Autoantibody profiling in systemic lupus erythematosus
Song-Chou Hsieh,1 Chia-Li Yu1,2
1Department of Internal Medicine, 2Institute of Molecular Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
Abstract: Systemic lupus erythematosus (SLE) is an archetype of systemic autoimmune disease characterized by the production of a broad spectrum of autoantibodies. More than 100 autoantibodies have been found in the sera of patients with SLE, including antibodies against nuclear, cytoplasmic, surface-membrane, and extracellular antigens. There has been considerable debate as to whether these antinuclear autoantibodies (ANAs) are merely biomarkers for disease or are responsible for organ/tissue damage in SLE. In recent years, sufficient evidence has supported the hypothesis that many ANAs, such as anti-double-stranded DNA (anti-dsDNA), antiribosomal P, anti-Sm, antiribonucleoprotein (anti-RNP), and even anti-Sjögren's syndrome (SS)-B/La antibodies not only act against specific nuclear antigens but also cross-react with different surface-expressed cognate molecules. The binding of autoantibodies to the cell surface leads to their penetration into the cell's interior to elicit cellular damage. There are at least four conceivable routes for ANAs to penetrate the cytoplasm: (1) nonspecific Fcγ receptor-mediated uptake, (2) cell-surface caveolae-mediated endocytosis, (3) electrostatic interactions between positively charged amino acids of the complementarity-determining regions of the antibody molecule and the negatively charged surface membrane, and (4) the binding of the autoantibody with its cross-reactive cell surface-expressed cognate molecule, and its subsequent endocytosis into the cytoplasm. In this review, we discuss in detail the immunopathogenic mechanisms of the commonly encountered ANAs, such as anti-dsDNA, antiribosomal P, and anti-SSB/La, that are associated with lupus pathogenesis. Additionally, the detrimental thromboembolism-inducing anticardiolipin antibodies in patients with SLE were found to not only damage vascular endothelial cells, red blood cells, and platelets but also suppress lymphocyte proliferation, neutrophil phagocytosis, glomerular mesangial cell growth, and brain damage through their nonspecific membranotropic effects. For future clinical applications, useful biomarkers in SLE sera should be identified to determine disease susceptibility, diagnosis, activity evaluation, and specific organ damage.
Keywords: systemic lupus erythematosus, pathogenic autoantibody, cross-reactivity, autoantibody penetration, lupus pathogenesis, neuropsychiatric SLE
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