Thymic microenvironment and NZB mice: The abnormal thymic microenvironmentof New Zealand mice correlates with immunopathology

There are distinct microenvironmental abnormalities of thymic architecture in several murine models of SLE defined using immunohistochemistry and a pa nel of mAb dissected at thymic epithelial markers. To address the issue of the relationship between the thymic microenvironment and autoimmunity, we s tudied backcross (NZB x NZW) F1 x NZW mice in which 50% of offspring develo p nephritis associated with proteinuria and anti-DNA antibodies. We reasone d that if thymic abnormalities are associated with development of disease, the correlation of abnormalities with lupus-like disease in individual back cross mice will form the foundation for identification of the mechanisms in volved. In parallel, we directed a genetic linkage analysis, using markers previously shown to be linked to nephritis and IgG autoantibody production, to determine if such loci were similarly associated with microenvironmenta l changes. Our data demonstrate that all (NZB x NZW) F1 x NZW backcross mic e with disease have microenvironmental defects. Although the microenvironme ntal defects are not sufficient for development of autoimmune disease, the severity of thymic abnormalities correlates with titers of IgG autoantibodi es to DNA and with proteinuria. Consistent with past studies of (NZB x NZW) F1 x NZW mice, genetic markers on proximal chromosome 17 (near MHC) and di stal chromosome 4 showed trends for linkage with nephritis, Although the ma rkers chosen only covered about 10-15% of the genome, the results demonstra ted trends for linkage with thymic medullary abnormalities for loci on dist al chromosome 4 and distal chromosome 1. We believe it will be important to define the biochemical nature of the molecules recognized by these mAbs to understand the relationships between thymic architecture and immunopatholo gy, (C) 1999 Academic Press.