ETIOLOGY AND PATHOGENESIS OF PEMPHIGUS

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DESCRIPTION: (Adapted from the applicant's abstract) - This revised version of the renewal grant application describes a series of protocols aimed at disclosing the etiology of Brazilian pemphigus foliaceus or Fogo Selvagem (FS). FS is a human autoimmune disease mediated by pathogenic autoantibodies that are produced by immunogenetically predisposed individuals living in certain rural areas of Brazil. The epidemiology of FS points toward an, as yet unknown, environmental antigen as the trigger of the disease. The antigenic mimicry model predicts that desmoglein-1 (dsg1) harbors T and/or B cell epitopes that crossreact with the environmental agent that precipitates the disease. In the previous funding period, the investigators identified a new FS focus with a unique set of environmental, genetic, and cultural characteristics that they believe make it an ideal population on which to focus their etiologic studies. This community, the Limao Verde Reservation in central Brazil, is composed of approximately 1000 members of the Terena Indian tribe. Geographic, familial, and temporal clustering patterns have been detected among the 28 FS cases on this reservation, and the disease was found to be associated with HLA-DRB1*0404, 1402 & 1406 haplotypes (RR=14). In contrast, other Terena reservations in the region show very few or no documented FS cases. Aim 1 of this grant proposal includes a series of case control epidemiological studies designed to define further genetic and environmental risk factors of the disease. Controls from three populations will be studied: unaffected family members of FS patients, unrelated individuals from Limao Verde, and unaffected Terena Indians from a neighboring reservation. An ongoing prospective sero-epidemiological study of this population will be strengthened by an ELISA assay using recombinant dsg1. Aim 2 investigates the cellular and molecular regulatory mechanisms involved in the pathogenic autoimmune response in FS. Antigen-specific T cell clones and immortalized B cells from FS patients will be generated. This aim is supported by strong preliminary studies. Finally, Aim 3 represents a highly focused immunological investigation of potential etiologic agents of FS. The investigators' studies on salivary gland antigens from Simulium nigrimanum are based on previous data indicating that exposure to black flies is a risk factor for FS. Information obtained from these studies should be relevant in understanding the onset and development of FS and other human autoimmune diseases.