Aquaporin 4‐specific T cells in neuromyelitis optica exhibit a Th17 bias and recognize Clostridium ABC transporter

Abstract

Objective: Aquaporin 4 (AQP4)‐specific autoantibodies in neuromyelitis optica (NMO) are immunoglobulin (Ig)G1, a T cell‐dependent Ig subclass, indicating that AQP4‐specific T cells participate in NMO pathogenesis. Our goal was to identify and characterize AQP4‐specific T cells in NMO patients and healthy controls (HC). Methods: Peripheral blood T cells from NMO patients and HC were examined for recognition of AQP4 and production of proinflammatory cytokines. Monocytes were evaluated for production of T cell‐polarizing cytokines and expression of costimulatory molecules. Results: T cells from NMO patients and HC proliferated to intact AQP4 or AQP4 peptides (p11–30, p21–40, p61–80, p131–150, p156–170, p211–230, and p261–280). T cells from NMO patients demonstrated greater proliferation to AQP4 than those from HC, and responded most vigorously to p61–80, a naturally processed immunodominant determinant of intact AQP4. T cells were CD4 + , and corresponding to association of NMO with human leukocyte antigen (HLA)‐DRB1*0301 and DRB3, AQP4 p61–80‐specific T cells were HLA‐DR restricted. The T‐cell epitope within AQP4 p61–80 was mapped to 63–76, which contains 10 residues with 90% homology to a sequence within Clostridium perfringens adenosine triphosphate‐binding cassette (ABC) transporter permease. T cells from NMO patients proliferated to this homologous bacterial sequence, and cross‐reactivity between it and self‐AQP4 was observed, supporting molecular mimicry. In NMO, AQP4 p61–80‐specific T cells exhibited Th17 polarization, and furthermore, monocytes produced more interleukin 6, a Th17‐polarizing cytokine, and expressed elevated CD40 and CD80 costimulatory molecules, suggesting innate immunologic dysfunction. Interpretation: AQP4‐specific T‐cell responses are amplified in NMO, exhibit a Th17 bias, and display cross‐reactivity to a protein of an indigenous intestinal bacterium, providing new perspectives for investigating NMO pathogenesis. ANN NEUROL 2012;

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