We examined the immunogenicity of various connective tissue proteins in patients with chronic onchocercal dermatitis and the effect of filarial proteases on this host-parasite interaction. Sera from patients with onchocerciasis reacted strongly with cuticular collagens from filarial parasites and with mammalian laminin. Some sera also contained antibodies to elastin and collagen type IV, but none reacted with collagen types I-III or fibronectin. This pattern of reactivity was characteristic for onchocerciasis: sera from patients with mansonellosis reacted strongly with collagen type IV but only weakly with laminin. Reactivity with mammalian laminin or collagen could not be absorbed with cuticular proteins from filarial worms and vice versa. Digestion fragments of laminin treated with filarial proteases retain antigenic determinants recognized by sera from patients with onchocerciasis. In contrast, proteases from Onchocerca volvulus adults and microfilariae drastically decreased the reactivity of the same sera with collagen type IV. These results indicate that filarial proteases may contribute to the pathogenesis of chronic onchocercal dermatitis, directly, by enzymatically destroying connective tissue of the skin, and indirectly, by triggering autoimmune responses to self-determinants on connective tissue proteins that are normally hidden within the supramolecular structure of the extracellular matrix complex.