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.
Highlights
A database search for the word “lupus” in the title of biomedical publications brings up 39,306 papers as of the writing of this manuscript
The missing piece: molecules of innate immunity contribute to endothelial integrity One important question that has been left largely unanswered so far is why and how exactly are the vascular wall and surrounding tissues damaged? How do the above named three main categories, impaired clearance, autoimmunity and vascular injury interact with each other? We propose that the answer lies in the protective role that innate clearance molecules play in endothelial renewal
The endothelial deprotection hypothesis assumes that the mechanisms of innate clearance and endothelial integrity share molecules like C1q and Natural IgM (nIgM), the two systems can interfere
Summary
A database search for the word “lupus” in the title of biomedical publications brings up 39,306 papers as of the writing of this manuscript. The fact that the absence of C1q and functional C1q deficiency leads to lupus development[86] suggests that initiation of the classical pathway activation is required for the removal of cellular debris and prevention of development of immune complex disease This balanced binding to EC, subendothelial collagen and cellular debris can be tipped basically by three main factors: decrease. Antibodies generated in the lymphoid organs will enter the circulation and immune complexes may or may not be formed, depending on the presence or absence of antigen Once these autoantibodies appear, they could sustain organ specific damage and disease course by binding to their targets thanks to increased permeability by general impairment in endothelial regeneration. I confirm that the funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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