Centre for Biological Sciences, University of Southampton, Southampton General Hospital, Southampton, United Kingdom.
Invest Ophthalmol Vis Sci. 2014 Jan 13;55(1):247-58. doi: 10.1167/iovs.13-11821.
Several lines of evidence suggest the involvement of antibodies and immune complex inflammation in AMD, a blinding disease with a strong inflammatory component. To examine this further, we developed a novel experimental mouse model of retinal inflammation and evaluated whether inflammation associated with immune complex formation was present in eyes of AMD donors.
A localized immune complex-mediated reaction was induced in the retina of wild-type (WT), Fc receptor γ chain-deficient (γ(-/-)), and C1q-deficient (C1q(-/-)) mice, and donor eyes were obtained after death from donors with early or wet AMD and from healthy control subjects. The presence of immune complexes, Fcγ receptors (FcγRs), and markers of macrophage/microglia activation was investigated by immunohistochemistry.
In WT and C1q(-/-) mice, immune complex deposition in the retina led to a robust inflammatory response with activation of microglia, recruitment of myeloid cells, and increased expression of FcγRI through FcγRIV and major histocompatibility complex class II. This response was not observed in γ(-/-) mice lacking activating FcγRs. We found that early AMD was associated with deposition of IgG, C1q, and membrane attack complex in the choriocapillaris and with increased numbers of CD45+ cells expressing FcγRIIa and FcγRIIb. Furthermore, FcγRIIa and FcγRIIb were observed in eyes of donors with wet AMD.
Our studies suggest that immune complexes may contribute to AMD pathogenesis through interaction of IgG with FcγRs and might inform about possible adverse effects associated with therapeutic antibodies.
有几条证据表明，在具有强烈炎症成分的致盲性疾病 AMD 中，抗体和免疫复合物炎症起作用。为了进一步研究这一点，我们开发了一种新型实验性小鼠视网膜炎症模型，并评估了 AMD 供体眼中是否存在与免疫复合物形成相关的炎症。
在野生型（WT）、Fc 受体 γ 链缺陷（γ(-/-)）和 C1q 缺陷（C1q(-/-)）小鼠的视网膜中诱导局部免疫复合物介导的反应，并在早期或湿性 AMD 供体死亡后获得供体眼和健康对照者的供体眼。通过免疫组织化学检测免疫复合物、Fcγ 受体（FcγRs）和巨噬细胞/小胶质细胞激活标志物的存在。
在 WT 和 C1q(-/-) 小鼠中，视网膜中免疫复合物的沉积导致强烈的炎症反应，小胶质细胞激活，髓样细胞募集，并通过 FcγRIV 和主要组织相容性复合物 II 增加 FcγRI 的表达。在缺乏激活 FcγRs 的 γ(-/-) 小鼠中未观察到这种反应。我们发现，早期 AMD 与脉络膜毛细血管中 IgG、C1q 和膜攻击复合物的沉积以及表达 FcγRIIa 和 FcγRIIb 的 CD45+细胞数量增加有关。此外，在湿性 AMD 供体的眼中观察到 FcγRIIa 和 FcγRIIb。
我们的研究表明，免疫复合物可能通过 IgG 与 FcγRs 的相互作用导致 AMD 发病机制，并可能提示与治疗性抗体相关的潜在不良反应。
