Abstract
Post-translational modifications on proteins are important in biological processes but may create neo-epitopes that induce autoimmune responses. In this study, we measured the serum IgG and IgM response to a set of non-modified or acetyl- and methyl-modified peptides corresponding to residues 1–19 of the histone 3 N-terminal tail in systemic lupus erythematosus (SLE) patients and healthy subjects. Our results indicated that the SLE patients and healthy subjects produced antibodies (Abs) to the peptides, but the two groups had different Ab isotype and epitope preferences. Abs to the non-modified form, H31–19, were of the IgG isotype and produced by SLE patients. They could not recognize the scrambled H31–19, which contained the same amino acid composition but a different sequence as H31–19. In comparison, healthy subjects in general did not produce IgG against H31–19. However, about 70% of the healthy subjects produced IgM Abs against mono-methylated K9 of H31–19 (H31–19K9me). Our further studies revealed that ε-amine mono-methylated lysine could completely inhibit the IgM binding to H31–19K9me, but lysine had no inhibitory effect. In addition, the IgM Abs could bind peptides containing a mono-methylated lysine residue but with totally different sequences. Thus, mono-methylated lysine was the sole epitope for the IgM. Interestingly, SLE patients had much lower levels of this type of IgM. There was no obvious correlation between the IgM levels and disease activity and the decreased IgM was unlikely caused by medical treatments.We also found that the IgM Abs were not polyreactive to dsDNA, ssDNA, lipopolysaccharide (LPS) or insulin and they did not exist in umbilical cord serum, implying that they were not natural Abs. The IgM Abs against mono-methylated lysine are present in healthy subjects but are significantly lower in SLE patients, suggesting a distinct origin of production and special physiological functions.
Highlights
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of various autoantibodies
There was no obvious correlation between the IgM levels and disease activity and the decreased IgM was unlikely caused by medical treatments.We found that the IgM Abs were not polyreactive to dsDNA, ssDNA, lipopolysaccharide (LPS) or insulin and they did not exist in umbilical cord serum, implying that they were not natural Abs
To determine if SLE patients produced IgG or IgM against a set of synthetic peptides corresponding to the 1–19 N-terminal residues of H3 (i.e., peptides without modifications (H31–19), acetylation on lysine 9 (H31–19K9ac) and mono, di, or trimethylation on lysine 4 or lysine 9 (H31–19K4me, H31– 19K4me2, H31–19K4me3, H31–19K9me, H31–19K9me2 and H31–19K9me3)), we performed an ELISA using sera from 62 pediatric-onset SLE (pSLE) and 75 adult SLE (aSLE) patients
Summary
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of various autoantibodies (autoAbs) Many of these antibodies (Abs) are reactive to components in the cell nuclei, such as dsDNA, nucleosomes, Sm, La, Ro, etc. As the major components of nucleosomes, histones are common autoantigens in SLE. These autoAbs form immune complexes with the antigens, which leads to excessive activation of complement and phagocytes, resulting in severe inflammation and multiorgan damage. AutoAbs to all five of the histones have been found in SLE patients and lupus mouse models [2,6] Most of these autoAbs recognize epitopes exposed on nucleosome surfaces, such as the 22–42 residues of H19, 1–25 residues of H2B, 1–21 residues of H3, and 1–29 residues of H4. There are fewer autoAbs against epitopes that are not located on histone tails, such as residues 65– 85 of H2A and residues 40–55 of H3 [7,8,9,10,11]
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