Enhanced interaction of HLA-DM with HLA-DR in enlarged vacuoles of hereditary and infectious lysosomal diseases

Following biosynthesis, class II MHC molecules are transported through a ly sosome-like compartment, where they acquire antigenic peptides for presenta tion to T cells at the cell surface. This compartment is characterized by t he presence of HLA-DM, which catalyzes the peptide loading process, Here we report that the morphology and function of the class II loading compartmen t is affected in diseases with a phenotypic change in lysosome morphology, Swollen lysosomes are observed in cells from patients with the hereditary i mmunodeficiency Chediak-Higashi syndrome and in cells infected with Coxiell a burnetii, the rickettsial organism that causes Q fever. In both disease s tates, we observed that HLA-DR and HLA-DM accumulate in enlarged intracellu lar compartments, which label with the lysosomal marker LAMP-I, The distrib ution of class I MHC molecules was not affected, localizing disease effects to the endocytic pathway. Thus, cellular mechanisms controlling lysosome b iogenesis also affect formation of the class II loading compartment, Analys is of cell surface class II molecules revealed that their steady-state leve rs were not reduced on diseased cells. However, in both disease states, enh anced interaction between HLA-DR and HLA-DM was detected. In the Chediak-Hi gashi syndrome cells; this correlated with more efficient removal of the CL IP peptide. These findings suggest a mechanism for perturbation of Ag prese ntation by class II molecules and consequent immune deficiencies in both di seases.