Autoantibodies to the extracellular matrix microfibrillar protein, fibrillin-1, in patients with scleroderma and other connective tissue diseases

A duplication in the fibrillin-1 gene has been implicated as the cause of t he tight skin 1 (tsk1) phenotype, an animal model of scleroderma or systemi c sclerosis (SSc), In addition to the production of abnormal fibrillin-1 pr otein, the tsk1 mouse also produces autoantibodies to fibrillin-1. Among a population of Choctaw Native Americans with the highest prevalence of SSc y et described, a chromosome 15q haplotype containing the fibrillin-1 gene ha s been strongly associated with SSc, With a recombinant human fibrillin-1 p rotein, autoantibodies to fibrillin-1 were detected in the sera of Native A merican SSc patients that correlated significantly with disease, Abs to fib rillin-1 also mere detected in sera from Japanese, Caucasian, and African-A merican SSc patients. Compared with other ethnic groups, Japanese and Nativ e American SSc patients had significantly higher frequencies of antifibrill in-1 Abs. Sera from patients with diffuse SSc, calcinosis, Raynaud's, esoph ageal dysmotility, sclerodactyly, and telangiectasias syndrome and mixed co nnective tissue disease also had significantly higher frequencies of anti-f ibrillin-1 Abs than sera from controls or patients with other non-SSc conne ctive tissue diseases (lupus, rheumatoid arthritis, and Sjogren's syndrome) . Ab specificity for fibrillin-1 was demonstrated by the lack of binding to a panel of other purified autoantigens. The results presented demonstrate for the first time the presence of high levels of anti-fibrillin-1 Abs in a significant portion of patients with SSc.