GENETIC CELLULAR AND MOLECULAR STUDIES OF FAS IN SLE

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DESCRIPTION (Adapted from Investigator's abstract): SLE is a disease of diverse clinical, serologic and pathologic features. The diversity is likely explained by the inheritance of different combinations of susceptibility genes, possibly in combination with environmental factors. Mice with the lpr and gld phenotype have long been considered a model for SLE. Recently, loss of function mutations in the Fas and Fas ligand genes have been found to be responsible for the phenotype. Over the last funding period, we and others, have gained understanding in how mutations in the Fas apoptotic pathway lead to autoimmunity in mice. In addition to Fas pathway mutations, background genes have a striking effect on clinical expression of autoimmunity in different strains of mice. Humans with the Ipr phenotype were first described in 1967 at the Cornell Medical Center. We have accumulated 10 such families, some with extended pedigrees. The phenotype in individuals with Fas mutations ranges from clinically asymptomatic to full blown SLE. The major goal of this project is to is to identify the additional modifier genes responsible for expression of lupus-like disease in humans. Preliminary studies of families with Fas mutations suggest that a small number of genetic factors with relatively strong effect determine disease expression. Functional analysis of Fas-mediated apoptosis (FMA) in the families of CSS probands have suggested that the additional genetic defect lies in the apoptotic pathway. Aim 1A will determine whether family members have abnormalities in the genes or the proteins in the proximal Fas apoptosis pathway (FADD, FLICE and caspases). Aim IB will determine whether alternative apoptosis pathways such as TNF, DR3, DR4 are impaired in family members. Aim 2 will test the hypothesis that clinical expression of disease requires the interaction of a heterozygous Fas mutation with a second gene. We will attempt to localize the second gene by linkage analysis and by association studies. Aim 3 will examine whether the same genetic defects identified in Aims 1 and 2 occur in patients with SLE.