Genes determining autoimmune disease in New Zealand mice

Abstract

The genetic basis of autoimmune haemolytic anaemia in NZB mice has been investigated using crosses and backcrosses with the NZC strain. These mating combinations reveal two dominant or co-dominant genes governing occurrence of the disorder. One of these, Aia-2, is common to both the NZB and the NZC strains. The other gene, Aia-1, is peculiar to the NZB strain and is linked to the b (black/brown) coat colour locus on chromosome 4. The cross-over value of 37+/-4% places this gene in the neighbourhood of the minor histocompatibility locus H-18, provided it is on the same side of the b locus. Previously, we have obtained evidence that the lupus nephritis of the (NZB X NZW)F(1) mice is determined by three dominant or co-dominant genes, Lpn-1, Lpn-2 and Lpn-3. Lpn-2 appears to be tightly linked to the H-2 complex, Lpn-1 has a cross-over frequency of 33+/-3% with H-2 placing it in the neighbourhood of a hybrid histocompatibility (Hh) locus on chromosome 17, and Lpn-3 is on a separate, unknown chromosome. In this paper we present data from an out-cross study between (NZW X NZC)F(1) and NZB mice, which indicate that Lpn-3 is not linked to Igh-C and is therefore not an immunoglobulin heavy chain V gene. Whilst it remains possible that Lpn-3 is a kappa or lambda light chain V gene and that Aia-2 is a V gene, Lpn-1 and Aia-1 are clearly not H or kappa V genes, nor are they in the major histocompatibility gene complex. Their apparent association with the Hh and H-18 loci suggests that they may be genes coding for minor histocompatibility loci. Such genes could influence immune response repertoire, and hence genetic predisposition to autoimmune disease, through the clonal deletion and paratope-idiotope network reactions which we have postulated to be the mechanisms mediating the effect of the major histocompatibility antigen genes.