Altered BCR and TLR signals promote enhanced positive selection of autoreactive transitional B cells in Wiskott-Aldrich syndrome.
Altered BCR and TLR signals promote enhanced positive selection of autoreactive transitional B cells in Wiskott-Aldrich syndrome.
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DOI：
10.1084/jem.20150585
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发表时间：
2015-09-21
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影响因子：
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通讯作者：
Rawlings DJ
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作者：
Kolhatkar NS;Brahmandam A;Thouvenel CD;Becker-Herman S;Jacobs HM;Schwartz MA;Allenspach EJ;Khim S;Panigrahi AK;Luning Prak ET;Thrasher AJ;Notarangelo LD;Candotti F;Torgerson TR;Sanz I;Rawlings DJ
Kolhatkar等人报道，改变的BCR和TLR信号传导协调增加了表达低亲和力自身反应性BCR的过渡性B细胞的阳性选择，导致其在幼稚B细胞区室中富集。这些发现对于理解Wiskott-Aldrich综合征患者和其他自身免疫易感个体中促进B细胞选择改变的事件具有重要意义。Wiskott-Aldrich综合征（WAS）是一种X-连锁免疫缺陷疾病，常与全身性自身免疫相关，包括自身抗体介导的血细胞减少症。WAS蛋白（WASp）缺陷型B细胞增加了B细胞受体（BCR）和Toll样受体（TLR）信号传导，表明这些途径可能影响成熟、幼稚BCR库的建立。为了直接研究这种可能性，我们评估了WASP缺陷小鼠和WAS受试者（n = 12）中的幼稚B细胞特异性和组成。BCR库的高通量测序和单细胞克隆分析显示，在小鼠边缘区和人幼稚B细胞中，重链的使用和低亲和力自身反应特异性的富集发生了改变。尽管包括缺失、无反应性和受体编辑在内的负选择机制相对不受干扰，但WASP缺陷型过渡型B细胞在体内表现出由抗原和Myd 88依赖性信号介导的增殖增强。最后，使用BCR测序和细胞表面分析与单克隆抗体识别固有的自身反应性重链，我们显示富集在自身反应性细胞，特别是在过渡到幼稚成熟B细胞阶段的WAS受试者。我们的综合数据支持这样一种模型，其中WAS和可能的其他自身免疫性疾病中B细胞内在、BCR和TLR信号的适度改变足以通过自身反应性过渡B细胞的阳性选择来改变B细胞耐受性。
Kolhatkar et al. report that altered BCR and TLR signaling orchestrates increased positive selection of transitional B cells expressing low-affinity self-reactive BCRs, leading to their enrichment within the naive B cell compartment. These findings have important implications to understand events that promote altered B cell selection in both Wiskott-Aldrich syndrome patients and in other autoimmune-prone individuals. Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency disorder frequently associated with systemic autoimmunity, including autoantibody-mediated cytopenias. WAS protein (WASp)–deficient B cells have increased B cell receptor (BCR) and Toll-like receptor (TLR) signaling, suggesting that these pathways might impact establishment of the mature, naive BCR repertoire. To directly investigate this possibility, we evaluated naive B cell specificity and composition in WASp-deficient mice and WAS subjects (n = 12). High-throughput sequencing and single-cell cloning analysis of the BCR repertoire revealed altered heavy chain usage and enrichment for low-affinity self-reactive specificities in murine marginal zone and human naive B cells. Although negative selection mechanisms including deletion, anergy, and receptor editing were relatively unperturbed, WASp-deficient transitional B cells showed enhanced proliferation in vivo mediated by antigen- and Myd88-dependent signals. Finally, using both BCR sequencing and cell surface analysis with a monoclonal antibody recognizing an intrinsically autoreactive heavy chain, we show enrichment in self-reactive cells specifically at the transitional to naive mature B cell stage in WAS subjects. Our combined data support a model wherein modest alterations in B cell–intrinsic, BCR, and TLR signals in WAS, and likely other autoimmune disorders, are sufficient to alter B cell tolerance via positive selection of self-reactive transitional B cells.