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 been known for several years, its role in disease pathogenesis is not understood. Recently, a few investigators have proposed that presentation of B27-derived peptides by MHC class II molecules may be the underlying mechanism. HLA-B27 transgenic rat and mouse models have provided a new tool for understanding the exact role of B27 in disease pathogenesis. HLA-B27 mice lacking endogenous β₂-microglobulin (B27⁺β₂m°) develop disease after they are transferred from the barrier facility to the conventional colony. This model was utilized to test the hypothesis that B27-derived peptide presented by MHC class II molecules is the cause of the disease. The MHC class II knockout gene, Aβ°, was bred into our B27⁺β₂m°mice, and disease manifestation was monitored. These mice develop spontaneous disease, demonstrating that MHC class II molecules do not play a major role in B27- related 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 against the heavy chain of B27 reduced the incidence of disease in B27⁺β₂m°mice. Our results clearly demonstrate that B27 heavy chains are directly involved in the disease process.