Becerra E, Scully M A, Leandro M J, Heelas E O, Westwood J-P, De La Torre I, Cambridge G
Department of Rheumatology, University College London, London, UK.
Clin Exp Immunol. 2015 Mar;179(3):414-25. doi: 10.1111/cei.12472.
Autoantibodies inhibiting the activity of the metalloproteinase, ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), underlie the pathogenesis of thrombotic thrombocytopenic purpura (TTP). Rituximab (RTX) combined with plasma-exchange (PEX) is an effective treatment in TTP. Patients can remain in remission for extended periods following PEX/RTX, and this is associated with continuing reduction in antibodies to ADAMTS13. Factors controlling B cell differentiation to autoantibody production, including stimulation through the B cell receptor and interactions with the B cell-activating factor (BAFF), may thus impact length of remission. In this cross-sectional study, we measured naive and memory B cell phenotypes [using CD19/immunoglobulin (Ig)D/CD27] following PEX/RTX treatment in TTP patients at B cell return (n=6) and in 12 patients in remission 10-68 months post-RTX. We also investigated relationships among serum BAFF, soluble CD23 (sCD23(-) a surrogate measure of acquiring B memory (CD27(+) ) phenotype) and BAFF receptor (BAFF-R) expression. At B cell return after PEX/RTX, naive B cells predominated and BAFF-R expression was reduced compared to healthy controls (P<0.001). In the remission group, despite numbers of CD19(+) B cells within normal limits in most patients, the percentage and absolute numbers of pre-switch and memory B cells remained low, with sCD23 levels at the lower end of the normal range. BAFF levels were correlated inversely with BAFF-R expression and time after therapy. In conclusion, the long-term effects of RTX therapy in patients with TTP included slow regeneration of memory B cell subsets and persistently reduced BAFF-R expression across all B cell subpopulations. This may reflect the delay in selection and differentiation of potentially autoreactive (ADAMTS13-specific) B cells, resulting in relatively long periods of low disease activity after therapy.
抑制金属蛋白酶ADAMTS13（含血小板反应蛋白基序的解聚素和金属蛋白酶13）活性的自身抗体是血栓性血小板减少性紫癜（TTP）发病机制的基础。利妥昔单抗（RTX）联合血浆置换（PEX）是治疗TTP的有效方法。患者在接受PEX/RTX治疗后可长期缓解，这与抗ADAMTS13抗体持续减少有关。因此，控制B细胞分化为自身抗体产生的因素，包括通过B细胞受体的刺激以及与B细胞激活因子（BAFF）的相互作用，可能会影响缓解期的长短。在这项横断面研究中，我们在TTP患者接受PEX/RTX治疗后B细胞恢复时（n = 6）以及12例RTX治疗后缓解10 - 68个月的患者中，测量了初始B细胞和记忆B细胞表型[使用CD19/免疫球蛋白（Ig）D/CD27]。我们还研究了血清BAFF、可溶性CD23（sCD23，获得B记忆（CD27 +）表型的替代指标）和BAFF受体（BAFF-R）表达之间的关系。在PEX/RTX后B细胞恢复时，初始B细胞占主导，与健康对照相比，BAFF-R表达降低（P<0.001）。在缓解组中，尽管大多数患者CD19 + B细胞数量在正常范围内，但转换前B细胞和记忆B细胞的百分比及绝对数量仍然较低，sCD23水平处于正常范围下限。BAFF水平与BAFF-R表达及治疗后时间呈负相关。总之，RTX治疗对TTP患者的长期影响包括记忆B细胞亚群再生缓慢以及所有B细胞亚群中BAFF-R表达持续降低。这可能反映了潜在自身反应性（ADAMTS-13特异性）B细胞选择和分化的延迟，导致治疗后疾病活动度较低的时期相对较长。
