NON-MHC GENES DETERMINE THE DEVELOPMENT OF LUPUS NEPHRITIS IN H-2 IDENTICAL MOUSE STRAINS

Susceptibility to systemic lupus erythematosus (SLE) and, in particula r, lupus nephritis is strongly influenced by genetic factors. Previous studies have shown that MHC-related antigens influence the developmen t of SLE. In the current study, we set out to investigate how non-MHC genes influence the pathogenesis of glomerulonephritis in chronic graf t-versus-host disease (GVHD) in mice, a model for lupus nephritis. For the induction of GVHD we used parent-to-F-1 hybrid mouse strain combi nations. DBA/2, BALB/c, BALB.D2 and C57B1/10.D2 (BL10.D2) donor lympho cytes carrying an H-2(d) haplotype were injected into H-2(b/d) F-1 hyb rids of BL10 mice, which differed only at non-MHC loci. Within these h ybrid strains the development of immune complex glomerulonephritis was investigated by monitoring the occurrence of autoantibodies in the ci rculation, deposition of immunoglobulins in the glomeruli, development of albuminuria, and glomerulosclerosis. In diseased DBA/2 mice albumi nuria developed 6 weeks after induction of the disease. Mice with a BA LE background developed a lupus-like syndrome characterized by albumin uria starting 8 weeks after induction of the GVHD. During the developm ent of the GVHD, polyclonal B cell activation occurred in both the DBA /2 and BALB/c strains, resulting in the formation of autoantibodies. O nly the strain combination using DBA/2 mice developed anti-GBM antibod ies. In DBA/2 and BALE strain combinations immune complexes were detec ted in a granular pattern along the glomerular capillary walls. In the DBA/2 recipients a linear pattern of immunoglobulin depositions prece ded the granular phase. This study demonstrates that: (i) non-MHC gene s govern the pathogenesis of immune complex nephritis in this model by influencing the autoantibody profile; and (ii) the presence of anti-G BM antibodies in the early stages of the disease is a conditio sir re qua non for the development of full-blown glomerulonephritis and glome rulosclerosis in this model.