This project has concentrated upon the immunogenetics of systemic lupus erythematosus. The original observation that heterozygotes of MB1 and MB2 (now DQ1 and DQ2) are related to the production of anti-Ro autoantibodies in Sjogren's Syndrome (54) has now been extended to and conformed in systemic lupus erythematosus (55,56). Gene complementation has been established as the genetic basis for this relationship by analysis of restriction fragment length polymorphisms of DQA1 and DQB1 genes (8). The most recent analysis at the DNA sequence level using DQ oligotyping has shown the related DQ1 allels (DQ1A*0101, *0102 and *0103) in aggregate contribute to this gene complementation effect in combination with DQB1*0201. Moreover, T cell receptor alleles, which themselves are associated to anti-Ro production, act in a cooperative fashion with the DQ alleles for anti-Ro autoantibody production. Other immunogenetic studies have also been performed. Rather than pursuing molecular interactions that govern the association of DQ and T cell receptor alleles with anti-Ro autoantibodies, the investigators have elected to pursue more basic informatin concerning the genetic origins of lupus by initiating a linkage study. The recent discovery and mapping of highly polymorphic short nucleotide repeats in genomic human DNA has made a linkage study feasible in lupus, even considering the genetic complexities that lupus poses. Theoretical work has been underway for over a year, culminating in the development of a practical experimental plan. Our more recent efforts have focused upon accruing multiplex pedigrees and initiating the process of allele assignment with the newly available marker loci. Two hundred DNA primers (105 of which are in our possession) from a selection of these polymorphic markers of defined and mapped loci are available by which to assign alleles linked to candidate genes. For the coming cycle of funding the investigator proposes to evaluate linkage in multiplex pedigrees fro lupus at three levels: first with autoimmune serology, second with the clinical classification (i.e. diagnosis) of lupus, and third with features of lupus. Finding linkage to autoimmune serology is predicted to require the fewest multiplex pedigrees and least effort. Subsequently, the data base developed will be extended to define linkage to lupus and finally to particular clinical manifestations and laboratory findings. Substantial progress has already been made and there is sufficient power in the pedigrees already collected to predict that finding genetic linkage to autoantibodies is likely. The collection of pedigrees will continue so that linkage can be defined with the diagnosis and manifestations of lupus with the continuation of the accrual procedures now in place. If systemic lupus erythematosus is ever to be understood, then both the genetic and environmental features which make it possible for this disease to occur must be identified. This study seeking linkage is a critical first step in defining the genetic environment in which lupus arises and is sustained.
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