Correlation of Complement Activation in Aqueous and Vitreous in Patients With Proliferative Diabetic Retinopathy

Abstract

Purpose A growing body of evidence suggests complement dysregulation is present in the vitreous of patients with diabetic eye disease. Further translational study could be simplified if aqueous—as opposed to vitreous—were used to sample the intraocular complement environment. Here, we analyze aqueous samples and assess whether a correlation exists between aqueous and vitreous complement levels. Methods We collected aqueous, vitreous, and plasma samples from patients with and without proliferative diabetic retinopathy (PDR) undergoing vitrectomy. We assessed correlation between complement levels in aqueous and vitreous samples after using a normalizing ratio to correct for vascular leakage. Spearman correlation coefficients were used to assess the correlation between complement levels in the aqueous and vitreous. Results Aqueous samples were obtained from 17 cases with PDR and 28 controls. In all patients, aqueous Ba, C3a, and albumin levels were strongly correlated with vitreous levels (Spearman correlation coefficient of 0.8 for Ba and C3a and 0.7 for albumin; all P values < 0.0001). In PDR eyes only, aqueous and vitreous C3a levels were significantly correlated (Spearman correlation coefficient 0.7; P = 0.002), whereas in control eyes, both Ba and C3a (Spearman correlation coefficients of 0.7; P < 0.0001) were significantly correlated. Conclusions A strong correlation exists between aqueous and vitreous complement levels in diabetic eye disease. Translational Relevance The results establish that accurate sampling of the intraocular complement can be done by analyzing aqueous specimens, allowing for the rapid and safe measurement of experimental complement targets and treatment response.

Ocular Vascular Diseases: From Retinal Immune Privilege to Inflammation

“…Similarly, strong associations are found between CFH, CFB, and C3 variants and ROP occurrence in a clinical investigation, indicating a possible involvement of the alternative complement pathway in ROP [157]. In systemic investigation of DR patients, the level of C3, C3-activated fragment C3bα', and CFH are upregulated in the vitreous of PDR patients [170], and a strong correlation exists between aqueous and vitreous complement levels in diabetic eye disease [171].…”

Correlation of Aqueous, Vitreous, and Serum Protein Levels in Patients With Retinal Diseases

“…These studies varied in sample size, ranging from 11 to 98 patients, and encompassed diverse retinal disease categories, including macular hole, retinal detachment, (non-)proliferative diabetic retinopathy, and retinal vein occlusion. Among these 10 studies, eight generally supported a direct protein correlation between AH and VH, 17 – 19 , 21 , 37 – 40 whereas two studies did not provide robust evidence for such a correlation. 22 , 23 For a summary of the correlation coefficients and the significance of these studies, refer to Supplementary Table S3 .…”

Complement: Functions, location and implications

“…Here, we will focus on the common autoimmune diseases [148] such as systemic lupus erythematosus (SLE) [149,150], diabetes [151,152], rheumatoid arthritis (RA) [153] and multiple sclerosis (MS) [154]. These diseases are polygenic [155,156] with complement proteins playing critical roles in aggravating and sometimes inducing the disease pathology.…”

“…Dysfunction of the immune system due to abnormal responses to self‐antigens, is the underlying factor causing about 80 inflammatory diseases, the autoimmune diseases, for which the current therapies are often toxic and less than fully effective [10]. Here, we will focus on the common autoimmune diseases [148] such as systemic lupus erythematosus (SLE) [149, 150], diabetes [151, 152], rheumatoid arthritis (RA) [153] and multiple sclerosis (MS) [154]. These diseases are polygenic [155, 156] with complement proteins playing critical roles in aggravating and sometimes inducing the disease pathology.…”