Rheumatic Fever: Genetics

Genetics

That ARF might be the result of a host genetic predisposition has intrigued inves-tigators for over a century. It has been variously suggested that the disease gene is transmitted in an autosomal dominant fashion, in an autosomal recessive fashion with limited penetrance, or that it is pos-sibly related to the genes conferring blood-group secretor status.

Renewed interest in the genetics of ARF occurred with the recognition that gene products of the human MHC (major his-tocompatibility complex) were associated with certain clinical disease states. Using an alloserum from a multiparous donor, an increased frequency of a B-cell alloantigen was reported in several genetically distinct and ethnically diverse populations of ARF individuals and was not MHC related.

Most recently, a monoclonal antibody (D8/17) was prepared by immunizing mice with B cells from an ARF patient. A B-cell antigen identified by this antibody was found to be expressed on increased num-bers of B cells in 100 percent of rheumatic fever patients of diverse ethnic origins and only in 10 percent of normal individuals. The antigen defined by this monoclonal antibody showed no association with or linkage to any of the known MHC hap-lotypes, nor did it appear to be related to B-cell activation antigens.

These studies are in contrast to other reports in which an increased frequency of certain human leucocyte antigens (HLAs) was seen in ARF patients. There are marked differences in the increased frequency of the HLAs, depending on the racial fea-tures of the patient group. These seem-ingly conflicting results concerning HLA and RF susceptibility prompt speculation that these reported associations might be of class II genes close to (or in linkage dis-equilibrium with) but not identical to the putatative RF susceptibility gene. Alter-natively, and more likely, susceptibility to ARF is polygenic, and the D8/17 antigen might be associated with only one of the genes (i.e., those of the MHC encoding for the D-related [DR] antigens) conferring susceptibility. Although the full explana-tion remains to be determined, the pres-ence of the D8/17 antigen does appear to identify a population at special risk of contracting ARF.