Antibody-Mediated Coengagement of FcγRIIb and B Cell Receptor Complex Suppresses Humoral Immunity in Systemic Lupus Erythematosus
Antibody-Mediated Coengagement of FcγRIIb and B Cell Receptor Complex Suppresses Humoral Immunity in Systemic Lupus Erythematosus
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DOI：
10.4049/jimmunol.1003412
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发表时间：
2011-04-01
影响因子：
4.4
通讯作者：
Szymkowski, David E.
中科院分区：
文献类型：
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作者：
Horton, Holly M.;Chu, Seung Y.;Szymkowski, David E.
低亲和力Ab受体Fc γ RIIb参与下调B细胞活化，其功能障碍与小鼠和人的自身免疫有关。我们设计了一种抗人CD19抗体的Fc结构域，以高亲和力结合Fc gamma RIIb，促进Fc gamma RIIb与BCR复合物的共结合。该抗体（XmAb5871）刺激Fc γ RIIb的ITIM磷酸化，抑制bcr诱导的健康志愿者和系统性红斑狼疮（SLE）患者B细胞的钙动员、增殖和共刺激分子表达，以及LPS、IL-4或BAFF诱导的B细胞增殖。在SLE或健康人PBMC移植的SCID小鼠中，XmAb5871抑制了对破伤风类毒素的体液免疫，降低了血清IgM、IgG和IgE水平。XmAb5871治疗也增加了移植了来自独特SLE患者的PBMC的小鼠的存活率。与抗cd20抗体不同，Fc γ RIIb和BCR复合物的协同作用不会促进人PBMC培养物或小鼠B细胞的消耗。因此，活化B细胞中Fc γ RIIb抑制通路的扩增可能代表了一种针对SLE和其他自身免疫性疾病的新型B细胞靶向免疫抑制治疗方法，该方法应避免与B细胞耗竭相关的并发症。免疫学杂志，2011,18(6):423 - 433。
Engagement of the low-affinity Ab receptor Fc gamma RIIb downregulates B cell activation, and its dysfunction is associated with autoimmunity in mice and humans. We engineered the Fc domain of an anti-human CD19 Ab to bind Fc gamma RIIb with high affinity, promoting the coengagement of Fc gamma RIIb with the BCR complex. This Ab (XmAb5871) stimulated phosphorylation of the ITIM of Fc gamma RIIb and suppressed BCR-induced calcium mobilization, proliferation, and costimulatory molecule expression of human B cells from healthy volunteers and systemic lupus erythematosus (SLE) patients, as well as B cell proliferation induced by LPS, IL-4, or BAFF. XmAb5871 suppressed humoral immunity against tetanus toxoid and reduced serum IgM, IgG, and IgE levels in SCID mice engrafted with SLE or healthy human PBMC. XmAb5871 treatment also increased survival of mice engrafted with PBMC from a unique SLE patient. Unlike anti-CD20 Ab, coengagement of Fc gamma RIIb and BCR complex did not promote B cell depletion in human PBMC cultures or in mice. Thus, amplification of the Fc gamma RIIb inhibitory pathway in activated B cells may represent a novel B cell-targeted immunosuppressive therapeutic approach for SLE and other autoimmune diseases that should avoid the complications associated with B cell depletion. The Journal of Immunology, 2011, 186: 4223-4233.