Human class I major histocompatibility complex allele HLA-B27 is associated with a group of human diseases called "spondyloarthropathies." Studies on transgenic rats expressing HLA-B27 and human beta 2-microglobulin have confirmed the role of HLA-B27 in disease pathogenesis. Here we report spontaneous inflammatory arthritis in HLA-B27 transgenic mice lacking beta 2-microglobulin (B27+ beta 2m-/-). In the absence of beta 2-microglobulin, B27+ beta 2m-/- animals do not express the HLA-B27 transgene on the cell surface and have a very low level of CD8+ T cells. Most of the B27+ beta 2m-/- male mice showed nail changes, hair loss, and swelling in paws, which leads to ankylosis. The symptoms occur only after the B27+ beta 2m-/- mice are transferred from the specific pathogen-free mouse colony. These results suggest that aberrant assembly, transport, and expression of the HLA-B27 molecule may predispose an individual for development of the disease when exposed to an appropriate environmental trigger.