Autoantibodies associated with lupus induced by diverse drugs target a similar epitope in the (H2A-H2B)-DNA complex.

Rubin, Robert L.; Bell, Susanne A.; Burlingame, Rufus W.

doi:10.1172/jci115832

Cited by 99 publications

(41 citation statements)

References 41 publications

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“…Indeed, direct antibody transfer studies have clearly demonstrated that anti-dsDNA antibodies can inflict renal pathology (34). Also consistent with this view is the observation that patients with drug-induced lupus who exhibit serum anti-H2A/H2B/DNA antibodies (in the absence of anti-dsDNA antibodies) do not go on to develop GN (35,36). However, it is intriguing to note that among the lupus patients seroprofiled by Burlingame et al (31), anti-chromatin and anti-H2A/H2B/DNA (rather than anti-dsDNA) ANAs correlated best with proteinuria.…”

Section: Figurementioning

confidence: 73%

Genetic dissection of lupus pathogenesis: a recipe for nephrophilic autoantibodies

et al. 1999

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Sle1 and Sle3 are 2 loci that confer susceptibility to lupus nephritis in the NZM2410 strain of mice. Our previous work has shown that B6.NZMc1 mice, congenic for Sle1, exhibit loss of tolerance to chromatin but do not develop any pathogenic autoantibodies or disease. B6.NZMc7 mice, congenic for Sle3, exhibit low-grade polyclonal B-and T-cell activation, elevated CD4/CD8 ratios, and mildly penetrant glomerulonephritis. In contrast to these monocongenics, the present study reveals that B6.NZMc1|c7 mice, bicongenic for Sle1 and Sle3, exhibit splenomegaly, significantly expanded populations of activated B and CD4 + T cells, and a robust, variegated IgG autoantibody response targeting multiple components of chromatin (including double-stranded DNA), intact glomeruli, and basement membrane matrix antigens. As one might predict, these mice, particularly the females, exhibit highly penetrant glomerulonephritis.These findings lend strong support to a two-step epistatic model for the formation of pathogenic, nephrophilic autoantibodies in lupus. Whereas loci such as Sle1 may serve to breach tolerance to chromatin, full-blown pathogenic maturation of the autoantibody response appears to require additional input from other loci (such as Sle3) and gender-based factors.

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Section: Figurementioning

confidence: 73%

Genetic dissection of lupus pathogenesis: a recipe for nephrophilic autoantibodies

et al. 1999

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“…An F(ab')2 fragment from a patient with procainamide-induced lupus blocked > 90% of the anti-[(H2A-H2B) -DNA] reactivity in six of six sera from other patients with procainamide-induced lupus, four of four with quinidineinduced lupus, as well as sera from patients with lupus induced by acebutolol, penicillamine, and isoniazid (55). Thus, autoantibodies from humans with SLE, two strains of lupus-prone mice, and patients with lupus caused by five different drugs all recognize identical or overlapping epitopes on chromatin.…”

Section: Resultsmentioning

confidence: 98%

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

Burlingame¹,

Ml²,

Starkebaum³

et al. 1994

J. Clin. Invest.

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289

177

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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.)

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“…Despite a large amount of autoantibodies and abnormal lymphocyte activation, B6.Sle1 mice do not develop clinical nephritis. In many respects, this strain reflects what is seen in drug-induced lupus, which is also characterized by H2A/H2B/DNA autoantibodies in the absence of renal disease (18).…”

mentioning

confidence: 78%

The Major Murine Systemic Lupus Erythematosus Susceptibility LocusSle1Results in Abnormal Functions of Both B and T Cells

Sobel

Satoh

Chen

et al. 2002

The Journal of Immunology

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Sle1 is a major susceptibility locus in the NZM2410 murine model of systemic lupus erythematosus. When isolated on a C57BL/6 background in the B6.Sle1 congenic strain, Sle1 results in the production of high levels of anti-chromatin IgG Abs, histone-specific T cells, and increased B and T cell activation. We have shown by mixed bone marrow chimeras with allotypic markers that Sle1 is expressed in B cells. Using the same technique, we now show that it is also expressed in T cells. To assess whether Sle1 results in intrinsic defects in B or T cells, we have bred the μMT and Tcrα−/− mutations onto B6.Sle1 resulting in the absence of circulating B cells and αβ T cells in B6.Sle1.μMT and B6.Sle1.Tcrα−/−, respectively. The immune phenotypes in these two strains were compared with that of B6.Sle1 and B6.μMT or B6.Tcrα−/−. Sle1-expressing B cells broke tolerance to chromatin in the absence of T cells, as shown by high levels of anti-ssDNA IgM Abs in B6.Sle1.Tcrα−/− mice, and had an increased expression of activation markers. Conversely, increased expression of activation markers and increased cytokine production were observed in Sle1-expressing T cells in the absence of B cells in B6.Sle1.μMT mice. However, the production of IgG antinuclear Abs required the presence of both T and B cells. These experiments showed that Sle1 expression results in both B and T cells intrinsic defects and demonstrate that the documented involvement of each cell compartment in the production of anti-chromatin Abs corresponds to genetic defects rather than bystander effects.

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Autoantibodies associated with lupus induced by diverse drugs target a similar epitope in the (H2A-H2B)-DNA complex.

Cited by 99 publications

References 41 publications

Genetic dissection of lupus pathogenesis: a recipe for nephrophilic autoantibodies

Genetic dissection of lupus pathogenesis: a recipe for nephrophilic autoantibodies

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

The Major Murine Systemic Lupus Erythematosus Susceptibility LocusSle1Results in Abnormal Functions of Both B and T Cells

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