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Characterization of cellular and humoral autoimmune responses to histone H1 and core histones in human systemic lupus erythematosus
  1. G H Stummvoll (georg.stummvoll{at}meduniwien.ac.at)
  1. Medical Uiversity of Vienna, Austria
    1. R D Fritsch (ruth.fritsch{at}meduniwien.ac.at)
    1. Department of Rheumatology, University Medical Center Utrecht, Netherlands
      1. B Meyer (brigitte.a.meyer{at}meduniwien.ac.at)
      1. Division of Rheumatology, Medical University of Vienna, Austria
        1. E Hoefler (elisabeth.hoefler{at}wienkav.at)
        1. Second Department of Medicine, Hietzing Hospital, Austria
          1. M Aringer (martin.aringer{at}meduniwien.ac.at)
          1. Technical University of Dresden, Germany
            1. J S Smolen (josef.smolen{at}wienkav.at)
            1. Medical University of Vienna, Austria
              1. G Steiner (guenter.steiner{at}meduniwien.ac.at)
              1. Medical University of Vienna, Austria

                Abstract

                Objective: To address key aspects of anti-histone autoimmunity in systemic lupus erythematosus (SLE), we performed a detailed characterization of cellular and humoral autoreactivity to histone H1 and the four core histones H2A, H2B, H3, H4 in patients with SLE and healthy controls.

                Methods: Peripheral blood mononuclear cells of 41 SLE patients and 28 healthy controls were exposed to individual histones and proliferation was measured by [3H]-thymidine incorporation. H1-reactive T-cell clones were drawn by limiting dilution. Cytokines and total IgG in culture supernatants was measured by ELISA, autoantibodies to histones were determined by ELISA and immunoblotting.

                Results: Proliferative responses to H1 were more frequent and more pronounced in cell cultures from SLE patients (p<0.002), while among the core histones only the response to H2A was increased in patient cultures (p<0.01). All histones elicited a Th1-like cytokine response both in patients and controls (high IFNγ and TNFα, no IL-4) with H1 inducing the highest levels of TNFα. However, H1 stimulated production of IgG and anti-histone antibodies only in cell cultures derived from SLE patients. H1-specific T-cell clones from patients and controls showed a CD4+CD28+ phenotype and a Th1 cytokine profile. Anti-histone antibodies were detected in 51% of SLE patients, were primarily directed to H1, H3 and H4 and predominantly of the IgG2 subtype.

                Conclusion: Histone H1 constitutes a major B-cell and T-cell autoantigen in SLE triggering a proinflammatory Th1 response and driving autoantibody production. This suggests that histone H1 may be of considerable relevance for the pathogenesis of SLE.

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