B-cell activation influences T-cell polarization and outcome of anti-CD20 B-cell depletion in central nervous system autoimmunity.
B-cell activation influences T-cell polarization and outcome of anti-CD20 B-cell depletion in central nervous system autoimmunity.
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DOI：
10.1002/ana.22081
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发表时间：
2010-09
影响因子：
11.2
通讯作者：
Zamvil, Scott S.
中科院分区：
文献类型：
--
作者：
Weber, Martin S.;Prod'homme, Thomas;Patarroyo, Juan C.;Molnarfi, Nicolas;Karnezis, Tara;Lehmann-Horn, Klaus;Danilenko, Dimitry M.;Eastham-Anderson, Jeffrey;Slavin, Anthony J.;Linington, Christopher;Bernard, Claude C. A.;Martin, Flavius;Zamvil, Scott S.
临床研究表明，抗CD20B细胞去除治疗多发性硬化可能是一种有效的治疗方法。我们用两种实验性自身免疫性脑脊髓炎(EAE)模型研究了其免疫调节机制。小鼠EAE由重组髓鞘少突胶质细胞糖蛋白(RMOG)或MOG多肽(P)35-55诱导，前者被认为是B细胞致病因素，后者不需要B细胞。在rMOG诱导的EAE中，B细胞被激活，并作为抗原提呈细胞(APC)促进促炎性MOG特异性Th1和Th17细胞的分化。B细胞耗尽可预防或逆转rMOG诱导的EAE，这与CNS炎症减轻、脑膜B细胞消除以及MOG特异性Th1和Th17细胞减少有关。相反，在MOGp35-55诱导的EAE中，B细胞没有激活或有效地极化促炎性MOG特异性T细胞，类似于幼稚的B细胞。在这个EAE环境中，抗CD20治疗加重了EAE，但不阻碍Th1或Th17细胞的发展。不管使用哪种EAE模型，B细胞耗尽降低了调节性T细胞的频率，并增加了剩余的APC促进脑源性T细胞发育的能力。我们的研究强调了B细胞在中枢神经系统自身免疫性疾病的发病机制和调控中的独特作用。去除抗原激活的B细胞的临床益处可能主要与消除促炎B细胞的APC功能有关。然而，在某些临床环境中，消除参与调节T细胞和其他APC的未激活的B细胞可能是不可取的。
Clinical studies indicate that anti-CD20 B cell depletion may be an effective multiple sclerosis therapy. We investigated mechanisms of its immune modulation using two paradigms of experimental autoimmune encephalomyelitis (EAE). Murine EAE was induced by either recombinant myelin oligodendrocyte glycoprotein (rMOG), a model in which B cells are considered to contribute pathogenically, or MOG peptide (p)35–55, a model that does not require B cells. In EAE induced by rMOG, B cells became activated and, when serving as antigen presenting cells (APC), promoted differentiation of proinflammatory MOG-specific Th1 and Th17 cells. B cell depletion prevented or reversed established rMOG-induced EAE, which was associated with less CNS inflammation, elimination of meningeal B cells, and reduction of MOG-specific Th1 and Th17 cells. In contrast, in EAE induced by MOG p35–55, B cells did not become activated or efficiently polarize proinflammatory MOG-specific T cells, similar to naïve B cells. In this EAE setting, anti-CD20 treatment exacerbated EAE, and did not impede development of Th1 or Th17 cells. Irrespective of the EAE model used, B cell depletion reduced the frequency of regulatory T cells, and increased the capacity of remaining APC to promote development of encephalitogenic T cells. Our study highlights distinct roles for B cells in pathogenesis and regulation of CNS autoimmune disease. Clinical benefit from depletion of antigen-activated B cells may relate primarily to abrogation of proinflammatory B cell APC function. However, in certain clinical settings, elimination of unactivated B cells, which participate in regulation of T cells and other APC, may be undesirable.
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影响因子：
4.4
作者：
CHEN, JZ;TROUNSTINE, M;HUSZAR, D
通讯作者：
HUSZAR, D
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：
11.2
作者：
Hawker, Kathleen;O'Connor, Paul;Smith, Craig H.
通讯作者：
Smith, Craig H.
影响因子：
15.9
作者：
Hu, Chang-Yun;Rodriguez-Pinto, Daniel;Wen, Li
通讯作者：
Wen, Li
影响因子：
158.5
作者：
Edwards, JCW;Szczepanski, L;Shaw, T
通讯作者：
Shaw, T