T cell deletional tolerance restricts AQP4 but not MOG CNS autoimmunity.
T cell deletional tolerance restricts AQP4 but not MOG CNS autoimmunity.
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DOI：
10.1073/pnas.2306572120
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发表时间：
2023-07-25
影响因子：
11.1
通讯作者：
Zamvil, Scott S.
中科院分区：
文献类型：
--
作者：
Sagan, Sharon A.;Moinfar, Zahra;Moseley, Carson E.;Dandekar, Ravi;Spencer, Collin M.;Verkman, Alan S.;Ottersen, Ole Petter;Sobel, Raymond A.;Sidney, John;Sette, Alessandro;Anderson, Mark S.;Steinman, Lawrence;Wilson, Michael R.;Sabatino, Joseph J., Jr.;Zamvil, Scott S.
水通道蛋白4（Aquaporin-4，AQP 4）是视神经肌萎缩症（neuromyelodioptica，NMO）的自身抗原，在中枢神经系统（CNS）和其他组织中均有表达。髓鞘少突胶质细胞糖蛋白（MOG）是MOG抗体相关疾病的靶点，仅限于CNS。野生型小鼠抵抗AQP 4诱导的自身免疫，但不抵抗MOG诱导的自身免疫。与MOG不同，WT小鼠对AQP 4的耐受性受到外周T细胞依赖性的致病性AQP 4特异性T细胞凋亡耗竭的保护。鉴定的致病性AQP 4表位以高亲和力结合MHC II，并与不同的水通道蛋白共享同源性。我们假设存在交叉耐受性，相反，AQP 4耐受性的中断可能允许T细胞对其他水通道蛋白的反应性。“自身抗原模拟”可能有助于与NMO相关的自身免疫性疾病的发展，包括干燥综合征，可能代表“自身免疫性水通道蛋白病”。水通道蛋白-4（AQP 4）特异性Th 17细胞被认为在视神经肌萎缩症（NMO）发病机制中具有核心作用。当建立NMO模型时，只有来自AQP 4缺陷（AQP 4 −/−）而不是野生型（WT）小鼠的AQP 4反应性Th 17细胞在受体WT小鼠中引起CNS自身免疫，表明严格调节的机制通常确保对AQP 4的耐受性。在这里，我们发现致病性AQP 4 T细胞表位结合MHC II具有非常高的亲和力。对T细胞受体（TCR）α/β使用的检查显示，来自AQP 4 −/−小鼠的AQP 4特异性T细胞采用了不同的TCR库，并表现出克隆扩增。选择性胸腺AQP 4缺陷不能完全恢复AQP 4反应性T细胞，表明胸腺阴性选择本身不能解释WT小鼠中AQP 4特异性耐受。事实上，AQP 4特异性Th 17细胞导致受体WT或B细胞缺陷小鼠瘫痪，随后完全恢复，这与供体T细胞凋亡有关。然而，供体AQP 4反应性T细胞存活，并在T和B细胞均缺乏的受体小鼠或仅缺乏T细胞的小鼠中引起持续性瘫痪。因此，AQP 4 CNS自身免疫受到AQP 4反应性T细胞的T细胞依赖性缺失的限制。相反，髓鞘少突胶质细胞糖蛋白（MOG）特异性T细胞存活，并导致WT小鼠持续的疾病。这些发现强调了外周T细胞对AQP 4缺失耐受的重要性，这可能与理解健康和NMO中AQP 4反应性T细胞的平衡有关。T细胞对在多种组织中表达的AQP 4的耐受性不同于对MOG的耐受性，MOG是一种表达受限的自身抗原。
Aquaporin-4 (AQP4), the autoantigen in neuromyelitis optica (NMO), is expressed in central nervous system (CNS) and other tissues. Myelin oligodendrocyte glycoprotein (MOG), the target in MOG antibody–associated disease, is restricted to the CNS. Wild-type mice resist AQP4-induced, but not MOG-induced, autoimmunity. Unlike MOG, tolerance to AQP4 in WT mice is protected by peripheral T cell–dependent apoptotic depletion of pathogenic AQP4-specific T cells. Pathogenic AQP4 epitopes identified bind MHC II with high affinity and share homology with distinct aquaporins. We postulate that there is cross-tolerance, and conversely, a break in AQP4 tolerance may permit T cell reactivity to other aquaporins. “Self-antigen mimicry” could contribute to development of autoimmune conditions associated with NMO, including Sjögren’s syndrome, possibly representing “autoimmune aquaporinopathy.” Aquaporin-4 (AQP4)-specific Th17 cells are thought to have a central role in neuromyelitis optica (NMO) pathogenesis. When modeling NMO, only AQP4-reactive Th17 cells from AQP4-deficient (AQP4−/−), but not wild-type (WT) mice, caused CNS autoimmunity in recipient WT mice, indicating that a tightly regulated mechanism normally ensures tolerance to AQP4. Here, we found that pathogenic AQP4 T cell epitopes bind MHC II with exceptionally high affinity. Examination of T cell receptor (TCR) α/β usage revealed that AQP4-specific T cells from AQP4−/− mice employed a distinct TCR repertoire and exhibited clonal expansion. Selective thymic AQP4 deficiency did not fully restore AQP4-reactive T cells, demonstrating that thymic negative selection alone did not account for AQP4-specific tolerance in WT mice. Indeed, AQP4-specific Th17 cells caused paralysis in recipient WT or B cell-deficient mice, which was followed by complete recovery that was associated with apoptosis of donor T cells. However, donor AQP4-reactive T cells survived and caused persistent paralysis in recipient mice deficient in both T and B cells or mice lacking T cells only. Thus, AQP4 CNS autoimmunity was limited by T cell–dependent deletion of AQP4-reactive T cells. In contrast, myelin oligodendrocyte glycoprotein (MOG)-specific T cells survived and caused sustained disease in WT mice. These findings underscore the importance of peripheral T cell deletional tolerance to AQP4, which may be relevant to understanding the balance of AQP4-reactive T cells in health and in NMO. T cell tolerance to AQP4, expressed in multiple tissues, is distinct from tolerance to MOG, an autoantigen restricted in its expression.
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影响因子：
11.2
作者：
Bennett, Jeffrey L.;Lam, Chiwah;Kalluri, Sudhakar Reddy;Saikali, Philippe;Bautista, Katherine;Dupree, Cecily;Glogowska, Magdalena;Case, David;Antel, Jack P.;Owens, Gregory P.;Gilden, Don;Nessler, Stefan;Stadelmann, Christine;Hemmer, Bernhard
通讯作者：
Hemmer, Bernhard
影响因子：
5.8
作者：
Jarius, Sven;Jacobi, Christian;Wildemann, Brigitte
通讯作者：
Wildemann, Brigitte
影响因子：
7.1
作者：
Jones MV;Huang H;Calabresi PA;Levy M
通讯作者：
Levy M
DOI：
10.1111/bpa.12099
发表时间：
2014-01
期刊：
Brain pathology (Zurich, Switzerland)
影响因子：
--
作者：
Lucchinetti CF;Guo Y;Popescu BF;Fujihara K;Itoyama Y;Misu T
通讯作者：
Misu T
DOI：
10.1073/pnas.1110655108
发表时间：
2011-10-25
影响因子：
11.1
作者：
Haj-Yasein, Nadia Nabil;Vindedal, Gry Fluge;Nagelhus, Erlend Arnulf
通讯作者：
Nagelhus, Erlend Arnulf