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.