The endothelial deprotection hypothesis for lupus pathogenesis: the dual role of C1q as a mediator of clearance and regulator of endothelial permeability

Abstract

Systemic lupus erythematosus (SLE) is a heterogeneous multifactorial systemic autoimmune disease affecting several organs. SLE can start relatively early in life and results in impaired quality of life and shortened life expectancy because of a gradual disease progression leading to cardiovascular, renal and neoplastic disease. The basic mechanisms of the pathogenesis of the disease still remain to be clarified. It is clear that complement proteins play a key and complex role in the development of SLE. Complement component C1q has been known to be a fundamental component of lupus development, but most explanations focus on its role in apoptotic debris removal. Importantly, C1q was recently found to play a key role in the maintenance of vascular endothelial integrity. We suggest that apoptotic products, endothelial cells and extracellular matrix components, which display negatively charged moieties, compete for binding to molecules of the innate humoral immune response, like C1q. Genetic or acquired factors leading to an increased load of apoptotic cell debris and decrease or absence of C1q therefore interfere with the regulation of endothelial permeability and integrity. Furthermore, we suggest that lupus is the net result of an imbalance between the two functions of immune clearance and vascular endothelial integrity maintenance, an imbalance triggered and sustained by autoimmunity, which skews C1q consumption by IgG-mediated complement classical pathway activation on autoantigens. In this triangle of innate clearance, autoimmunity and endothelial integrity, C1q plays a central role. Hence, we interpret the pathogenesis of lupus by identifying three key components, namely innate immune clearance, autoimmunity and endothelial integrity and we establish a link between these components based on the protective role that innate clearance molecules play in endothelial renewal. By including the vasoprotective role of C1q in the interpretation of SLE development we attempt to provide novel explanations for the symptoms, organ damage, diagnostic and therapeutic difficulties of the disease.

C1q Deficiency and Neuropsychiatric Systemic Lupus Erythematosus

“…Furthermore, in the last years, C1q has been demonstrated to be of importance in vascular endothelial permeability and integrity. C1q and mannose-binding lectin have been reported in in vitro studies to help in the removal of atherogenic lipoproteins, which has been proposed as a link between C1q deficiency and cardiovascular disease in SLE, as seen in our patient (36, 37). …”

Endothelial Alterations in Systemic Lupus Erythematosus and Rheumatoid Arthritis: Potential Effect of Monocyte Interaction

“…SLE is a chronic systemic autoimmune disease, characterized by loss of immunological tolerance of B cells, with the subsequent autoantibody production against double-stranded DNA, nuclear proteins such as Smith (Sm) and phospholipids, among others [ 8 , 9 ]. These antibodies may directly bind to endothelial cells or are part of the circulating IC that can be deposited in the vessels, promoting inflammatory responses of innate immune cells and increasing endothelial permeability and leukocyte infiltration to the affected tissues [ 9 ].…”

“…SLE is a chronic systemic autoimmune disease, characterized by loss of immunological tolerance of B cells, with the subsequent autoantibody production against double-stranded DNA, nuclear proteins such as Smith (Sm) and phospholipids, among others [ 8 , 9 ]. These antibodies may directly bind to endothelial cells or are part of the circulating IC that can be deposited in the vessels, promoting inflammatory responses of innate immune cells and increasing endothelial permeability and leukocyte infiltration to the affected tissues [ 9 ]. In addition, the continuous exposure of patrolling monocytes of these patients to circulating autoantibodies and IC may also lead to chronic endothelial cell activation mediated by the interaction with monocytes, causing injuries of blood vessels and vasculitis [ 43 ].…”

Risk factors for progression of carotid intima-media thickness in patients with systemic lupus erythematosus: protocol for an observational cohort study in China

“…SLE may affect the integrity and repair mechanisms of endothelial cells through direct binding of antibodies to endothelial cells or deposition of circulating immune complexes. This then results in endothelial damage that promotes atherogenesis 6. Accelerated atherosclerosis in SLE may also be related to the presence of antiphospholipid antibodies, which increase the risk of thrombosis in SLE 7–9…”