Complement Activation in the Vitreous of Patients With Proliferative Diabetic Retinopathy

Abstract

PURPOSE. A growing body of evidence points to complement dysregulation in diabetes. Early studies have indicated the presence of complement components inside the eye in patients with diabetic retinopathy, but these data have been confounded by leakage of proteins from the systemic circulation into the vitreous cavity. METHODS. We took samples of plasma and vitreous from patients with and without proliferative diabetic retinopathy (PDR) and measured levels of 16 complement components as well as albumin. We employed a normalized ratio using local and systemic complement and albumin levels to control for vascular leakage into the vitreous cavity. RESULTS. Before normalizing, we found significantly higher levels of 16 complement components we measured in PDR eyes compared to controls. After normalizing, levels of C4, factor B, and C5 were decreased compared to controls, while C3a and Ba levels were elevated compared to controls. We also found higher ratios of C3a/C3, C5a/C5, and Ba/factor B in PDR eyes compared to controls. CONCLUSIONS. We found evidence of local, intraocular activation of C3, C5, and factor B. The normalized data suggest involvement of the alternative complement pathway. By showing activation of specific complement components in PDR, this study identifies targets for diagnostic and therapeutic potential.

The Vitreous Ecosystem in Diabetic Retinopathy: Insight into the Patho-Mechanisms of Disease

“…The complement system consists of three major pathways: classic, alternative, and lectin [177]. Complement in the diabetic vitreous has been investigated in recent years [138,178,179]. The classic pathway has not been implied in vitreous studies in PDR eyes.…”

“…The classic pathway has not been implied in vitreous studies in PDR eyes. The alternative pathway, however, with elevated levels of the central complement C3 and specifically C3bα , C5a, and Ba, has been noted in the vitreous of PDR eyes [53,138,178,179]. Similar to the interpretation of elevated interleukins, the question of whether circulating complement may have influenced vitreous levels is important.…”

“…For example, lipopolysaccharide (LPS), through passage from the breakdown of the blood-eye barrier, may be involved in activating the complement system in PDR [26]. However, in one recent study, elevated levels of complement suggesting activation of the alternative pathway were confirmed with correction for vascular leakage in the vitreous (usage of the albumin ratio [53]) to exclude influences from the general circulation [179]. A fragment of C5, C5a, has been shown to be elevated in the PDR vitreous to levels 16 times control levels, without a concomitant increase in serum, also suggesting production from local tissues [178].…”

Changes in the blood complement system in the development of diabetic retinopathy in the elderly

“…ДР имеет сложную патофизиологию, которая охватывает все функции сетчатки, включая нейрональную активность и изменения в сосудистой системе сетчатки, приводящие к нейровоспалению, постепенной нейродегенерации и видимым сосудистым осложнениям [2, 3]. Нарушения в иммунной регуляции запускают каскад воспалительных реакций, изменяющих иммунные защитные механизмы, включая популяцию микроглии и систему комплемента [4][5][6][7]. Несмотря на важную роль системы комплемента в системном воспалительном ответе и нарушении регуляции при сахарном диабете 2-го типа отдельные компоненты системы комплемента остаются недостаточно изученными как на уровне организма, так и на местном уровне [6,8,9].…”

“…Однако повышение уровня данного фактора может быть механизмом обратной связи для поддержания уровня С 3 ba -компоненты системы комплемента [14]. В других исследованиях [4] у пациентов 54 лет с ДР в сыворотке крови выявлены высокие уровни С 2 -компоненты, фактора Д и С 5 -компоненты системы комплемента, имеющие статистически значимые различия по сравнению с содержанием в стекловидном теле. Так, уровень С 2 -компоненты в сыворотке крови составил 8419 нг/мл, тогда как в стекловидном теле -2502 нг/мл, фактора Д 2779 нг/мл и 388 нг/мг соответственно, С 5 -компоненты системы комплемента 46,98 нг/мл и 41,05 нг/мл соответственно.…”