Severe destructive autoimmune lesions with aging in murine Sjogren's syndrome through Fas-mediated apoptosis

When we evaluated the age-associated changes in autoimmune exocrinopathy in a NFS/sld murine model for primary Sjogren's syndrome (SS), severe destruc tive autoimmune lesions developed in the salivary and lacrimal glands in th e aged mice, compared with those observed in the younger model. We detected a decreased secretion of saliva and tear flow in the aged group. A signifi cant increase of TUNEL+-apoptotic epithelial duct cells in the salivary gla nds was detected in the aged SS animal model. A higher proportion of mouse salivary gland cells bearing Fas was found in the aged group, whereas no si gnificant changes were seen on tissue-infiltrating CD4(+) T cells bearing F ast in the salivary glands from young and aged mice. We detected an increas ed cleavage product of organ-specific autoantigen, 120-kd alpha-fodrin, in the aged sallvary gland tissues on immunoblotting, and an increase in serum autoantibody production against 120-kd, alpha-fodrin by enzyme-linked immu nosorbent assay. An increase in the proliferative response of splenic T cel ls against organ-specific autoantigen was observed, whereas nonspecific con canavalin A responsiveness was decreased in the aged mice. In addition, a d ecrease in Fas expression was found on splenic CD4(+) T cells in the aged m ice, and anti-Fas mAb-stimulated apoptosis was down-regulated on CD4(+) T c ells. These results indicate that age-associated dysregulation of CD4(+) T cells may play a crucial role on acceleration of organ-specific autoimmune lesions in a murine model for primary SS through Fas-mediated apoptosis.