084/jem.20151978

  158. 158.

    Ait-Azzouzene D Kono DH Gonzalez-Quintial R McHeyzer-Williams LJ Lim M Wickramarachchi D Deletion of IgG-switched autoreactive B cells and defects in Fas(lpr) lupus mice. J Immunol (2010 ) 185(2):1015–27.

    Not in our library10.4049/jimmunol.1000698

  159. 159.

    Rice JS Newman J Wang C Michael DJ Diamond B. Receptor editing in peripheral B cell tolerance. Proc Natl Acad Sci U S A (2005 ) 102(5):1608–13.

    Not in our library10.1073/pnas.0409217102

  160. 160.

    Hande S Notidis E Manser T. Bcl-2 obstructs negative selection of autoreactive, hypermutated antibody V regions during memory B cell development. Immunity (1998 ) 8(2):189–98.

    Not in our library10.1016/s1074-7613(00)80471-9

  161. 161.

    Notidis E Heltemes L Manser T. Dominant, hierarchical induction of peripheral tolerance during foreign antigen-driven B cell development. Immunity (2002 ) 17(3):317–27.

    Not in our library10.1016/s1074-7613(02)00392-8

  162. 162.

    Pulendran B Kannourakis G Nouri S Smith KG Nossal GJ. Soluble antigen can cause enhanced apoptosis of germinal-centre B cells. Nature (1995 ) 375(6529):331–4.

    Not in our library10.1038/375331a0

  163. 163.

    Wang YH Diamond B B cell receptor revision diminishes the autoreactive B cell response after antigen activation in mice. J Clin Invest (2008 ) 118(8):2896–907.

    Not in our library10.1172/jci35618

  164. 164.

    Scheid JF Mouquet H Kofer J Yurasov S Nussenzweig MC Wardemann H. Differential regulation of self-reactivity discriminates between IgG+ human circulating memory B cells and bone marrow plasma cells. Proc Natl Acad Sci U S A (2011 ) 108(44):18044–8.

    Not in our library10.1073/pnas.1113395108

  165. 165.

    Pelletier N McHeyzer-Williams LJ Wong KA Urich E Fazilleau N McHeyzer-Williams MG. Plasma cells negatively regulate the follicular helper T cell program. Nat Immunol (2010 ) 11(12):1110–8.

    Not in our library10.1038/ni.1954

  166. 166.

    William J Euler C Christensen S Shlomchik MJ. Evolution of autoantibody responses via somatic hypermutation outside of germinal centers. Science (2002 ) 297(5589):2066–70.

    Not in our library10.1126/science.1073924

  167. 167.

    Deng R Hurtz C Song Q Yue C Xiao G Yu H Extrafollicular CD4+ T-B interactions are sufficient for inducing autoimmune-like chronic graft-versus-host disease. Nat Commun (2017 ) 8(1):978.

    Not in our library10.1038/s41467-017-00880-2

  168. 168.

    Odegard JM Marks BR DiPlacido LD Poholek AC Kono DH Dong C ICOS-dependent extrafollicular helper T cells elicit IgG production via IL-21 in systemic autoimmunity. J Exp Med (2008 ) 205(12):2873–86.

    Not in our library10.1084/jem.20080840

  169. 169.

    Luzina IG Atamas SP Storrer CE daSilva LC Kelsoe G Papadimitriou JC Spontaneous formation of germinal centers in autoimmune mice. J Leukoc Biol (2001 ) 70(4):578–84.

    Not in our library10.1189/jlb.70.4.578

  170. 170.

    Li Y Li H Weigert M. Autoreactive B cells in the marginal zone that express dual receptors. J Exp Med (2002 ) 195(2):181–8.

    Not in our library10.1084/jem.20011453

  171. 171.

    Julien S Soulas P Garaud JC Martin T Pasquali JL B cell positive selection by soluble self-antigen. J Immunol (2002 ) 169(8):4198–204.

    Not in our library10.4049/jimmunol.169.8.4198

  172. 172.

    Cariappa A Tang M Parng C Nebelitskiy E Carroll M Georgopoulos K The follicular versus marginal zone B lymphocyte cell fate decision is regulated by Aiolos, Btk, and CD21. Immunity (2001 ) 14(5):603–15.

    Not in our library10.1016/s1074-7613(01)00135-2

  173. 173.

    Martin F Kearney JF. Positive selection from newly formed to marginal zone B cells depends on the rate of clonal production, CD19, and btk. Immunity (2000 ) 12(1):39–49.

    Not in our library10.1016/s1074-7613(00)80157-0

  174. 174.

    Cerutti A Cols M Puga I. Marginal zone B cells: virtues of innate-like antibody-producing lymphocytes. Nat Rev Immunol (2013 ) 13(2):118–32.

    Not in our library10.1038/nri3383

  175. 175.

    Phan TG Gardam S Basten A Brink R. Altered migration, recruitment, and somatic hypermutation in the early response of marginal zone B cells to T cell-dependent antigen. J Immunol (2005 ) 174(8):4567–78.

    Not in our library10.4049/jimmunol.174.8.4567

  176. 176.

    Zhou Z Niu H Zheng YY Morel L. Autoreactive marginal zone B cells enter the follicles and interact with CD4+ T cells in lupus-prone mice. BMC Immunol (2011 ) 12:7.

    Not in our library10.1186/1471-2172-12-7

  177. 177.

    Grimaldi CM Michael DJ Diamond B. Cutting edge: expansion and activation of a population of autoreactive marginal zone B cells in a model of estrogen-induced lupus. J Immunol (2001 ) 167(4):1886–90.

    Not in our library10.4049/jimmunol.167.4.1886

  178. 178.

    Wither JE Loh C Lajoie G Heinrichs S Cai YC Bonventi G Colocalization of expansion of the splenic marginal zone population with abnormal B cell activation and autoantibody production in B6 mice with an introgressed New Zealand Black chromosome 13 interval. J Immunol (2005 ) 175(7):4309–19.

    Not in our library10.4049/jimmunol.175.7.4309

  179. 179.

    Atencio S Amano H Izui S Kotzin BL. Separation of the New Zealand Black genetic contribution to lupus from New Zealand Black determined expansions of marginal zone B and B1a cells. J Immunol (2004 ) 172(7):4159–66.

    Not in our library10.4049/jimmunol.172.7.4159

  180. 180.

    Amano H Amano E Moll T Marinkovic D Ibnou-Zekri N Martinez-Soria E The Yaa mutation promoting murine lupus causes defective development of marginal zone B cells. J Immunol (2003 ) 170(5):2293–301.

    Not in our library10.4049/jimmunol.170.5.2293

  181. 181.

    Nickerson KM Christensen SR Shupe J Kashgarian M Kim D Elkon K TLR9 regulates TLR7- and MyD88-dependent autoantibody production and disease in a murine model of lupus. J Immunol (2010 ) 184(4):1840–8.

    Not in our library10.4049/jimmunol.0902592

  182. 182.

    Teichmann LL Schenten D Medzhitov R Kashgarian M Shlomchik MJ. Signals via the adaptor MyD88 in B cells and DCs make distinct and synergistic contributions to immune activation and tissue damage in lupus. Immunity (2013 ) 38(3):528–40.

    Not in our library10.1016/j.immuni.2012.11.017

  183. 183.

    Christensen SR Kashgarian M Alexopoulou L Flavell RA Akira S Shlomchik MJ. Toll-like receptor 9 controls anti-DNA autoantibody production in murine lupus. J Exp Med (2005 ) 202(2):321–31.

    Not in our library10.1084/jem.20050338

  184. 184.

    Christensen SR Shupe J Nickerson K Kashgarian M Flavell RA Shlomchik MJ. Toll-like receptor 7 and TLR9 dictate autoantibody specificity and have opposing inflammatory and regulatory roles in a murine model of lupus. Immunity (2006 ) 25(3):417–28.

    Not in our library10.1016/j.immuni.2006.07.013

  185. 185.

    Teichmann LL Ols ML Kashgarian M Reizis B Kaplan DH Shlomchik MJ. Dendritic cells in lupus are not required for activation of T and B cells but promote their expansion, resulting in tissue damage. Immunity (2010 ) 33(6):967–78.

    Not in our library10.1016/j.immuni.2010.11.025

  186. 186.

    Wong CK Wong PT Tam LS Li EK Chen DP Lam CW. Activation profile of toll-like receptors of peripheral blood lymphocytes in patients with systemic lupus erythematosus. Clin Exp Immunol (2010 ) 159(1):11–22.

    Not in our library10.1111/j.1365-2249.2009.04036.x

  187. 187.

    Flores-Borja F Kabouridis PS Jury EC Isenberg DA Mageed RA. Decreased Lyn expression and translocation to lipid raft signaling domains in B lymphocytes from patients with systemic lupus erythematosus. Arthritis Rheum (2005 ) 52(12):3955–65.

    Not in our library10.1002/art.21416

  188. 188.

    Pritchard NR Cutler AJ Uribe S Chadban SJ Morley BJ Smith KG. Autoimmune-prone mice share a promoter haplotype associated with reduced expression and function of the Fc receptor FcgammaRII. Curr Biol (2000 ) 10(4):227–30.

    Not in our library10.1016/s0960-9822(00)00344-4

  189. 189.

    Suurmond J Calise J Malkiel S Diamond B DNA-reactive B cells in lupus. Curr Opin Immunol (2016 ) 43:1–7.

    Not in our library10.1016/j.coi.2016.07.002

  190. 190.

    Chaturvedi A Dorward D Pierce SK. The B cell receptor governs the subcellular location of toll-like receptor 9 leading to hyperresponses to DNA-containing antigens. Immunity (2008 ) 28(6):799–809.

    Not in our library10.1016/j.immuni.2008.03.019

  191. 191.

    Lau CM Broughton C Tabor AS Akira S Flavell RA Mamula MJ RNA-associated autoantigens activate B cells by combined B cell antigen receptor/toll-like receptor 7 engagement. J Exp Med (2005 ) 202(9):1171–7.

    Not in our library10.1084/jem.20050630

  192. 192.

    Poovassery JS Bishop GA. Type I IFN receptor and the B cell antigen receptor regulate TLR7 responses via distinct molecular mechanisms. J Immunol (2012 ) 189(4):1757–64.

    Not in our library10.4049/jimmunol.1200624

  193. 193.
    Accelerated development of IgG autoantibodies and autoimmune disease in the absence of secreted IgM · 2000
    Not checked
  194. 194.

    Haynes NM Allen CD Lesley R Ansel KM Killeen N Cyster JG. Role of CXCR5 and CCR7 in follicular Th cell positioning and appearance of a programmed cell death gene-1high germinal center-associated subpopulation. J Immunol (2007 ) 179(8):5099–108.

    Not in our library10.4049/jimmunol.179.8.5099

  195. 195.

    Elsner RA Ernst DN Baumgarth N. Single and coexpression of CXCR4 and CXCR5 identifies CD4 T helper cells in distinct lymph node niches during influenza virus infection. J Virol (2012 ) 86(13):7146–57.

    Not in our library10.1128/jvi.06904-11

  196. 196.

    Herlands RA Christensen SR Sweet RA Hershberg U Shlomchik MJ T cell-independent and toll-like receptor-dependent antigen-driven activation of autoreactive B cells. Immunity (2008 ) 29(2):249–60.

    Not in our library10.1016/j.immuni.2008.06.009

  197. 197.

    Wang L Zhao P Ma L Shan Y Jiang Z Wang J Increased interleukin 21 and follicular helper T-like cells and reduced interleukin 10+ B cells in patients with new-onset systemic lupus erythematosus. J Rheumatol (2014 ) 41(9):1781–92.

    Not in our library10.3899/jrheum.131025

  198. 198.

    He B Qiao X Cerutti A. CpG DNA induces IgG class switch DNA recombination by activating human B cells through an innate pathway that requires TLR9 and cooperates with IL-10. J Immunol (2004 ) 173(7):4479–91.

    Not in our library10.4049/jimmunol.173.7.4479

  199. 199.

    Sweet RA Christensen SR Harris ML Shupe J Sutherland JL Shlomchik MJ A new site-directed transgenic rheumatoid factor mouse model demonstrates extrafollicular class switch and plasmablast formation. Autoimmunity (2010 ) 43(8):607–18.

    Not in our library10.3109/08916930903567500

  200. 200.

    Arce E Jackson DG Gill MA Bennett LB Banchereau J Pascual V. Increased frequency of pre-germinal center B cells and plasma cell precursors in the blood of children with systemic lupus erythematosus. J Immunol (2001 ) 167(4):2361–9.

    Not in our library10.4049/jimmunol.167.4.2361

  201. 201.

    Zhang X Lindwall E Gauthier C Lyman J Spencer N Alarakhia A Circulating CXCR5+CD4+helper T cells in systemic lupus erythematosus patients share phenotypic properties with germinal center follicular helper T cells and promote antibody production. Lupus (2015 ) 24(9):909–17.

    Not in our library10.1177/0961203314567750

  202. 202.

    Brink R. The imperfect control of self-reactive germinal center B cells. Curr Opin Immunol (2014 ) 28:97–101.

    Not in our library10.1016/j.coi.2014.03.001

  203. 203.

    Guo W Smith D Aviszus K Detanico T Heiser RA Wysocki LJ. Somatic hypermutation as a generator of antinuclear antibodies in a murine model of systemic autoimmunity. J Exp Med (2010 ) 207(10):2225–37.

    Not in our library10.1084/jem.20092712

  204. 204.

    Mietzner B Tsuiji M Scheid J Velinzon K Tiller T Abraham K Autoreactive IgG memory antibodies in patients with systemic lupus erythematosus arise from nonreactive and polyreactive precursors. Proc Natl Acad Sci U S A (2008 ) 105(28):9727–32.

    Not in our library10.1073/pnas.0803644105

  205. 205.

    Paul E Nelde A Verschoor A Carroll MC. Follicular exclusion of autoreactive B cells requires FcgammaRIIb. Int Immunol (2007 ) 19(4):365–73.

    Not in our library10.1093/intimm/dxm002

  206. 206.

    Dai X James RG Habib T Singh S Jackson S Khim S A disease-associated PTPN22 variant promotes systemic autoimmunity in murine models. J Clin Invest (2013 ) 123(5):2024–36.

    Not in our library10.1172/jci66963

  207. 207.

    Nowosad CR Spillane KM Tolar P. Germinal center B cells recognize antigen through a specialized immune synapse architecture. Nat Immunol (2016 ) 17(7):870–7.

    Not in our library10.1038/ni.3458

  208. 208.

    Walsh ER Pisitkun P Voynova E Deane JA Scott BL Caspi RR Dual signaling by innate and adaptive immune receptors is required for TLR7-induced B-cell-mediated autoimmunity. Proc Natl Acad Sci U S A (2012 ) 109(40):16276–81.

    Not in our library10.1073/pnas.1209372109

  209. 209.

    Jackson SW Scharping NE Kolhatkar NS Khim S Schwartz MA Li QZ Opposing impact of B cell-intrinsic TLR7 and TLR9 signals on autoantibody repertoire and systemic inflammation. J Immunol (2014 ) 192(10):4525–32.

    Not in our library10.4049/jimmunol.1400098

  210. 210.

    Das A Heesters BA Bialas A O’Flynn J Rifkin IR Ochando J Follicular dendritic cell activation by TLR Ligands promotes autoreactive B cell responses. Immunity (2017 ) 46(1):106–19.

    Not in our library10.1016/j.immuni.2016.12.014

  211. 211.

    Woods M Zou YR Davidson A. Defects in germinal center selection in SLE. Front Immunol (2015 ) 6:425.

    Not in our library10.3389/fimmu.2015.00425

  212. 212.

    Diamond B Scharff MD. Somatic mutation of the T15 heavy chain gives rise to an antibody with autoantibody specificity. Proc Natl Acad Sci U S A (1984 ) 81(18):5841–4.

    Not in our library10.1073/pnas.81.18.5841

  213. 213.

    Zhang J Roschke V Baker KP Wang Z Alarcon GS Fessler BJ Cutting edge: a role for B lymphocyte stimulator in systemic lupus erythematosus. J Immunol (2001 ) 166(1):6–10.

    Not in our library10.4049/jimmunol.166.1.6

  214. 214.

    Coquery CM Loo WM Wade NS Bederman AG Tung KS Lewis JE BAFF regulates follicular helper t cells and affects their accumulation and interferon-gamma production in autoimmunity. Arthritis Rheumatol (2015 ) 67(3):773–84.

    Not in our library10.1002/art.38950

  215. 215.

    Mackay F Woodcock SA Lawton P Ambrose C Baetscher M Schneider P Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations. J Exp Med (1999 ) 190(11):1697–710.

    Not in our library10.1084/jem.190.11.1697

  216. 216.

    Simpson N Gatenby PA Wilson A Malik S Fulcher DA Tangye SG Expansion of circulating T cells resembling follicular helper T cells is a fixed phenotype that identifies a subset of severe systemic lupus erythematosus. Arthritis Rheum (2010 ) 62(1):234–44.

    Not in our library10.1002/art.25032

  217. 217.

    Nakou M Papadimitraki ED Fanouriakis A Bertsias GK Choulaki C Goulidaki N Interleukin-21 is increased in active systemic lupus erythematosus patients and contributes to the generation of plasma B cells. Clin Exp Rheumatol (2013 ) 31(2):172–9.

    Not in our library

  218. 218.

    Wong CK Wong PT Tam LS Li EK Chen DP Lam CW. Elevated production of B cell chemokine CXCL13 is correlated with systemic lupus erythematosus disease activity. J Clin Immunol (2010 ) 30(1):45–52.

    Not in our library10.1007/s10875-009-9325-5

  219. 219.

    Linterman MA Rigby RJ Wong RK Yu D Brink R Cannons JL Follicular helper T cells are required for systemic autoimmunity. J Exp Med (2009 ) 206(3):561–76.

    Not in our library10.1084/jem.20081886

  220. 220.

    Jacquemin C Schmitt N Contin-Bordes C Liu Y Narayanan P Seneschal J OX40 ligand contributes to human lupus pathogenesis by promoting T follicular helper response. Immunity (2015 ) 42(6):1159–70.

    Not in our library10.1016/j.immuni.2015.05.012

  221. 221.

    Luo J Niu X Liu H Zhang M Chen M Deng S. Up-regulation of transcription factor Blimp1 in systemic lupus erythematosus. Mol Immunol (2013 ) 56(4):574–82.

    Not in our library10.1016/j.molimm.2013.05.241

  222. 222.

    Guimaraes PM Scavuzzi BM Stadtlober NP Franchi Santos L Lozovoy MAB Iriyoda TMV Cytokines in systemic lupus erythematosus: far beyond Th1/Th2 dualism lupus: cytokine profiles. Immunol Cell Biol (2017 ) 95(9):824–31.

    Not in our library10.1038/icb.2017.53

  223. 223.

    Salazar-Camarena DC Ortiz-Lazareno PC Cruz A Oregon-Romero E Machado-Contreras JR Munoz-Valle JF Association of BAFF, APRIL serum levels, BAFF-R, TACI and BCMA expression on peripheral B-cell subsets with clinical manifestations in systemic lupus erythematosus. Lupus (2016 ) 25(6):582–92.

    Not in our library10.1177/0961203315608254

  224. 224.

    Hoyer BF Moser K Hauser AE Peddinghaus A Voigt C Eilat D Short-lived plasmablasts and long-lived plasma cells contribute to chronic humoral autoimmunity in NZB/W mice. J Exp Med (2004 ) 199(11):1577–84.

    Not in our library10.1084/jem.20040168

  225. 225.

    Lo MS Zurakowski D Son MB Sundel RP. Hypergammaglobulinemia in the pediatric population as a marker for underlying autoimmune disease: a retrospective cohort study. Pediatr Rheumatol Online J (2013 ) 11(1):42.

    Not in our library10.1186/1546-0096-11-42

  226. 226.

    Cassese G Lindenau S de Boer B Arce S Hauser A Riemekasten G Inflamed kidneys of NZB/W mice are a major site for the homeostasis of plasma cells. Eur J Immunol (2001 ) 31(9):2726–32.

    Not in our library10.1002/1521-4141(200109)31:9<2726::aid-immu2726>3.0.co;2-h

  227. 227.

    Starke C Frey S Wellmann U Urbonaviciute V Herrmann M Amann K High frequency of autoantibody-secreting cells and long-lived plasma cells within inflamed kidneys of NZB/W F1 lupus mice. Eur J Immunol (2011 ) 41(7):2107–12.

    Not in our library10.1002/eji.201041315

  228. 228.

    Wang A Fairhurst AM Tus K Subramanian S Liu Y Lin F CXCR4/CXCL12 hyperexpression plays a pivotal role in the pathogenesis of lupus. J Immunol (2009 ) 182(7):4448–58.

    Not in our library10.4049/jimmunol.0801920

  229. 229.

    Deng Y Tsao BP. Updates in lupus genetics. Curr Rheumatol Rep (2017 ) 19(11):68.

    Not in our library10.1007/s11926-017-0695-z

  230. 230.

    Vaughn SE Kottyan LC Munroe ME Harley JB. Genetic susceptibility to lupus: the biological basis of genetic risk found in B cell signaling pathways. J Leukoc Biol (2012 ) 92(3):577–91.

    Not in our library10.1189/jlb.0212095

  231. 231.

    Teruel M Alarcon-Riquelme ME. The genetic basis of systemic lupus erythematosus: what are the risk factors and what have we learned. J Autoimmun (2016 ) 74:161–75.

    Not in our library10.1016/j.jaut.2016.08.001

  232. 232.

    Ghodke-Puranik Y Niewold TB. Immunogenetics of systemic lupus erythematosus: a comprehensive review. J Autoimmun (2015 ) 64:125–36.

    Not in our library10.1016/j.jaut.2015.08.004

  233. 233.

    Zhou XJ Cheng FJ Qi YY Zhao MH Zhang H A replication study from Chinese supports association between lupus-risk allele in TNFSF4 and renal disorder. Biomed Res Int (2013 ) 2013:597921

    Not in our library10.1155/2013/597921

  234. 234.

    Manku H Langefeld CD Guerra SG Malik TH Alarcon-Riquelme M Anaya JM Trans-ancestral studies fine map the SLE-susceptibility locus TNFSF4. PLoS Genet (2013 ) 9(7):e1003554.

    Not in our library10.1371/journal.pgen.1003554

  235. 235.

    Lamagna C Hu Y DeFranco AL Lowell CA. B cell-specific loss of Lyn kinase leads to autoimmunity. J Immunol (2014 ) 192(3):919–28.

    Not in our library10.4049/jimmunol.1301979

  236. 236.

    Hua Z Gross AJ Lamagna C Ramos-Hernandez N Scapini P Ji M Requirement for MyD88 signaling in B cells and dendritic cells for germinal center anti-nuclear antibody production in Lyn-deficient mice. J Immunol (2014 ) 192(3):875–85.

    Not in our library10.4049/jimmunol.1300683

  237. 237.

    Simpfendorfer KR Olsson LM Manjarrez Orduno N Khalili H Simeone AM Katz MS The autoimmunity-associated BLK haplotype exhibits cis-regulatory effects on mRNA and protein expression that are prominently observed in B cells early in development. Hum Mol Genet (2012 ) 21(17):3918–25.

    Not in our library10.1093/hmg/dds220

  238. 238.

    Simpfendorfer KR Armstead BE Shih A Li W Curran M Manjarrez-Orduno N Autoimmune disease-associated haplotypes of BLK exhibit lowered thresholds for B cell activation and expansion of Ig class-switched B cells. Arthritis Rheumatol (2015 ) 67(11):2866–76.

    Not in our library10.1002/art.39301

  239. 239.

    Samuelson EM Laird RM Maue AC Rochford R Hayes SM. Blk haploin-sufficiency impairs the development, but enhances the functional responses, of MZ B cells. Immunol Cell Biol (2012 ) 90(6):620–9.

    Not in our library10.1038/icb.2011.76

  240. 240.

    Texido G Su IH Mecklenbrauker I Saijo K Malek SN Desiderio S The B-cell-specific Src-family kinase Blk is dispensable for B-cell development and activation. Mol Cell Biol (2000 ) 20(4):1227–33.

    Not in our library10.1128/mcb.20.4.1227-1233.2000

  241. 241.

    Kozyrev SV Abelson AK Wojcik J Zaghlool A Linga Reddy MV Sanchez E Functional variants in the B-cell gene BANK1 are associated with systemic lupus erythematosus. Nat Genet (2008 ) 40(2):211–6.

    Not in our library10.1038/ng.79

  242. 242.

    Yokoyama K Su Ih IH Tezuka T Yasuda T Mikoshiba K Tarakhovsky A BANK regulates BCR-induced calcium mobilization by promoting tyrosine phosphorylation of IP(3) receptor. EMBO J (2002 ) 21(1–2):83–92.

    Not in our library10.1093/emboj/21.1.83

  243. 243.

    Aiba Y Yamazaki T Okada T Gotoh K Sanjo H Ogata M BANK negatively regulates Akt activation and subsequent B cell responses. Immunity (2006 ) 24(3):259–68.

    Not in our library10.1016/j.immuni.2006.01.002

  244. 244.

    Rieck M Arechiga A Onengut-Gumuscu S Greenbaum C Concannon P Buckner JH. Genetic variation in PTPN22 corresponds to altered function of T and B lymphocytes. J Immunol (2007 ) 179(7):4704–10.

    Not in our library10.4049/jimmunol.179.7.4704

  245. 245.

    Hasegawa K Martin F Huang G Tumas D Diehl L Chan AC PEST domain-enriched tyrosine phosphatase (PEP) regulation of effector/memory T cells. Science (2004 ) 303(5658):685–9.

    Not in our library10.1126/science.1092138

  246. 246.

    Schickel JN Kuhny M Baldo A Bannock JM Massad C Wang H PTPN22 inhibition resets defective human central B cell tolerance. Sci Immunol (2016 ) 1(1):aaf7153

    Not in our library10.1126/sciimmunol.aaf7153

  247. 247.

    Vang T Congia M Macis MD Musumeci L Orru V Zavattari P Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant. Nat Genet (2005 ) 37(12):1317–9.

    Not in our library10.1038/ng1673

  248. 248.

    Graham RR Cotsapas C Davies L Hackett R Lessard CJ Leon JM Genetic variants near TNFAIP3 on 6q23 are associated with systemic lupus erythematosus. Nat Genet (2008 ) 40(9):1059–61.

    Not in our library10.1038/ng.200

  249. 249.

    Musone SL Taylor KE Lu TT Nititham J Ferreira RC Ortmann W Multiple polymorphisms in the TNFAIP3 region are independently associated with systemic lupus erythematosus. Nat Genet (2008 ) 40(9):1062–4.

    Not in our library10.1038/ng.202

  250. 250.

    Adrianto I Wen F Templeton A Wiley G King JB Lessard CJ Association of a functional variant downstream of TNFAIP3 with systemic lupus erythematosus. Nat Genet (2011 ) 43(3):253–8.

    Not in our library10.1038/ng.766

  251. 251.

    Tavares RM Turer EE Liu CL Advincula R Scapini P Rhee L The ubiquitin modifying enzyme A20 restricts B cell survival and prevents autoimmunity. Immunity (2010 ) 33(2):181–91.

    Not in our library10.1016/j.immuni.2010.07.017

  252. 252.

    Chu Y Vahl JC Kumar D Heger K Bertossi A Wojtowicz E B cells lacking the tumor suppressor TNFAIP3/A20 display impaired differentiation and hyperactivation and cause inflammation and autoimmunity in aged mice. Blood (2011 ) 117(7):2227–36.

    Not in our library10.1182/blood-2010-09-306019

  253. 253.

    Hovelmeyer N Reissig S Xuan NT Adams-Quack P Lukas D Nikolaev A A20 deficiency in B cells enhances B-cell proliferation and results in the development of autoantibodies. Eur J Immunol (2011 ) 41(3):595–601.

    Not in our library10.1002/eji.201041313

  254. 254.

    Adrianto I Wang S Wiley GB Lessard CJ Kelly JA Adler AJ Association of two independent functional risk haplotypes in TNIP1 with systemic lupus erythematosus. Arthritis Rheum (2012 ) 64(11):3695–705.

    Not in our library10.1002/art.34642

  255. 255.

    Nanda SK Venigalla RK Ordureau A Patterson-Kane JC Powell DW Toth R Polyubiquitin binding to ABIN1 is required to prevent autoimmunity. J Exp Med (2011 ) 208(6):1215–28.

    Not in our library10.1084/jem.20102177

  256. 256.

    Manjarrez-Orduno N Marasco E Chung SA Katz MS Kiridly JF Simpfendorfer KR CSK regulatory polymorphism is associated with systemic lupus erythematosus and influences B-cell signaling and activation. Nat Genet (2012 ) 44(11):1227–30.

    Not in our library10.1038/ng.2439

  257. 257.

    Floto RA Clatworthy MR Heilbronn KR Rosner DR MacAry PA Rankin A Loss of function of a lupus-associated FcgammaRIIb polymorphism through exclusion from lipid rafts. Nat Med (2005 ) 11(10):1056–8.

    Not in our library10.1038/nm1288

  258. 258.

    Blank MC Stefanescu RN Masuda E Marti F King PD Redecha PB Decreased transcription of the human FCGR2B gene mediated by the -343 G/C promoter polymorphism and association with systemic lupus erythematosus. Hum Genet (2005 ) 117(2–3):220–7.

    Not in our library10.1007/s00439-005-1302-3

  259. 259.

    Kono H Kyogoku C Suzuki T Tsuchiya N Honda H Yamamoto K FcgammaRIIB Ile232Thr transmembrane polymorphism associated with human systemic lupus erythematosus decreases affinity to lipid rafts and attenuates inhibitory effects on B cell receptor signaling. Hum Mol Genet (2005 ) 14(19):2881–92.

    Not in our library10.1093/hmg/ddi320

  260. 260.

    Tiller T Kofer J Kreschel C Busse CE Riebel S Wickert S Development of self-reactive germinal center B cells and plasma cells in autoimmune Fc gammaRIIB-deficient mice. J Exp Med (2010 ) 207(12):2767–78.

    Not in our library10.1084/jem.20100171

  261. 261.

    Takai T Ono M Hikida M Ohmori H Ravetch JV. Augmented humoral and anaphylactic responses in Fc gamma RII-deficient mice. Nature (1996 ) 379(6563):346–9.

    Not in our library10.1038/379346a0

  262. 262.

    Xiang Z Cutler AJ Brownlie RJ Fairfax K Lawlor KE Severinson E FcgammaRIIb controls bone marrow plasma cell persistence and apoptosis. Nat Immunol (2007 ) 8(4):419–29.

    Not in our library10.1038/ni1440

  263. 263.

    Niewold TB Kelly JA Flesch MH Espinoza LR Harley JB Crow MK. Association of the IRF5 risk haplotype with high serum interferon-alpha activity in systemic lupus erythematosus patients. Arthritis Rheum (2008 ) 58(8):2481–7.

    Not in our library10.1002/art.23613

  264. 264.

    Feng D Stone RC Eloranta ML Sangster-Guity N Nordmark G Sigurdsson S Genetic variants and disease-associated factors contribute to enhanced interferon regulatory factor 5 expression in blood cells of patients with systemic lupus erythematosus. Arthritis Rheum (2010 ) 62(2):562–73.

    Not in our library10.1002/art.27223

  265. 265.

    Purtha WE Swiecki M Colonna M Diamond MS Bhattacharya D. Spontaneous mutation of the Dock2 gene in Irf5-/- mice complicates interpretation of type I interferon production and antibody responses. Proc Natl Acad Sci U S A (2012 ) 109(15):E898–904.

    Not in our library10.1073/pnas.1118155109

  266. 266.

    Yasuda K Watkins AA Kochar GS Wilson GE Laskow B Richez C Interferon regulatory factor-5 deficiency ameliorates disease severity in the MRL/lpr mouse model of lupus in the absence of a mutation in DOCK2. PLoS One (2014 ) 9(7):e103478.

    Not in our library10.1371/journal.pone.0103478

  267. 267.

    Thackray LB Shrestha B Richner JM Miner JJ Pinto AK Lazear HM Interferon regulatory factor 5-dependent immune responses in the draining lymph node protect against West Nile virus infection. J Virol (2014 ) 88(19):11007–21.

    Not in our library10.1128/jvi.01545-14

  268. 268.

    Abelson AK Delgado-Vega AM Kozyrev SV Sanchez E Velazquez-Cruz R Eriksson N STAT4 associates with systemic lupus erythematosus through two independent effects that correlate with gene expression and act additively with IRF5 to increase risk. Ann Rheum Dis (2009 ) 68(11):1746–53.

    Not in our library10.1136/ard.2008.097642

  269. 269.

    Liang Y Pan HF Ye DQ. Therapeutic potential of STAT4 in autoimmunity. Expert Opin Ther Targets (2014 ) 18(8):945–60.

    Not in our library10.1517/14728222.2014.920325

  270. 270.

    Xu Z Duan B Croker BP Morel L. STAT4 deficiency reduces autoantibody production and glomerulonephritis in a mouse model of lupus. Clin Immunol (2006 ) 120(2):189–98.

    Not in our library10.1016/j.clim.2006.03.009

  271. 271.

    Muto A Ochiai K Kimura Y Itoh-Nakadai A Calame KL Ikebe D Bach2 represses plasma cell gene regulatory network in B cells to promote antibody class switch. EMBO J (2010 ) 29(23):4048–61.

    Not in our library10.1038/emboj.2010.257

  272. 272.

    Morris DL Sheng Y Zhang Y Wang YF Zhu Z Tombleson P Genome-wide association meta-analysis in Chinese and European individuals identifies ten new loci associated with systemic lupus erythematosus. Nat Genet (2016 ) 48(8):940–6.

    Not in our library10.1038/ng.3603

  273. 273.

    Hipp N Symington H Pastoret C Caron G Monvoisin C Tarte K IL-2 imprints human naive B cell fate towards plasma cell through ERK/ELK1-mediated BACH2 repression. Nat Commun (2017 ) 8(1):1443.

    Not in our library10.1038/s41467-017-01475-7

  274. 274.

    Kim SJ Gregersen PK Diamond B. Regulation of dendritic cell activation by microRNA let-7c and BLIMP1. J Clin Invest (2013 ) 123(2):823–33.

    Not in our library10.1172/jci64712

  275. 275.

    Kim SJ Schatzle S Ahmed SS Haap W Jang SH Gregersen PK Increased cathepsin S in Prdm1-/- dendritic cells alters the TFH cell repertoire and contributes to lupus. Nat Immunol (2017 ) 18(9):1016–24.

    Not in our library10.1038/ni.3793

  276. 276.
    Association of NCF2, IKZF1, IRF8, IFIH1, and TYK2 with Systemic Lupus Erythematosus · 2011
    No notice
  277. 277.

    Carotta S Willis SN Hasbold J Inouye M Pang SH Emslie D The transcription factors IRF8 and PU.1 negatively regulate plasma cell differentiation. J Exp Med (2014 ) 211(11):2169–81.

    Not in our library10.1084/jem.20140425

  278. 278.

    Lee CH Melchers M Wang H Torrey TA Slota R Qi CF Regulation of the germinal center gene program by interferon (IFN) regulatory factor 8/IFN consensus sequence-binding protein. J Exp Med (2006 ) 203(1):63–72.

    Not in our library10.1084/jem.20051450

  279. 279.
    Association of novel polymorphisms in TMEM39A gene with systemic lupus erythematosus in a Chinese Han population · 2017
    Not checked
  280. 280.

    Cortes M Georgopoulos K. Aiolos is required for the generation of high affinity bone marrow plasma cells responsible for long-term immunity. J Exp Med (2004 ) 199(2):209–19.

    Not in our library10.1084/jem.20031571

  281. 281.

    Wang JH Avitahl N Cariappa A Friedrich C Ikeda T Renold A Aiolos regulates B cell activation and maturation to effector state. Immunity (1998 ) 9(4):543–53.

    Not in our library10.1016/s1074-7613(00)80637-8

  282. 282.

    Russell L John S Cullen J Luo W Shlomchik MJ Garrett-Sinha LA. Requirement for transcription factor Ets1 in B cell tolerance to self-antigens. J Immunol (2015 ) 195(8):3574–83.

    Not in our library10.4049/jimmunol.1500776

  283. 283.

    John SA Clements JL Russell LM Garrett-Sinha LA. Ets-1 regulates plasma cell differentiation by interfering with the activity of the transcription factor Blimp-1. J Biol Chem (2008 ) 283(2):951–62.

    Not in our library10.1074/jbc.m705262200

  284. 284.

    Lu X Zoller EE Weirauch MT Wu Z Namjou B Williams AH Lupus risk variant increases pSTAT1 binding and decreases ETS1 expression. Am J Hum Genet (2015 ) 96(5):731–9.

    Not in our library10.1016/j.ajhg.2015.03.002

  285. 285.
    Genome-Wide Association Study in Asian Populations Identifies Variants in ETS1 and WDFY4 Associated with Systemic Lupus Erythematosus · 2010
    No notice
  286. 286.

    Ols ML Cullen JL Turqueti-Neves A Giles J Shlomchik MJ. Dendritic cells regulate extrafollicular autoreactive B cells via T cells expressing Fas and Fas ligand. Immunity (2016 ) 45(5):1052–65.

    Not in our library10.1016/j.immuni.2016.10.005

  287. 287.

    Wu J Metz C Xu X Abe R Gibson AW Edberg JC A novel polymorphic CAAT/enhancer-binding protein beta element in the FasL gene promoter alters Fas ligand expression: a candidate background gene in African American systemic lupus erythematosus patients. J Immunol (2003 ) 170(1):132–8.

    Not in our library10.4049/jimmunol.170.1.132

  288. 288.

    Shen N Fu Q Deng Y Qian X Zhao J Kaufman KM Sex-specific association of X-linked toll-like receptor 7 (TLR7) with male systemic lupus erythematosus. Proc Natl Acad Sci U S A (2010 ) 107(36):15838–43.

    Not in our library10.1073/pnas.1001337107

  289. 289.

    Soni C Wong EB Domeier PP Khan TN Satoh T Akira S B cell-intrinsic TLR7 signaling is essential for the development of spontaneous germinal centers. J Immunol (2014 ) 193(9):4400–14.

    Not in our library10.4049/jimmunol.1401720

  290. 290.

    Blasius AL Arnold CN Georgel P Rutschmann S Xia Y Lin P Slc15a4, AP-3, and Hermansky-Pudlak syndrome proteins are required for toll-like receptor signaling in plasmacytoid dendritic cells. Proc Natl Acad Sci U S A (2010 ) 107(46):19973–8.

    Not in our library10.1073/pnas.1014051107

  291. 291.

    Sasawatari S Okamura T Kasumi E Tanaka-Furuyama K Yanobu-Takanashi R Shirasawa S The solute carrier family 15A4 regulates TLR9 and NOD1 functions in the innate immune system and promotes colitis in mice. Gastroenterology (2011 ) 140(5):1513–25.

    Not in our library10.1053/j.gastro.2011.01.041

  292. 292.

    Kobayashi T Shimabukuro-Demoto S Yoshida-Sugitani R Furuyama-Tanaka K Karyu H Sugiura Y The histidine transporter SLC15A4 coordinates mTOR-dependent inflammatory responses and pathogenic antibody production. Immunity (2014 ) 41(3):375–88.

    Not in our library10.1016/j.immuni.2014.08.011

  293. 293.

    Baccala R Gonzalez-Quintial R Blasius AL Rimann I Ozato K Kono DH Essential requirement for IRF8 and SLC15A4 implicates plasmacytoid dendritic cells in the pathogenesis of lupus. Proc Natl Acad Sci U S A (2013 ) 110(8):2940–5.

    Not in our library10.1073/pnas.1222798110

Cited by papers we hold 7

Reads

Read by people on this page

None yet.

Checked or read by AI through naulon

None yet.

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.

Are you an author?

Is this your paper?

Claim it to add your note and be paid when agents cite it. Free.