Genetic control of giant perivascular space formation in the thymus of NOD mice.

Abstract

The immune system of NOD mice exhibits several anomalies, one being the intrathymic formation of giant perivascular spaces (PVSs) filled with mature thymocytes and some B-cells, intermingled within a network of extracellular matrix. The abnormal retention of thymocytes on their way 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 F1 hybrids, the association with some of the known diabetes susceptibility loci (Idd genes) in a panel of NOD and reciprocal C57BL congenic strains, and the relative contribution of epithelial versus hematopoietic stroma. The analysis of F1 hybrid thymuses reveals a dominant expression of thymic giant PVS that is only marginally influenced by the outcross strain. 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 C57BL congenic mice present abnormal PVS. Finally, the expression of giant PVS in parental --> F1 bone marrow chimeras is predominantly controlled by the thymic NOD-derived hematopoietic microenvironment. In conclusion, the giant PVS formation in the NOD mouse thymus is a dominantly inherited anomaly associated with hematopoietic-derived tissue and with non-MHC genes. The exact contribution of PVS to the autoimmune process remains to be definitively established.