Valenzuela N M, Trinh K R, Mulder A, Morrison S L, Reed E F
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA.
Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, CA.
Am J Transplant. 2015 Jun;15(6):1502-18. doi: 10.1111/ajt.13174. Epub 2015 Feb 3.
It is currently unclear which donor specific HLA antibodies confer the highest risk of antibody-mediated rejection (AMR) and allograft loss. In this study, we hypothesized that two distinct features (HLA IgG subclass and Fcγ receptor [FcγR] polymorphisms) which vary from patient to patient, influence the process of monocyte trafficking to and macrophage accumulation in the allograft during AMR in an interrelated fashion. Here, we investigated the contribution of human IgG subclass and FcγR polymorphisms in monocyte recruitment in vitro by primary human aortic endothelium activated with chimeric anti-HLA I human IgG1 and IgG2. Both subclasses triggered monocyte adhesion to endothelial cells, via a two-step process. First, HLA I crosslinking by antibodies stimulated upregulation of P-selectin on endothelium irrespective of IgG subclass. P-selectin-induced monocyte adhesion was enhanced by secondary interactions of IgG with FcγRs, which was highly dependent upon subclass. IgG1 was more potent than IgG2 through differential engagement of FcγRs. Monocytes homozygous for FcγRIIa-H131 adhered more readily to HLA antibody-activated endothelium compared with FcγRIIa-R131 homozygous. Finally, direct modification of HLA I antibodies with immunomodulatory enzymes EndoS and IdeS dampened recruitment by eliminating antibody-FcγR binding, an approach that may have clinical utility in reducing AMR and other forms of antibody-induced inflammation.
目前尚不清楚哪些供体特异性HLA抗体导致抗体介导的排斥反应（AMR）和移植器官丢失的风险最高。在本研究中，我们假设两个因人而异的不同特征（HLA IgG亚类和Fcγ受体 [FcγR] 多态性）以相互关联的方式影响AMR期间单核细胞向移植器官的迁移过程以及巨噬细胞在移植器官中的积聚。在此，我们通过用嵌合抗HLA I人IgG1和IgG2激活的原代人主动脉内皮细胞，研究了人IgG亚类和FcγR多态性在体外单核细胞募集中的作用。两个亚类均通过两步过程触发单核细胞与内皮细胞的粘附。首先，抗体介导的HLA I交联刺激内皮细胞上P选择素的上调，而与IgG亚类无关。IgG与FcγR的二次相互作用增强了P选择素诱导的单核细胞粘附，这高度依赖于亚类。通过FcγR的不同结合，IgG1比IgG2更有效。与FcγRIIa-R131纯合子相比，FcγRIIa-H131纯合的单核细胞更容易粘附于HLA抗体激活的内皮细胞。最后，用免疫调节酶EndoS和IdeS对HLA I抗体进行直接修饰，通过消除抗体-FcγR结合来抑制募集，这种方法可能在减少AMR和其他形式的抗体诱导炎症方面具有临床应用价值。
