Aquaporin 4-specific T Cells in Neuromyelitis Optica Exhibit a Th17 Bias and Recognize Clostridium ABC Transporter

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Binding Cassette Transporters / genetics*
  • ATP-Binding Cassette Transporters / metabolism
  • Adult
  • Aquaporin 4 / genetics
  • Aquaporin 4 / metabolism*
  • Cell Proliferation
  • Clostridium / genetics*
  • Clostridium / immunology
  • Clostridium / metabolism
  • Epitopes, T-Lymphocyte / genetics*
  • Epitopes, T-Lymphocyte / immunology
  • Female
  • Humans
  • Male
  • Middle Aged
  • Neuromyelitis Optica / genetics
  • Neuromyelitis Optica / immunology*
  • Neuromyelitis Optica / metabolism
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism

Substances

  • ATP-Binding Cassette Transporters
  • Aquaporin 4
  • Epitopes, T-Lymphocyte