ROLE OF THE MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-II EA GENE IN LUPUS SUSCEPTIBILITY IN MICE

The gene(s) encoded within major histocompatibility complex (MHC) act as one of the major genetic elements contributing to the susceptibilit y of murine systemic lupus erythematosus (SLE). We have recently demon strated that lupus susceptibility is more closely linked to the I-E- H -2(b) haplotype than to the I-E+ H-2(d) haplotype in lupus-prone BXSB and (NZB x BXSB) F-1 hybrid mice. To investigate whether the reduced s usceptibility to SLE in H-2(d) mice is related to the expression of th e MHC class II Ea gene (absent in H-2(b) mice), we determined the poss ible role of the Ea gene as a lupus protective gene in mice. Our resul ts showed that (i) the development of SLE was almost completely preven ted in BXSB (H-2(b)) mice expressing two copies of the Ead transgene a t the homozygous level as well as in BXSB H-2(k) (I-E+) congenic mice as for H-2(d) BXSB mice, and (ii) the expression of two functional Eh (transgenic and endogenous) genes in either H-2(d/b) (NZB x BXSB)Fr or H-2(k/b) (MRL x BXSB) F-1 mice provided protection from SLE at levels comparable to those conferred by the H-2(d/d) or H-2(k/k) haplotype, In addition, the level of the Ea gene-mediated protection appeared to be dependent on the genetic susceptibility to SLE in individual lupus- prone mice. Our results indicate that the reduced susceptibility assoc iated with the I-E+ H-2(d) and H-2(k) haplotypes (versus the I-E- H-2( b) haplotype) is largely, if not all, contributed by the apparent auto immune suppressive effect of the Ea gene, independently of the express ion of the I-A or other MHC-linked genes.