Division of Hematology, Duke University Medical Center, Durham, North Carolina, USA.
Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
J Thromb Haemost. 2022 Nov;20(11):2656-2665. doi: 10.1111/jth.15856. Epub 2022 Sep 1.
Anti-platelet factor 4 (PF4)/heparin immune complexes that cause heparin-induced thrombocytopenia (HIT) activate complement via the classical pathway. Previous studies have shown that the alternative pathway of complement substantially amplifies the classical pathway of complement activation through the C3b feedback cycle.
These studies sought to examine the contributions of the alternative pathway to complement activation by HIT antibodies.
Using IgG monoclonal (KKO) and/or patient-derived HIT antibodies, we compared the effects of classical pathway (BBK32 and C1-esterase inhibitor [C1-INH]), alternative pathway (anti-factor B [fB] or factor D [fD] inhibitor) or combined classical and alternative pathway inhibition (soluble complement receptor 1 [sCR1]) in whole blood or plasma.
Classical pathway inhibitors BBK32 and C1-INH and the combined classical/alternative pathway inhibitor sCR1 prevented KKO/HIT immune complex-induced complement activation, including release of C3 and C5 activation products, binding of immune complexes to B cells, and neutrophil activation. The alternative pathway inhibitors fB and fD, however, did not affect complement activation by KKO/HIT immune complexes. Similarly, alternative pathway inhibition had no effect on complement activation by unrelated immune complexes consisting of anti-dinitrophenyl (DNP) antibody and the multivalent DNP--keyhole limpet hemocyanin antigen.
Collectively, these findings suggest the alternative pathway contributes little in support of complement activation by HIT immune complexes. Additional in vitro and in vivo studies are required to examine if this property is shared by most IgG-containing immune complexes or if predominance of the classic pathway is limited to immune complexes composed of multivalent antigens.
抗血小板因子 4（PF4）/肝素免疫复合物引起肝素诱导的血小板减少症（HIT），通过经典途径激活补体。先前的研究表明，补体替代途径通过 C3b 反馈循环显著放大经典途径补体激活。
这些研究旨在检查补体激活替代途径对 HIT 抗体的贡献。
使用 IgG 单克隆（KKO）和/或患者来源的 HIT 抗体，我们比较了经典途径（BBK32 和 C1-酯酶抑制剂[C1-INH]）、替代途径（抗因子 B[fB]或因子 D[fD]抑制剂）或经典和替代途径联合抑制（可溶性补体受体 1[sCR1]）在全血或血浆中的作用。
经典途径抑制剂 BBK32 和 C1-INH 以及经典/替代途径联合抑制剂 sCR1 可预防 KKO/HIT 免疫复合物诱导的补体激活，包括 C3 和 C5 激活产物的释放、免疫复合物与 B 细胞的结合以及中性粒细胞的激活。然而，替代途径抑制剂 fB 和 fD 并不影响 KKO/HIT 免疫复合物引起的补体激活。同样，替代途径抑制对与无关的免疫复合物（由抗二硝基苯（DNP）抗体和多价 DNP-贻贝血红蛋白抗原组成）的补体激活也没有影响。
总之，这些发现表明替代途径对 HIT 免疫复合物激活补体的支持作用不大。需要进行更多的体外和体内研究，以检查这种特性是否被大多数含有 IgG 的免疫复合物共享，或者经典途径的优势是否仅限于由多价抗原组成的免疫复合物。
