Nucleosomes are major T and B cell autoantigens in systemic lupus erythematosus

Abstract

Objective. Double-stranded DNA (dsDNA) is a well-known target of autoantibodies in systemic lupus erythematosus (SLE). The majority of these autoanti-bodies are of the IgG isotype and show affinity matura-tion, both of which are known hallmarks of T cell help. T cell responses to autoantigens, including DNA, have been reported only incidentally in SLE patients. Nevertheless , in murine SLE, naked DNA and complexed DNA (nucleosomes) are known to be recognized by T cells. This study aimed to characterize the antinucleo-some response and its clinical impact on human SLE. Methods. Nucleosomes were prepared from chicken erythrocytes. Sera from SLE and control patients were investigated by enzyme-linked immunosor-bent assay (ELISA) for nucleosome-specific antibody responses. Peripheral blood mononuclear cells (PBMC) from SLE and control patients were analyzed by a kinetic T cell proliferation assay. PBMC were subsequently analyzed for nucleosome-specific T cell proliferation. Results. Of 136 SLE patients, 56% were seropos-itive for antinucleosome antibodies. In contrast, only 3% of 309 control patients (with rheumatoid arthritis, mixed connective tissue disease, undifferentiated connective tissue disease, Lyme borreliosis, scleroderma, Sjögren's syndrome, ulcerative colitis, hepatitis B virus infection, or human immunodeficiency virus infection) were seropositive. Thus, the antinucleosome ELISA had a sensitivity of 56%, a specificity of 97%, and a diagnostic confidence of 90% when applied to SLE. It was therefore superior to an anti-DNA ELISA that demonstrated a 69% diagnostic confidence in the same population. Antinucleosome reactivity in SLE patients correlated significantly with disease activity (P < 0.0001), nephritis (P < 0.002), and psychosis (P < 0.02). When proliferation assays were applied, 14 of 26 SLE patients (54%) were positive for nucleosome-specific T cells that proliferated in response to their cognate antigen. A suppressed response was elicited in 3 SLE patients (12%); in these patients, the PBMC response to nucleo-somes was lower than the proliferation of PBMC in the presence of culture medium only. PBMC from the remaining 9 SLE patients (35%) were nonresponsive to nucleosomes in either way. Responding, nonresponding, and suppressed populations differed from each other significantly (P < 0.0001). None of the PBMC from 7 healthy donors and 10 control patients could be stimulated with nucleosomal antigens. Conclusion. We present evidence that nucleo-somes are major autoantigens in human SLE and that antinucleosomal antibodies are highly specific for the disease. The antinucleosome ELISA has been shown to be superior to the anti-dsDNA ELISA and may thus be a significantly better tool for diagnosing SLE. Nucleosome-specific T cells in SLE patients may help B cells class switch to IgG and undergo affinity matura-tion.

Sialic acid–binding Ig‐like lectin 1 expression in inflammatory and resident monocytes is a potential biomarker for monitoring disease activity and success of therapy in systemic lupus erythematosus

“…All SLE patients had active disease, and their mean score on the SLE Disease Activity Index (SLEDAI) (32) was 17 (range [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26]. SLE patients had a mean C-reactive protein (CRP) level of 5.7 mg/liter, and a mean erythrocyte sedimentation rate (ESR) of 40 mm/hour.…”

“…First, increased apoptosis of monocytes leads to generation of blood nucleosomes, which are a major target of the autoantibody immune response in SLE (16,17). Moreover, this accelerated apoptosis of monocytes is associated with the formation of autoantibodies and with organ damage (18,19).…”

Arginine mutation alters binding of a human monoclonal antibody to antigens linked to systemic lupus erythematosus and the antiphospholipid syndrome

“…Antinucleosome antibodies are found in patients with SLE (36) and develop prior to the development of anti-dsDNA antibodies in murine models of lupus (37). Some antibodies known to be pathogenic in mice were initially thought to bind naked dsDNA, but have subsequently been shown to bind nucleosomes or chromatin instead (11,27,38).…”

CD4+ T Cells from (New Zealand Black × New Zealand White)F1 Lupus Mice and Normal Mice Immunized Against Apoptotic Nucleosomes Recognize Similar Th Cell Epitopes in the C Terminus of Histone H3

“…In SLE, however, cognate interaction between autoreactive Th cells and autoreactive B cells is probably initially involved in the production of autoantibodies (21). Autoreactive Th cells directed against nucleosomes have been described in lupus patients (22). The presence of pathogenic autoantibody-inducing Th cells specific for chromatin subparticles or histones has also been described in patients with lupus as well as in lupus mice (23)(24)(25).…”