Nucleosomes in the pathogenesis of systemic lupus erythematosus

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The apoptotic cell: a source of lupus antigens

Human and murine SLE are characterized by the appearance in the blood of an array of autoantibodies that are directed against nuclear components. Frequently-targeted antigens include nucleosomes (the elementary unit of chromatin), splicing ribonucleoproteins, phospholipids, and the ribonucleoproteins, Ro/SS-A and La/SS-B. Why and how antigens that share so little in common in terms of structure and subcellular localization often appear in clusters in the circulation of SLE patients or lupus

Apoptosis in systemic lupus erythematosus: too little or too much?

Apoptosis is the process of programmed cell death that leads to the redistribution and breakdown of intracellular structures, including the nucleus. During apoptosis, chromatin is cleaved by specific DNAses and the nucleosome, the fundamental unit of chromatin that consists of an octamer of two copies each of histones H2A, H2B, H3, and H4, around which is wrapped a stretch of helical DNA that is146 base pairs in length (Fig. 1), is released. Thus, the nucleosome contains structures (DNA and

Systemic lupus erythematosus: a defect in clearance of apoptotic cells?

In addition to increased apoptosis, abnormalities in the clearance of apoptotic cells may contribute to an important source of possibly immunogenic antigens in SLE. In physiologic situations, release of intracellular components in the extracellular milieu is prevented efficiently by phagocytosis of apoptotic cells by macrophages [33]. There were reports that macrophages from patients who had SLE had defects in the phagocytosis of apoptotic cells, although this defect was not characterized at

Modified autoantigens: a source of immunogenic autoantigens?

During apoptosis, many nuclear constituents redistribute and cluster in cell membrane blebs and also are subjected to posttranslational modifications that are believed to alter their immunogenicity. A current hypothesis in SLE etiology is that apoptosis/apoptotic cell clearance defects may lead to the availability of modified (cryptic) antigens for which T and B cells have not been tolerized. During physiologic apoptosis, posttranslational protein modifications include proteolysis,

Factors that may contribute to autoantigen immunogenicity

Phagocytosis of apoptotic cells has been considered to be an “immunologically neutral” process that does not lead to production of inflammatory mediators by macrophages [81], [82]. A key discovery in the field of apoptosis came from the demonstration that removal of apoptotic cells by phagocytes is a double-active process. This process actively suppresses an inflammatory response through downregulation of proinflammatory cytokine production (tumor necrosis factor [TNF]-α, interleukin (IL)-1,

Apoptotic cells and nucleosomes are recognized by specific T-helper cells

The identification of nucleosome-specific CD4+ T cells in lupus-prone mice, long before disease develops [105], constituted a breakthrough in the understanding of the ethiopathogenic process in lupus. It was demonstrated that a single lupus nucleosome-specific Th clone can provide help to dsDNA-, histone-, or nucleosome-specific B cells which results in intermolecular help and cognate interaction between B and nucleosome-specific T cells. Study of the nucleosome-specific T cell α-chain showed

Specificity and structural characteristics

The best proof that nucleosomes (modified or not) are immunogenic in lupus comes from evidence in humans and mouse models of SLE that nucleosome-specific antibodies develop during disease. These antibodies react against quaternary nucleosomal epitopes that are formed by physical association between histones and DNA, but do not recognize the individual components of nucleosomes (DNA or histones). This nucleosomal antibody reactivity, first identified from monoclonal antibodies that were isolated

Mechanisms

For more than 40 years, the mechanisms by which antinuclear antibodies (in particular anti-dsDNA) participate in glomerular lesions in SLE have been the matter of much controversy. Basically, two “dogmas” (not necessarily mutually exclusive) may account for pathogenicity by anti-dsDNA antibodies. The first one claims that anti-dsDNA cross-react with non-DNA kidney antigens that are present in glomerular by virtue of similarities (and complementarity) between antibody V-region structures and

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