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Ann Neurol. 2012 Jul;72(1):53-64. doi: 10.1002/ana.23651. Epub 2012 Jul 17.

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

Author information

1
Departments of Neurology, University of California at San Francisco, USA.

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.

PMID:
22807325
PMCID:
PMC3405197
DOI:
10.1002/ana.23651
[Indexed for MEDLINE]
Free PMC Article
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