Systemic lupus erythematosus (SLE) and related autoimmune diseases are characterized by the presence of circulating antinuclear autoantibodies. Molecular mimicry, that is immunological cross-reactivity between retroviral and self antigens have been implicated in triggering autoimmunity. Autoantibodies to the human T-cell lymphotropic virus type I (HTLV-I) related endogenous retroviral element, HRES- 1, are detectable in sera of patients with SLE and overlap syndromes (OLS). The endogenous retroviral sequence (ERS) encoded 28 kD nuclear autoantigen, HRES-1/p28, contains antigenic epitopes cross-reactive with retroviral gag antigens. Moreover, the retroviral gag-related region of the 70K protein of U1 snRNP autoantigen complex shares three consecutive highly charged amino acids, Arg-Arg-Glu (RRE), an additional Arg and functionally similar Arg/Lys residues with HRES-1/p28 which represent cross-reactive epitopes between the two proteins. Previous studies revealed that prevalence of HRES-1 antibodies may be as high as 52 percent (50/96) in SLE, 59 percent (10/15) in scleroderma. 44 percent (8/18) in primary Sjogren's syndrome (SJS), and 19 percent (3/16) in polymyositis/dermatomyositis patients. 3.6 percent (4/111) of normal donors and none of 42 patients with AIDS or 50 asymptomatic HIV-infected patients had HRES-1 antibodies. While antibodies to RNP (ribonucleoprotein) were less prevalent (29/96; 30 percent), a significant correlation between anti-HRES-1 and anti-RNP was observed in patients with SLE and overlap syndromes (OLS). To delineate autoantigenic HRES-1 epitopes and define their relationship to anti-70K reactivities wild-type and mutated recombinant protein and peptide reagents will be produced and tested for recognition by sera of autoimmune patients. T cell responses as well as phenotype and epitope- recognition of HRES1/p28 reactive cells will be evaluated in HRES-1 seropositive and seronegative patients. Localization of HRES-1 and 70K proteins will be investigated in control and apoptotic cells. The proposed studies will determine the contributions of molecular mimicry and intracellular clustering in concurrence of anti-HRES and anti-70K reactivities and their relationship to HLA class II alleles and the disease process in SLE and OLS.
