| Systemic erythematosus lupus (SLE) is predominantly a female autoimmune disease that affects almost every organ system in the body. Recently there is some epidemiological evidence that the incidence of SLE has increased approximately three-fold over the past 2 decades, both in the United States and in Europe. The now available therapies are effective but are associated with serious adverse effects, such as inhibition all of the immune defense response. It is necessary to pursuit a special treatment that selectively targets the pathogenic autoimmunity only, leaving the remainder immune system intact.The disease of SLE is characterized by the presence of multiple autoantibodies in the patients, serum. In recent years, it has become clear that the formation of these antibodies is autoantigen-driven and T cell dependent, so the pathogenic autoAbs formation can be inhibited by induction immune tolerance with peptide vaccine based on autoantigen Th cell epitope. Such treatments have the advantage of selectively inhibiting the pathogenic autoimmunity, while preserving the normal immunologic defense mechanisms, and the tolerance-inducing therapies have been successfully used to suppress autoimmune response in organ-specific autoimmune diseases such as experimental autoimmune encephalomyelitis (EAE), multiple sclerosis(MS) and nonobese diabetic(NOD). However, unlike organ-specific autoimmune diseases, autoantigens of SLE are released from apoptotic peripheral blood mononuclear cells (PBMC), including nuclear, cytoplasmic and cell surface self- antigens, so it is the first step to define the major or key pathogenic antigen of SLE.Nucleosome is one of antigens generated by apoptotic cell, and is the general presence form of DNA outside cell. In recent years, several studies based on lupus-prone mice suggest nucleosome involve both in the induction of several pathogenic antibodies including ds-DNA antibodies and in tissue damage. However, it is remarkably different between the mechanism of lupus-prone and that of human. On the other hand, SLE involvesmultiple self-antigens, and there is significant antigen or epitope spreading, drifting and shifting in the production of autoAbs. Moreover, cross-activity may be present among autoactivity T cell and B cell. It is still not clearness of the relationship between nucleosome and the pathogenesis of human SLE. Furthermore, it remains to define if the nucloesome is a bona fide initial immunogen to drive autoAbs production of SLE.Herein, we make a further study based on the work of other laboratories. The main results are as follows: â‘ Levels of nucleosome released from PBMCs of SLE patients with active SLE are significantly higher than those of patients with inactive disease and normal controls. There were significantly positive correlations between nucleosome concentrations and SLEDAI as well as serum ds-DNA auto-antibody concentrations, low C3 levels. â‘¡ After immunization with nucleosome, BALB/c mice produced high titers of dsDNA and ANA autoantibody. Nephritis and immune complex deposition in renal glomeruli were also present. These firm evidence show that nucleosome plays a key role as a bona fide immunogen in the pathogenesis of human SLE. Nucleosomes, released by internucleosomal cleavage by endonucleases during cell apoptosis, are the fundamental units in the form of chromatin in eukaryotic cells. Each nucleosome consists of a core particle composed of an octamer of 2 copies of histones H2A, H2B, H3, and H4, around which is wrapped a stretch of helical DNA, ~150bp basepairs in length. The fact that antigen presentation could be blocked by leupeptin and pepstatin A, inhibitors of the endosomal proteases, cathepsin, respectively, suggests that peptides from the histone component of the nucleosomes contain the relevant epitopes for the pathogenic Th cells. Among the nucleosomal histone subtypes, the H2B and H4 are known to be highly conserved through evolution and exposed at the surface of free nucleosome. In the study, we focused on the H2B Th cell epitope...
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