Autoimmunity to isomerized histone H2B in systemic lupus erythematosus

Abstract

Histone H2B is a common target of autoantibodies in both spontaneous and drug-induced systemic lupus erythematosus (SLE). Recent studies demonstrate that Asp²⁵ of histone H2B (H2B) spontaneously converts to an isoaspartic acid (isoAsp) in vivo. Our laboratory has demonstrated that the posttranslational modification of an aspartic acid to an isoaspartic acid within self-peptides renders otherwise ignored peptides immunogenic. Analysis of serum from lupus-prone mice and histone antibody positive SLE patients revealed antibodies specific to the Asp and isoAsp H2B_21–35 peptide, and that the expression of these antibodies is dependent on TLR9. IsoAsp H2B_21–35 is immunogenic in non-autoimmune prone mice and mice lacking the ability to repair isoAsp have significantly reduced levels of antibodies to H2B. Asp H2B_21–35 incubated at physiological temperatures and pH acquires the isoAsp modification, demonstrating that H2B_21–35 is prone to spontaneous isoAsp formation in vivo. Autoimmunity to isoAsp H2B suggests that this form of the autoantigen may be critical in the induction of anti-histone autoantibodies in human SLE and in murine models of disease.

Keywords::

• Isoaspartyl
• B cells
• drug-induced lupus
• autoantigen
• autoantibodies

Acknowledgements

We thank Dr. Steven Clarke for providing the Tg PIMT mice and Dr. Mark Schlomchik and Kevin Nickerson for providing the 3H9 Tg MRL lpr sera. This work was supported by an Arthritis Investigator Award from the Arthritis Foundation (to H.A.D.), by NIH grants NS-17269 (to D.W.A.), AI-48120 (to M.J.M.), and AR-41032 (M.J.M.) and a grant from the Alliance for Lupus Research (to M.J.M.).

Declaration of interest : The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this paper.