Platelet-associated antibodies, cellular immunity and FCGR3a genotype influence the response to rituximab in immune thrombocytopenia
Platelet-associated antibodies, cellular immunity and FCGR3a genotype influence the response to rituximab in immune thrombocytopenia
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DOI：
10.1111/j.1365-2141.2012.09184.x
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发表时间：
2012-08-01
影响因子：
6.5
通讯作者：
Bussel, James B.
中科院分区：
文献类型：
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作者：
Cooper, Nichola;Stasi, Roberto;Bussel, James B.
利妥昔单抗广泛用于免疫性血小板减少症（ITP）等自身免疫性疾病，但其作用机制尚不清楚。本研究描述了利妥昔单抗对血小板相关抗体（PA-APAs）、B细胞和T细胞计数和克隆性（IGHV和TRG@基因重排）、FCGR3A (Fc？RIIIa)和FCGR2A (Fc？RIIa)多态性及其与抗cd40配体（CD40L）反应的相关性。反应者（6/8）比无反应者（2/10:P = 0.080.15）更频繁地下降PA-APA水平。2名应答者没有PA-APAs。两名PA-APAs下降的无反应患者的CD8水平非常高。一个无应答者有B细胞克隆，一个应答者和一个无应答者有T细胞克隆。15/16的患者对利妥昔单抗和antid40l有相同的反应。具有FCGR3A V/V多态性的患者对利妥昔单抗的反应更大（P = 0.03）。总之，应答者PA-APAs的下降证实了利妥昔单抗的体液作用。尽管PA-APA下降，但在CD8水平非常高的患者中没有反应表明T细胞介导的血小板/巨核细胞破坏的作用。对抗cd40l反应的一致性表明自身抗体产生细胞受T细胞控制。最后，FCGR多态性对应答的影响证实了FCGR介导的B细胞耗竭在自身免疫中的重要性。这对ITP的病理以及B细胞耗竭的免疫作用有一定的影响。
Rituximab is widely used in autoimmune diseases including immune thrombocytopenia (ITP), although the mechanism of effect remains unclear. This study describes the effects of rituximab on platelet-associated antibodies (PA-APAs), B and T cell counts and clonality ( IGHV and TRG@ gene rearrangements), FCGR3A (Fc?RIIIa) and FCGR2A (Fc?RIIa) polymorphisms and correlation to anti-CD40 ligand (CD40L) response. PA-APA levels fell more frequently in responders (6/8) than in non-responders (2/10: P = 0.080.15). Two responders had no PA-APAs. Two non-responders with a fall in PA-APAs had very high CD8 levels. One non-responder had a B cell clone, one responder and one non-responder had a T cell clone. 15/16 patients had the same responses to rituximab and antiCD40L. Patients with FCGR3A V/V polymorphisms were more likely to respond to rituximab (P = 0.03). In summary, the fall in PA-APAs in responders confirms the humoural effect of rituximab. Failure to respond in patients with very high CD8 levels, despite PA-APA fall indicates a role for T cell-mediated platelet/megakaryocyte destruction. Concordance of response to anti-CD40L suggests autoantibody-producing cells are under T cell control. Finally, the effect of FCGR polymorphisms on response confirms the importance of FCGR-mediated depletion of B cells in autoimmunity. This has implications on the pathology of ITP as well as the immunological effect of B cell depletion.