Wael Jarjour

THE 8.5-KB PSTI ALLELE OF THE STRESS PROTEIN GENE, HSP70-2 : AN INDEPENDENT RISK FACTOR FOR SYSTEMIC LUPUS ERYTHEMATOSUS IN AFRICAN AMERICANS ?

SLE is dramatically more prevalent in persons of African descent than in other populations. Several genes in the class III region of the MHC have been considered as potential susceptibility loci for this disorder, but the primary association(s) remains unknown. The stress protein gene, hsp70-2, is of special interest in this regard because it encodes a protein functionally relevant to antigen processing and presentation and has itself been identified as a putative susceptibility locus in organ-specific autoimmune diseases in Caucasians. To clarify the relationship of the hsp70-2 gene to SLE in African Americans, genomic DNA from 46 patients and 42 appropriately matched control subjects was analyzed for an RFLP of the hsp70-2 gene using the probe pH2.3 and the restriction endonuclease PstI, which identifies alleles of 8.5 and 9.0 kb. The 8.5-kb hsp70-2 allele was associated with SLE in this population (X2 = 8.2473, p = 0.0044). This association was not due to linkage disequilibrium with the C4A deletion or with HLA-DR3, as has been reported in Caucasians with IDDM. These data suggest that the 8.5-kb hsp70-2 allele may be an independent susceptibility marker for SLE in African Americans.

Autoantibodies to nucleolin cross-react with histone H1 in systemic Lupus erythematosus

IgM autoantibodies to nucleolin and histone H1 are strongly associated in the serum of patients with systemic lupus erythematosus. IgM eluted from immobilized nucleolin specifically stained histone H1 blotted to nitrocellulose; conversely, IgM eluates prepared from immobilized histone H1 stained nucleolin blots. We conclude that the linkage of anti-nucleolin and anti-histone H1 autoantibodies in SLE is due, at least in part, to immunologic cross-reactivity between these two autoantigens, which share certain similar structural features.

Stress Proteins in Autoimmunity

Interest in the idea that stress proteins (also called heat shock proteins) contribute to the development and persistence of autoimmunity derives from five principal observations. First, stress proteins are immunodominant antigens of all prokaryotic infectious microorganisms, many of which have been implicated as inducers of arthritis and autoimmune disease in genetically susceptible individuals. Second, the T-cell repertoire, especially that of T-cells bearing γδ TCRs, appears to be biased toward recognition of microbial stress proteins (and, possibly, host stress proteins as well) as part of an evolutionarily conserved mechanism for host defense against infection and for resolution of tissue inflammation. Third, stress proteins are highly conserved, as would be expected in view of their fundamentally important roles in cell biology. During infection, which entails “stress” for both the microorganism and the host, there is increased synthesis and altered expression of extremely similar sets of autologous and foreign stress proteins. Fourth, the inflammatory response associated with infection up-regulates HLA glycoproteins that present antigen peptides to T-cell receptors. This may amplify recognition signals for conserved stress protein peptides to a degree sufficient for stimulation of autoreactive T-cells that have escaped deletion in the thymus. The various “permissive” genetic effects that underlie autoimmune disease may allow an autoreactive immune response to stress proteins, or to other self-constituents that cross-react with stress proteins, to persist or recur in susceptible individuals. Finally, two animal models of human autoimmune disease, adjuvant arthritis in the rat and spontaneous type-1 diabetes in non-obese mice, have implicated a stress protein, hsp60, as the critical pathogenetic element.

Expression of Stress Proteins on the Surface of Cells of the Immune System

Localization of stress proteins on plasma membranes is of fundamental biologic and immunologic interest (reviewed in Winfield and Jarjour, 1990). For example, the detection of HSP70 as a peptide-binding protein on the surface of antigen-presenting cells implies a role for at least some members of this family of stress proteins in the recognition of MHC class II/antigen peptide complexes by T cell receptors (TCRs) (Lakey etal., 1987; Vanbuskirk etal., 1989). Furthermore, surface expression of autologous stress proteins, or stress protein epitopes, can render cells susceptible to specific immunological attack (Koga etal., 1989; Ottenhof etal., 1988). Relatively little information is available concerning which stress proteins are expressed on lymphoid cells and under what circumstances, however. In this review, recent immunologic and biochemical data from our laboratories that bear on these issues are summarized briefly.