Anti-Histone Antibodies in Systemic Lupus Erythematosus

Chapter 22E Anti-Histone Antibodies in Systemic Lupus Erythematosus


The first description of an immune phenomenon linked to autoantibodies against structures within chromatin goes back almost 60 years and was the detection of the lupus erythematosus (LE) cell phenomenon by Hargraves and colleagues.1 The LE cell was exclusively found in bone marrow aspirates of patients with SLE and constitutes a polymorphonuclear granulocyte having engulfed the nucleus of a previously dead cell (Fig. 22E.2). Later studies have shown that the formation of LE cells depends on the presence of antibodies, which bind complement and react against self-structures defined by chromatin. Later this structure was defined as histone H1.2,3 Their typical morphology, their high specificity, and the fact that LE cells could also be detected in blood samples from SLE patients qualified them as a highly useful laboratory tool to diagnose SLE. The introduction of direct analysis of autoantibodies by specific immunoassays replaced the more complicated LE cell test in the routine diagnosis in later years. A second breakthrough in the research on the immune response against chromatin was the detection of antibodies against double-stranded DNA by Deicher and colleagues in 1959. Thus, measuring antibodies against double-stranded DNA has been established and has become a standard procedure in the diagnosis and monitoring of SLE patients.47

SLE patients commonly develop reactivity to several components of chromatin.8 Apart from the well-known antibodies against single- and double-stranded DNA, histones and the complex structures formed by the assembly of histones with DNA are major antigenic structures in SLE (Fig. 22E.3). Thus, antibodies against individual histones, histones complexes, complexes of histones with DNA, and nucleosomes can be differentiated and all constitute antigenic targets. Many SLE patients develop autoantibody responses against several different components of chromatin, but in several patients also highly selective immune response against single components can be observed.


Antibodies to histones were first described in 1957 and constitute a typical feature of spontaneous SLE and drug-induced LE.8,9 Up to 75% of SLE patients develop anti-histone immune responses.1012 These antibodies can specifically target each individual histone with almost no cross-reactivity to other histones (Fig. 22E.4). Among the four core histones and the one linker histone (H1), strongest autoantibody responses are found against histone H1 and the core histones H2A and B. Antibodies against H1 are found in 50 to 60% of SLE patients9,10,1315 in cross-sectional analyses. The anti-H1 immune response is essential for the LE cell phenomenon (as discussed previously).3 Like most antibodies against chromatin structures, they belong to the IgG class.10 Autoantibody formation against histone H1, which compared to the core histones is phylogenetically less conserved, is predominantly directed against the trypsin-sensitive regions located within the amino- and carboxy-terminus of the molecule.1519 A more detailed study using H1-peptides located the site of major immune reactivity to amino acid residues 204 to 218 (a lysine-rich region at the C-terminal end of histone H1), whereas minor epitopes were found within the amino-terminal region.21 Interestingly, the carboxy-terminal end of histone H1 is the most conserved region of the protein and is essential for its interaction with DNA.

High-titer antibodies against H1 are highly specific for SLE. Rarely they are found in juvenile and adult rheumatoid arthritis if extra-articular manifestations are present in systemic sclerosis or in primary biliary cirrhosis. Their reactivity is usually low in these conditions.2124 Importantly, hydralazin- and procainamid-induced LE can display an anti-H1 immune response.25 A cross-sectional study with more than 400 sera of patients with rheumatic diseases has shown a similar specificity (98%) of anti-H1 as with antibodies against dsDNA or Sm.26 Interestingly, there is a strong concordance between H1 and dsDNA antibodies. Approximately two-thirds of anti-H1 positive samples contained anti-dsDNA antibodies and over 80% of anti-dsDNA positive sera showing anti-H1 reactivity, suggesting that these antibodies are immunopathologically linked.

Longitudinal analyses of anti-H1 reactivity in SLE patients revealed dynamic changes of antibody titers over time, which was closely related to changes in disease activity. Anti-H1 antibodies correlated with disease activity in a fashion similar to that of antibodies against double-stranded DNA. This is well in line with cross-sectional analyses showing higher disease activity and a higher frequency of severe organ involvement in SLE patients positively tested for the presence of LE cells or anti-H1 antibodies.13,27,28

Immune reactivity to the core histones (H2A, H2B, H3, and H4) is predominantly directed to H2B and somewhat less frequently to H2A. In contrast, autoantibodies to H3 and especially H4 are formed less frequently.29,30 Immune reactivity to individual core histones is closely linked to each other but much lesser to the appearance of anti-H1. As longitudinal analyses have shown, variation of anti-H2B response is also high over time in individual patients, but they reflect changes in disease activity less reliably than anti-H1 or anti-double-stranded DNA antibodies. An analysis of heavy and light change usage of B cells producing anti-H2A and anti-H2B antibodies has been performed by isolating four human monoclonal antibodies by a phage-display library. There was no clonal relation, as indicated by different heavy and kappa light chain groups as well different D and J gene arrangements among the antibodies.31

Due to the fact that the frequency and specificity of anti-histone antibodies as well as their linkage to disease activity varies among different histone components, the value of determining anti—total-histone reactivity seems to be rather limited. This is especially reflected in a number of conflicting data on the relationship of antibodies to total histone with SLE disease activity, showing a good, partial, or poor relation.9,10,3236

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Jul 24, 2018 | Posted by in MUSCULOSKELETAL MEDICINE | Comments Off on Anti-Histone Antibodies in Systemic Lupus Erythematosus
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