Anti-chromatin (anti-nucleosome) antibodies: Diagnostic and clinical value
Introduction
Systemic lupus erythematosus (SLE) is the most diverse of the autoimmune diseases and it is characterized by the production of multiple autoantibodies [1]. The initial description of the LE cell test by Hargraves in 1948 was one of the first laboratory abnormalities associated with SLE [2]. Today, the spectrum of autoantibodies detected in SLE is wide and complex [3]. The prevalence of anti-chromatin (nucleosome) antibodies in SLE varies from 50% to 100% [4], [5], being similar to that of positive LE cell [6]. The presence of these antibodies can be used, in conjunction with clinical findings and other laboratory tests, to help in the diagnosis of drug-induced lupus (DIL) and SLE. The presence of anti-chromatin antibodies has also been linked to glomerulonephritis in SLE patients [7].
Section snippets
Chromatin, nucleosomes and histones
Chromatin, the native complex of histones and DNA found in the cell nucleus of eukaryotes, is comprised of approximately 40% DNA, 40% histones and 20% non-histone proteins, RNA and other macromolecules. The fundamental subunit of chromatin is the nucleosome, which is composed of approximately 200 base pairs of DNA wrapped twice around the (H2A–H2B–H3–H4)2 histone octamer, with histone H1 bound on the outside (Fig. 1) [8], [9]. The periodic arrangement of histones along the DNA gives chromatin a
Anti-chromatin antibodies in murine models
A number of studies of lupus-like murine models have found genetic loci, such as SLE1, that are linked to the presence of anti-chromatin antibodies [12, reviewed in 7]. Li et al. [13] induced lupus-like syndrome in BALB/c mice after immunization with active chromatin. Mice developed anti-double-stranded-DNA antibodies (ds-DNA), anti-single-stranded-DNA (anti-ss-DNA) antibodies and anti-histone antibodies as well as a severe renal Ig deposition, mostly glomerular. Studies in knock-out mice (for
Techniques to measure anti-chromatin antibodies
A number of techniques have been used to measure anti-chromatin antibodies, including the LE cell test, latex agglutination of chromatin-coated beads, immunoprecipitation, reconstitution of acid extracted tissue reactions and ELISA [11]. The most useful forms of chromatin to use as the antigen in ELISA are H1-stripped chromatin and nucleosome core particles. In both cases, the native chromatin is solubilized by digestion with micrococcal nuclease, and H1 and non-histone proteins are removed by
Anti-chromatin antibodies in SLE
The two most important recurring observations concerning anti-chromatin antibodies are that this antibody is sensitive and specific for SLE and DIL, and the presence of anti-chromatin antibodies is often correlated with glomerulonephritis in patients with SLE. The findings that immune complexes comprising chromatin and anti-chromatin antibodies can deposit in the glomerular basement membrane of the kidney [10], and that anti-chromatin antibodies are a necessary component for the development of
Anti-chromatin (anti-nucleosome) and anti-tumour necrosis factor agents
Tumour necrosis factor (TNF)-α inhibitors (adalimumab, etanercept, infliximab) have proven to be highly effective in the treatment of several autoimmune diseases, mainly rheumatoid arthritis. They reduce disease activity and delay radiographic progression, with quite a good safety profile. Side effects of anti-TNF-α treatment include an increased risk for infection and induction of autoantibodies such as ANA, anti-ds-DNA, aCL and anti-chromatin antibodies.
Eriksson et al. [37] analyzed the
Conclusions
Most studies have found that anti-chromatin antibodies are very sensitive and specific markers of SLE. In patients with SLE there is a statistically significant correlation between anti-chromatin antibodies and renal involvement. Anti-chromatin reactivity is a useful marker to help in the diagnosis of people who are anti-ds-DNA negative but have SLE. Additionally, anti-chromatin antibodies are helpful in diagnosing DIL, as well as possibly identifying patients with autoimmune hepatitis who
Take-home messages
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Anti-chromatin antibodies are a very helpful marker in supporting the diagnosis of SLE in a patient with an unclear systemic autoimmune disorder.
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These antibodies have a high sensitivity (50–100%) and a very high specificity (90–99%) for SLE diagnosis.
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Anti-chromatin antibodies are helpful in diagnosing DIL as well as possibly identifying patients with autoimmune hepatitis.
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These antibodies are clinically correlated with kidney and disease activity in SLE patients.
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Anti-TNF-α agents may induce
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