Studies of the cellular immune response to heparan sulfate proteoglycan in the tight skin mouse

As in human scleroderma, tight skin (TSK/+) mice develop cutaneous hyperplasia with overproduction of extracellular matrix, including collagen and proteoglycans, associated with autoimmunity to a number of autoantigens. The present study investigated the presence of cellular autoimmunity to basement membrane heparan sulfate proteoglycan (HSPG) in diseased TSK/+ mice and their nondiseased littermates, pallid mice (+/pa). Lymphocyte proliferative responses to specific HSPG antigens, including intact HSPG, HSPG protein core (P. Core), and the glycosaminoglycan heparan sulfate (HS) were studied. Splenocytes from young TSK and control pallid mice reacted weakly to intact HSPG and HSPG P. Core antigens and did not respond to HS. However, lymphocytes from old TSK mice were reactive with HSPG and P. Core and demonstrated a de novo response to HS. The proliferative response to intact HSPG and HSPG P. Core in TSK mice was T cell dependent, but the response to HS was T cell independent. The T cell-dependent response was mediated by the CD4-positive subset and required the participation of class II major histocompatibility complex molecules. Cellular autoimmunity to HSPG, a critical cell surface and extracellular matrix component, may play a role in the disease suffered by TSK mice. Further studies are necessary to determine the mechanisms which link autoimmunity to HSPG with the pathology seen in TSK mice, particularly the overproduction of extracellular matrix and fibrosis.