The central role of chromatin in autoimmune responses to histones and DNA in systemic lupus erythematosus.

Abstract

To gain insight into the mechanisms of autoantibody induction, sera from 40 patients with systemic lupus erythematosus (SLE) were tested by ELISAs for antibody binding to denatured individual histones, native histone-histone complexes, histone-DNA subnucleosome complexes, three forms of chromatin, and DNA. Whole chromatin was the most reactive substrate, with 88% of the patients positive. By chi-square analysis, only the presence of anti-(H2A-H2B), anti-[(H2A-H2B) -DNA], and antichromatin were correlated with kidney disease measured by proteinuria > 0.5 g/d. SLE patients could be divided into two groups based on their antibody-binding pattern to the above substrates. Antibodies from about half of the patients reacted with chromatin and the (H2A-H2B) -DNA subnucleosome complex but displayed very low or no reactivity with native DNA or the (H3-H4)2-DNA subnucleosome complex. An additional third of the patients had antibody reactivity to chromatin, as well as to both subnucleosome structures and DNA. Strikingly, all sera that bound to any of the components of chromatin also bound to whole chromatin, and adsorption with chromatin removed 85-100% of reactivity to (H2A-H2B)-DNA, (H3-H4)2-DNA, and native DNA. Individual sera often bound to several different epitopes on chromatin, with some epitopes requiring quaternary protein-DNA interactions. These results are consistent with chromatin being a potent immunogenic stimulus in SLE. Taken together with previous studies, we suggest that antibody activity to the (H2A-H2B) -DNA component signals the initial breakdown of immune tolerance whereas responses to (H3-H4)2-DNA and native DNA reflect subsequent global loss of tolerance to chromatin. (J. Clin. Invest. 1994. 94:184-192.)

Loss of a single allele of SHIP exacerbates the immunopathology of Pten heterozygous mice

“…In both human and animal models of SLE, it is well known that autoantibodies to chromatin components such as DNA and histones commonly accompany the development of glomerulonephritis and flares of the disease. [25][26][27] Indeed, there is evidence that antibodies to histones and dsDNA participate in the pathogenesis of glomerulonephritis (reviewed in Berden 25 ). The presence of antihistone antibodies in these mice in the absence of antibodies to dsDNA is consistent with the observation that histone autoantibodies precede the appearance of anti-dsDNA in MRL/lpr mice 27 .…”

“…[25][26][27] Indeed, there is evidence that antibodies to histones and dsDNA participate in the pathogenesis of glomerulonephritis (reviewed in Berden 25 ). The presence of antihistone antibodies in these mice in the absence of antibodies to dsDNA is consistent with the observation that histone autoantibodies precede the appearance of anti-dsDNA in MRL/lpr mice 27 . Thus, it appears that the Pten +/À and Pten +/À SHIP +/À mice develop a pattern of antichromatin antibodies similar to that of a spontaneous model of SLE and glomerulonephritis.…”

Interleukin‐10 Response Abnormalities in Systemic Lupus Erythematosus

“…SLE is a disease that is characterized by the production of autoantibodies of multiple specificities, although typically, such antibodies are directed at groups of nucleus-related antigens such as DNA, RNA and nuclear proteins [34][35][36][37][38][39]. Although there is evidence for polyclonality in this response, molecular analysis of autoantibodies suggests an antigen and T cell-driven process, because these antibodies show evidence of somatic mutation in their complementarity-determining regions [15,[40][41][42].…”

Characterization of the antigenic determinants of the Leishmania infantum histone H3 recognized by antibodies elicited during canine visceral leishmaniasis

“…the amino-and carboxyl-terminal domains [21]. Since during the course of some autoimmune diseases like systemic lupus erythematosus (SLE) the elicited anti-histone antibodies are directed mainly against the histone 'tails' exposed on the nucleosomes [34], it has been suggested that chromatin cores rather than free histones would be responsible for the triggering of the humoral response [35]. Taking into account the equivalent locations of the antigenic determinants of the histones which are recognized by both SLE and VL sera, it is likely that a similar mechanism of epitope selection must operate during both pathological processes.…”