SPONTANEOUS INFLAMMATORY DISEASE IN HLA-B27 TRANSGENIC MICE IS INDEPENDENT OF MHC CLASS-II MOLECULES - A DIRECT ROLE FOR B27 HEAVY-CHAINS AND NOT B27-DERIVED PEPTIDES

Although association of HLA-B27 with human spondyloarthropathies has b een known for several years, its role in disease pathogenesis is not u nderstood. Recently, a few investigators have proposed that presentati on of B27-derived peptides by MHC class II molecules may be the underl ying mechanism, HLA-B27 transgenic rat and mouse models have provided a new tool for understanding the exact role of B27 in disease pathogen esis. HLA-B27 mice lacking endogenous beta(2)-microglobulin (B27(+)bet a(2)m(o)) develop disease after they are transferred from the barrier facility to the conventional colony. This model was utilized to test t he hypothesis that B27-derived peptide presented by MHC class II molec ules is the cause of the disease. The MHC class II knockout gene, A be ta(o), was bred into our B27(+)beta(2)m(o) mice, and disease manifesta tion was monitored. These mice develop spontaneous disease, demonstrat ing that MHC class II molecules do not play a major role in B27-relate d disease. Thus, the disease is not manifested by presentation of B27- derived peptides by class II molecules, since these mice are devoid of H2-A and H2-E molecules. Furthermore, in vivo treatment with mAb agai nst the heavy chain of B27 reduced the incidence of disease in B27(+)b eta(2)m(o) mice, Our results clearly demonstrate that 827 heavy chains are directly involved in the disease process.