Human Aquaporin 4<sub>281-300</sub>Is the Immunodominant Linear Determinant in the Context of HLA-DRB1*03:01

Arellano, Benjamine; Hussain, Rehana Z.; Zacharias, Tresa; Yoon, Jane; David, Chella S.; Zein, Sharif Hussein Sharif; Steinman, Lawrence; Forsthuber, Thomas G.; Greenberg, Benjamin; Lambracht-Washington, Doris; Ritchie, Alanna M.; Bennett, Jeffrey L.; Stüve, Olaf

doi:10.1001/archneurol.2012.1300

Cited by 18 publications

(13 citation statements)

References 37 publications

(23 reference statements)

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“…Although the authors of that study suggested that AQP4 (61-80) is a naturally processed determinant of AQP4, it is unclear whether AQP4(61-80)-specific T cells contribute to the formation of anti-AQP4 antibodies. Furthermore, T-cell epitopes of AQP4 have been reported in rats [39], mice [23,40,41], and humanized DRB1*0301 transgenic mice [42], but none of them has been confirmed to be a naturally processed epitope since active immunization has never been reported to induce clinical signs of disease in any of these models. Besides AQP4(201-220), a further IA b -restricted epitope of AQP4, i.e.…”

Section: Discussionmentioning

confidence: 99%

Deletional tolerance prevents AQP4‐directed autoimmunity in mice

et al. 2017

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Neuromyelitis optica (NMO) is an autoimmune disorder of the central nervous system (CNS) mediated by antibodies to the water channel protein AQP4 expressed in astrocytes. The contribution of AQP4-specific T cells to the class switch recombination of pathogenic AQP4-specific antibodies and the inflammation of the blood–brain barrier is incompletely understood, as immunogenic naturally processed T-cell epitopes of AQP4 are unknown. By immunizing Aqp4−/− mice with full-length murine AQP4 protein followed by recall with overlapping peptides, we here identify AQP4(201-220) as the major immunogenic IAb-restricted epitope of AQP4. We show that WT mice do not harbor AQP4(201–220)-specific T-cell clones in their natural repertoire due to deletional tolerance. However, immunization with AQP4(201–220) of Rag1−/− mice reconstituted with the mature T-cell repertoire of Aqp4−/− mice elicits an encephalomyelitic syndrome. Similarly to the T-cell repertoire, the B-cell repertoire of WT mice is “purged” of AQP4-specific B cells, and robust serum responses to AQP4 are only mounted in Aqp4−/− mice. While AQP4 (201–220)-specific T cells alone induce encephalomyelitis, NMO-specific lesional patterns in the CNS and the retina only occur in the additional presence of anti-AQP4 antibodies. Thus, failure of deletional T-cell and B-cell tolerance against AQP4 is a prerequisite for clinically manifest NMO.

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Section: Discussionmentioning

confidence: 99%

Deletional tolerance prevents AQP4‐directed autoimmunity in mice

et al. 2017

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“…What is particularly pertinent to NMO, is the observation that the N-terminal domain where the main B-cell epitope resides, is in an area where a significant T-cell epitope is also found (Arellano et al, 2012). In NMO patients, this T-cell epitope resides at amino acids 281-300 adjacent to the most prominent B-cell linear epitope which resides at amino acids 252-275 (Kampylafka et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Reactivity to AQP4 epitopes in relapsing–remitting multiple sclerosis

Alexopoulos

Kampylafka

Chatzi

et al. 2013

Journal of Neuroimmunology

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Autoantibodies against the water channel AQP4, expressed predominately in central nervous system astrocytes, are markers and pathogenic factors in Devic's disease. In this study we examined whether Multiple Sclerosis (MS) patients recognize antigenic epitopes on AQP4 that may define distinct disease subsets. We screened sera from 45 patients with relapsing-remitting MS (RRMS) and 13 patients with primary progressive MS (PMS). 23 Neuromyelitis Optica (NMO) patients previously characterized were used as assay positive/negative controls. Sera from 23 patients with Systemic Lupus Erythematosus, 23 with primary Sjogren syndrome without neurological involvement and from 28 healthy individuals were also used as controls. NMO-positive sera exhibited reactivity against the intracellular epitope AQPaa252-275, confirming previous observations. All RRMS sera tested negative for anti-AQP4 antibodies using a cell-based assay, but surprisingly, 13% of them reacted with the epitope AQPaa252-275. PMS, healthy and disease controls showed no specific reactivity. Whether these antibodies define distinct MS subsets and have a pathogenic potential pointing to convergent pathogenetic mechanism with NMO, or are simply markers of astrocytic damage, remains to be determined.

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“…82 Other immunodominant peptides of AQP4 have been reported. 83 B Cells. The presence of a pathogenic autoantibody and the demonstrated efficacy of rituximab, albeit not in a definitive, controlled study, highlight the importance of B cells.…”

Section: Immunopathogenesis T Cells Aquaporin 4 Igg Is An Igg1 Antibmentioning

confidence: 99%

Neuromyelitis Spectrum Disorders

Weinshenker

Wingerchuk

2017

Mayo Clinic Proceedings

240

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The understanding of neuromyelitis optica spectrum disorder (NMOSD) has evolved substantially since its initial description over a century ago. The discovery in 2004 of a pathogenic autoantibody biomarker targeting aquaporin 4 IgG revolutionized diagnosis and therapeutic development. Although NMOSD resembles multiple sclerosis (MS), differences were identified and articulated in the late 1990s. New diagnostic criteria incorporating the biomarker as well as better understanding of the clinical and radiologic features of NMOSD now permit accurate diagnosis and differentiation from MS. Aquaporin 4 IgG-associated NMOSD is now regarded as an immune astrocytopathy with lytic and nonlytic effects on astrocytes. A second autoantibody, myelin oligodendrocyte glycoprotein IgG, which targets myelin rather than astrocytes, leads to an NMOSD syndrome with clinical and radiologic features that overlap but are distinct from those of aquaporin 4 IgG-associated NMOSD and MS. We review current understanding of the clinical aspects, pathophysiology, and treatment of NMOSD.

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Human Aquaporin 4_281-300Is the Immunodominant Linear Determinant in the Context of HLA-DRB1*03:01

Cited by 18 publications

References 37 publications

Deletional tolerance prevents AQP4‐directed autoimmunity in mice

Deletional tolerance prevents AQP4‐directed autoimmunity in mice

Reactivity to AQP4 epitopes in relapsing–remitting multiple sclerosis

Neuromyelitis Spectrum Disorders

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Human Aquaporin 4281-300Is the Immunodominant Linear Determinant in the Context of HLA-DRB1*03:01

Cited by 18 publications

References 37 publications

Deletional tolerance prevents AQP4‐directed autoimmunity in mice

Deletional tolerance prevents AQP4‐directed autoimmunity in mice

Reactivity to AQP4 epitopes in relapsing–remitting multiple sclerosis

Neuromyelitis Spectrum Disorders

Contact Info

Product

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Human Aquaporin 4_281-300Is the Immunodominant Linear Determinant in the Context of HLA-DRB1*03:01