GENETIC-CONTROL OF GIANT PERIVASCULAR SPACE FORMATION IN THE THYMUS OF NOD MICE

The immune system of NOD mice exhibits several anomalies, one being th e intrathymic formation of giant perivascular spaces (PVSs) filled wit h mature thymocytes and some B-cells, intermingled within a network of extracellular matrix. The abnormal retention of thymocytes on their w ay to the periphery could have a profound impact on the nature of the exported cells and the regulation of autoimmune events. In the present study, we evaluated the appearance of this defect into F-1 hybrids, t he association with some of the known diabetes susceptibility loci (Id d genes) in a panel of NOD and reciprocal C57BL congenic strains, and the relative contribution of epithelial versus hematopoietic stroma. T he analysis of F-1 hybrid thymuses reveals a dominant expression of th ymic giant PVS that is only marginally influenced by the outcross stra in. Moreover, giant PVS expression in major histocompatibility complex (MHC) and Idd congenic mice is determined by the genetic background. All of the NOD congenics express the anomaly, irrespective of the Idd resistance alleles that have been introgressed, whereas none of the C5 7BL congenic mice present abnormal PVS. Finally, the expression of gia nt PVS in parental --> F-1 bone marrow chimeras is predominantly contr olled by the thymic NOD-derived hematopoietic microenvironment. In con clusion, the giant PVS formation in the NOD mouse thymus is a dominant ly inherited anomaly associated with hematopoietic-derived tissue and with non-MHC genes. The exact contribution of PVS to the autoimmune pr ocess remains to be definitively established.