The pathogenesis of lung complications in autoimmune disease remains unclear. To examine whether superantigens participate in the development of interstitial pneumonia in autoimmune disease, we instilled the bacterial superantigen staphylococcal enterotoxin B (SEB) into the tracheas of autoimmune and nonautoimmune mice. The intratracheal administration of SEB resulted in the induction of interstitial pneumonia manifested by infiltration of mononuclear cells into the alveolar septal walls and into the periarterial space and an increase in pulmonary interstitial collagen fibers in the autoimmune mouse strains. In the nonautoimmune strains, AKR, but not BALB/c and B10BR, mice also developed interstitial pneumonia after the intratracheal administration of SEB, although the degree of severity was milder than that induced in three autoimmune mouse strains. Although the intratracheal administration of another bacterial superantigen staphylococcal enterotoxin A also induced interstitial pneumonia, protein A which is a staphylococcal product but not a superantigen induced no remarkable change in lungs of MRL-+/+ mice. Immunohistologic studies revealed that not only SEB-reactive Vbeta8+ T cells, but also SEB-nonreactive Vbeta6+ T cells infiltrated the pulmonary lesions of SEB-primed MRL-+/+ mice, although this may be a secondary reaction for the Vbeta6+ T cells. The results of in vitro restimulation of spleen cells from SEB-primed BALB/c and SEB-primed MRL-+/+ mice with SEB suggest that incomplete induction of tolerance after the intratracheal administration of SEB may be involved in the pathogenesis of interstitial pneumonia induced in autoimmune mice. These results suggest participation of superantigens in the development of interstitial pneumonia in patients with autoimmune disease and other lung diseases such as idiopathic pulmonary fibrosis.