Autoantibody production in autoimmune diseases is related to particular alleles or haplotypes found in the major histocompatibility complex. Our laboratory has demonstrated a strong effect of gene interaction of HLA-DQ. Autoantibody production of anti-Ro/SSA, anti-La/AAB and rheumatoid factor in primary Sjogren's syndrome, and of anti-Ro/SSA in systemic lupus erythematosus is dramatically higher in patients heterozygous at HLA-DQ for alleles DQ1 and DQ2. Since the HLA-DQ surface molecule is composed of two peptides (Alpha and Beta) and since both of these peptides are polymorphic, trans-associated surface molecules may result which have unique antigenic specificities. The existence of these molecules has been previously demonstrated, but no immune reactivity specific for them has been previously known in man. We will test the hypothesis that autoantibody production in primary Sjorgren's syndrome and anti-Ro/SSA in systemic lupus erythematosus are enhanced as a result of gene complementation at HLA-DQ. We propose to directly identify the genes involved. Gene probes for the individual peptides, DQAlpha, DQBeta and DRAlpha will be hybridized to the restriction enzyme digested and Southern blotted genomic DNA from patients with primary Sjogren's syndrome, systemic lupus erythematosus and normals. Pedigrees from these patients will be analyzed to make haplotype designation of the restriction fragment length polymorphisms and of HLA serology. The possible models (especially gene complementation) will be tested for their capacity to explain the combined data obtained from autoantibody serology, the HLA data and restriction fragment length polymorphism typing analysis. Even if this analysis identifies a major effect from gene complementation, there will likely be a number of patients whose data does not fit the apparent main effect. Explanations for the exceptions to the major effects will be sought using other reagents. Monoclonal antibodies, HLA responsive T cell lines and gene probes will be raised and used to identify the critical structures of the contributing components to determine whether they are functionally similar to those accounting for the major effect (now found in DQ1/DQ2 heterozygotes). These additional reagents will be used to map these effects within the major histocompatibility complex. For carefully selected instances, the variable regions of the genes in question will be sequenced to make possible a search for important similarities in molecular structure. This study will bring us closer to the mechanism of autoimmune disease by elucidating the genetic elements which influence induction and/or production of autoantibodies in primary Sjogren's syndrome and systemic lupus erythematosus. Reagents generated may hold promise for improved diagnosis and, perhaps, therapy.
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