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BACKGROUND

Dysregulation of the complement system is involved in development of age-related macular degeneration (AMD). The complement cascade is regulated by membrane bound complement regulatory proteins (Cregs) on mononuclear leukocytes among others. This study aims to investigate systemic complement proteins and Cregs in AMD stages and their association with treatment response in neovascular AMD (nAMD).

METHODS

In this clinical prospective study, treatment-naïve patients with nAMD, intermediate AMD (iAMD) and healthy controls were recruited and systemic complement proteins C3, C3a and C5a were investigated with electrochemiluminescence immunoassays, and Creg expression (CD35, CD46 and CD59) on T cells (CD4 + and CD8+) and monocytes (classical, intermediate and non-classical) investigated with flow cytometry. Treatment response in nAMD patients was evaluated after loading dose and after one year, and categorized as good, partial or poor. Complement proteins and Creg expression levels were compared between healthy controls, iAMD and nAMD, as well as between good, partial and poor nAMD treatment response groups. Polymorphisms in the CFH and ARMS2 genes were analyzed and compared to complement proteins and Creg expression levels in nAMD patients.

RESULTS

One hundred patients with nAMD, 34 patients with iAMD and 61 healthy controls were included. 94 nAMD patients completed the 1-year follow-up. Distribution of treatment response in nAMD was 61 (65%) good, 26 (28%) partial, and 7 (7%) poor responders. The distribution of 1-year treatment response was 50 (53%) good, 33 (36%) partial, and 11 (11%) poor responders. The concentrations of systemic C3, C3a, and the C3a/C3-ratio were significantly increased in patients with nAMD compared to healthy controls (P < 0.001, P = 0.002, and P = 0.035, respectively). Systemic C3 was also increased in iAMD compared to healthy controls (P = 0.031). The proportion of CD46 + CD4 + T cells and CD59 + intermediate monocytes were significantly decreased in patients with nAMD compared to healthy controls (P = 0.018 and P = 0.042, respectively). The post-loading dose partial treatment response group had significantly lower concentrations of C3a and C5a compared to the good response group (P = 0.005 and P = 0.042, respectively). The proportion of CD35 + monocytes was significantly lower in the 1-year partial response group compared to the 1-year good response group (P = 0.039). High-risk CFH genotypes in nAMD patients was associated with increased C3a, C3a/C3-ratio, and expression levels of CD35 + CD8 + T cells and CD46 + classical monocytes, while expression level of CD46 + non-classical monocytes was decreased.

CONCLUSION

Elevated concentrations of systemic complement proteins were found in patients with iAMD and nAMD. Decreased Creg expression levels were found in patients with nAMD. Partially responding nAMD patients had a dysregulated complement system and Cregs compared to good responders.

BACKGROUND

METHODS

RESULTS

CONCLUSION

背景

补体系统的失调与年龄相关性黄斑变性（AMD）的发展有关。补体级联反应受到单核白细胞上的膜结合补体调节蛋白（Cregs）等的调节。本研究旨在探讨 AMD 各期系统性补体蛋白和 Cregs 及其与新生血管性 AMD（nAMD）治疗反应的关系。

方法

本临床前瞻性研究招募了未经治疗的 nAMD、中间型 AMD（iAMD）和健康对照者，用电化学发光免疫分析法检测系统性补体蛋白 C3、C3a 和 C5a，用流式细胞术检测 T 细胞（CD4+和 CD8+）和单核细胞（经典型、中间型和非经典型）上的 Creg 表达（CD35、CD46 和 CD59）。nAMD 患者在负荷剂量后和一年后进行治疗反应评估，并分为好、部分和差。将健康对照组、iAMD 和 nAMD 之间，以及 nAMD 良好、部分和差治疗反应组之间的补体蛋白和 Creg 表达水平进行比较。分析 CFH 和 ARMS2 基因的多态性，并与 nAMD 患者的补体蛋白和 Creg 表达水平进行比较。

结果

共纳入 100 例 nAMD 患者、34 例 iAMD 患者和 61 例健康对照者。94 例 nAMD 患者完成了 1 年随访。nAMD 的治疗反应分布为 61 例（65%）为好，26 例（28%）为部分，7 例（7%）为差。1 年治疗反应的分布为 50 例（53%）为好，33 例（36%）为部分，11 例（11%）为差。与健康对照组相比，nAMD 患者的系统性 C3、C3a 和 C3a/C3-比值明显升高（P<0.001、P=0.002 和 P=0.035）。与健康对照组相比，iAMD 患者的系统性 C3 也升高（P=0.031）。与健康对照组相比，nAMD 患者的 CD46+CD4+T 细胞和 CD59+中间型单核细胞比例明显降低（P=0.018 和 P=0.042）。与良好反应组相比，部分负荷剂量治疗反应组的 C3a 和 C5a 浓度明显降低（P=0.005 和 P=0.042）。与 1 年良好反应组相比，1 年部分反应组的 CD35+单核细胞比例明显降低（P=0.039）。nAMD 患者的高危 CFH 基因型与 C3a、C3a/C3-比值升高以及 CD35+CD8+T 细胞和 CD46+经典单核细胞的 Creg 表达水平升高有关，而 CD46+非经典单核细胞的表达水平降低。