Epitopes described in "Aquaporin 4-specific T cells in neuromyelitis optica exhibit a Th17 bias and recognize Clostridium ABC transporter."

Article Authors:Michel Varrin-Doyer; Collin M Spencer; Ulf Schulze-Topphoff; Patricia A Nelson; Robert M Stroud; Bruce A C Cree; Scott S Zamvil
Article Title:Aquaporin 4-specific T cells in neuromyelitis optica exhibit a Th17 bias and recognize Clostridium ABC transporter.
Reference Detail
Reference ID:1024943
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.
Affiliations:Departments of Neurology, University of California at San Francisco, USA.
Reference Type:Literature
PubMed ID:22807325
Journal:Ann Neurol
Journal Volume:72
Article Pages:53-64
Journal ISSN:0364-5134
Article Chemical List:Aquaporin 4;Epitopes, T-Lymphocyte
Article MeSH List:ATP-Binding Cassette Transporters(genetics; metabolism); Adult; Aquaporin 4(genetics; metabolism); Cell Proliferation; Clostridium(genetics; immunology; metabolism); Epitopes, T-Lymphocyte(genetics; immunology); Female; Humans; Male; Middle Aged; Neuromyelitis Optica(genetics; immunology; metabolism); T-Lymphocytes(immunology; metabolism)
Curation Last Updated:2015-06-05 03:36:52