Tolerance checkpoint bypass permits emergence of pathogenic T cells to neuromyelitis optica autoantigen aquaporin-4

Abstract

Aquaporin-4 (AQP4)-specific T cells are expanded in neuromyelitis optica (NMO) patients and exhibit Th17 polarization. However, their pathogenic role in CNS autoimmune inflammatory disease is unclear. Although multiple AQP4 T-cell epitopes have been identified in WT C57BL/6 mice, we observed that neither immunization with those determinants nor transfer of donor T cells targeting them caused CNS autoimmune disease in recipient mice. In contrast, robust proliferation was observed following immunization of AQP4-deficient (AQP4 , but not WT, mice induced paralysis in recipient WT and B-cell-deficient mice. AQP4-specific Th17-polarized cells induced more severe disease than Th1-polarized cells. Clinical signs were associated with opticospinal infiltrates of T cells and monocytes. Fluorescent-labeled donor T cells were detected in CNS lesions. Visual system involvement was evident by changes in optical coherence tomography. Fine mapping of AQP4 p201-220 and p135-153 epitopes identified peptides within p201-220 but not p135-153, which induced clinical disease in 40% of WT mice by direct immunization. Our results provide a foundation to evaluate how AQP4-specific T cells contribute to AQP4-targeted CNS autoimmunity (ATCA) and suggest that pathogenic AQP4-specific T-cell responses are normally restrained by central tolerance, which may be relevant to understanding development of AQP4-reactive T cells in NMO.is a rare, disabling, and sometimes fatal CNS autoimmune inflammatory demyelinating disease that causes attacks of paralysis and visual loss (1). Immunologic, epidemiologic, and pathologic evidence suggests T cells have an important role in the etiology of NMO (1-3). Pathogenic aquaporin-4 (AQP4)-specific antibodies in NMO serum are predominantly IgG1, a T-cell-dependent IgG subclass (4), and T-cell-mediated CNS inflammation permits CNS entry of those antibodies (5, 6). NMO susceptibility is associated with allelic MHC II genes, in particular HLA-DR17 (DRB1*0301) in certain populations (7). AQP4-specific T cells have been identified in patients (8, 9), and T cells specific for dominant AQP4 epitopes exhibit Th17 polarization (8). It is therefore important to understand factors that control development and regulate the expression of AQP4-specific T cells in NMO.One cannot feasibly test whether AQP4-reactive T cells participate directly in CNS inflammation in NMO patients. Animal models can permit in vivo evaluation of the role of AQP4-specific T cells in CNS autoimmunity. Although multiple AQP4 T-cell epitopes have been identified in WT mice and rats (10-13), attempts to create AQP4-targeted experimental NMO ("ENMO") with clinical manifestations of CNS autoimmune disease by either direct immunization of those determinants or adoptive transfer of T cells targeting them have been unsuccessful (11-13).Recently, it was observed that immunization of AQP4-deficient (AQP4 −/− ) mice with AQP4 peptide (p) 135-153 elicited T-cell proliferation and that those T cells induced mild clinical disease in 70% of recipient WT mice (14...

Bystander mechanism for complement-initiated early oligodendrocyte injury in neuromyelitis optica

“…The generally accepted pathogenesis mechanism in seropositive NMO involves AQP4-IgG entry into the central nervous system and binding to astrocyte AQP4, which causes primary complement- and cell-mediated astrocyte injury with secondary inflammation, blood-brain barrier disruption, and demyelination [17]. The involvement of AQP4-sensitized T cells has also been proposed based on CNS pathology following T cell administration [4, 27], though the relevance of non-humoral mechanisms in human NMO is unclear. Various alternative NMO pathogenesis mechanisms have been proposed [9, 10] but largely refuted [23, 25], including excitotoxic injury, AQP4-IgG inhibition of AQP4 water permeability, and AQP4-IgG-induced internalization of specific AQP4 isoforms.…”

Deletional tolerance prevents AQP4‐directed autoimmunity in mice

“…AQP4(135-153), has been reported in the repertoire of Aqp4 −/− mice [41,43]. However, since AQP4(135-153) was inferred as a relevant epitope by using an "in silico" approach predicting binding affinities of peptides to IA b [43], it is possible that AQP4(135-153) may not be a naturally processed epitope of AQP4. Here, we did not find a significant AQP4(135-153)-specific recall response upon immunization of Aqp4 −/− mice with full-length murine AQP4 protein.…”

Review: Recent advances in the understanding of the pathophysiology of neuromyelitis optica spectrum disorder

“…Inflammation in the CNS induced by myelin‐specific T cells facilitates the entry of pathogenic antibodies against AQP4 . Normally, the T‐cell immune response to AQP4 is regulated by stringent mechanisms of central and peripheral tolerance; however, certain AQP4‐specific T cells may enter the central nervous system to initiate disease development .…”