B-CELL DEFICIENCY DOES NOT ABROGATE DEVELOPMENT OF CUTANEOUS HYPERPLASIA IN MICE INHERITING THE DEFECTIVE FIBRILLIN-1 GENE

Tight-skin (TSK) mouse, the experimental model for scleroderma, develo ps cutaneous hyperplasia, cardiac hypertrophy, pulmonary emphysema and autoimmunity against scleroderma target autoantigens. The cutaneous h yperplasia is associated with the accumulation of microfibrils and ela stic fibers in the middle and deep dermis. Fibrillin-1 (Fbn-1) is a ma jor component of the 10-12 nm microfibrils found in the extracellular matrix. In this study we report the identification of a genetic marker in the Fbn-1 gene that can distinguish the mutant phenotype. TSK mice exhibit an unique polymorphism in the Fbn-1 gene. RNA analysis, PCR a nalysis and sequence determination of the mutant gene showed that the Fbn-1 gene polymorphism is due to intragenic duplication of a segment of the gene coding for 3.0 Kb of mRNA sequence (10 Kb of the genome). Histological analysis of skin samples from Fl progeny obtained by cros sing TSK mice with J(H)-/-, RAG2-/- or vit/vit showed a significant co rrelation between the inheritance of the defective Fbn-1 gene and the development of cutaneous hyperplasia. Further, our results also show t hat in mice deficient in mature B cells inheriting the defective Fbn-1 gene, development of cutaneous hyperplasia is not abrogated. Thus, pr oduction of autoantibodies or the presence of mature B lymphocytes do not play an integral role in the pathogenesis of cutaneous hyperplasia . (C) 1997 Academic Press Limited.