Objective: Aquaporin-4 (AQP4)-specific autoantibodies in neuromyelitis optica (NMO) are IgG1, a T cell-dependent Ig subclass, indicating AQP4-specific T cells participate in NMO pathogenesis. The investigators’ goal was to identify and characterize AQP4-specific T cells in NMO patients and healthy controls (HC).
Methods: Peripheral blood T cells from NMOers 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 NMOers and HC proliferated to intact AQP4 or AQP4 peptides. T cells from NMOers demonstrated greater proliferation to AQP4 than HC, and responded most vigorously to peptide residues 61-80 (p61-80), a naturally processed (is formed by the natural breakdown on the protein) immunodominant determinant of intact AQP4. T cells were CD4+, and corresponding to association of NMO with 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 ten residues with 90% homology to a sequence within Clostridium perfringens ABC transporter permease. T cells from NMOers 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 IL-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 bacteria, providing new perspectives for investigating NMO pathogenesis.
NMO is an MS-like disease that is associated with immune responses to a water channel that is predominantly located in astrocytes, an important cell in the brain. This study suggests that NMO could result from a cross-reactive immune response to gut bacteria. This would suggest that a course of anti-biotics could potentially influence NMO. Likewise it has been suggested previously that responses to EBV could cross-react with myelin responses in MS.”