Cellular and humoral autoreactivity in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a morbid, refractory lung disorder with an unknown pathogenesis. To investigate potential adaptive immune mechanisms in IPF, we compared phenotypes and effector functions of peripheral CD4 T cells, autoantibody production, and proliferative responses of pulmonary hilar lymph node CD4 T cells to autologous lung extracts from afflicted patients and normals. Our results show that greater proportions of peripheral CD4 T lymphocytes in IPF subjects expressed MHC class II and CD154 (CD40L), and they more frequently elaborated TGF-beta1, IL-10, and TNF-alpha. Abnormal CD4 T cell clonal expansions were found in all IPF patients, and 82% of these subjects also had IgG autoantibodies against cellular Ags. IPF lung extracts stimulated proliferations of autologous CD4 T cells, unlike preparations from normals or those with other lung diseases, and the IPF proliferative responses were enhanced by repeated cycles of stimulation. Thus, CD4 T cells from IPF patients have characteristics typical of cell-mediated pathologic responses, including augmented effector functions, provision of facultative help for autoantibody production, oligoclonal expansions, and proliferations driven by an Ag present in diseased tissues. Recognition that an autoreactive immune process is present in IPF can productively focus efforts toward identifying the responsible Ag, and implementing more effective therapies.

Reduction in fibrotic tissue formation in mice genetically deficient in plasminogen activator inhibitor-1.

Mice with homozygous deletion of the plasminogen activator inhibitor-1 gene (PAI-1(-/-)) are relatively protected from bleomycin-induced pulmonary fibrosis. At least part of the protective effect appears to occur during the latter stages of the pathological process when fibrotic tissue is being deposited. To investigate the effect of PAI-1 deficiency on fibrosis, we studied the accumulation of fibrotic tissue within subcutaneously implanted polyvinyl alcohol sponges. Similar to the effect of PAI-1 deficiency on bleomycin-induced pulmonary fibrosis, the accumulation of fibrotic tissue within implanted sponges occurred more slowly in PAI-1(-/-) compared to wild-type mice. Another striking difference observed in the PAI-1(-/-) mice was the rapid removal of a fibrin-rich matrix that formed within the sponges by 1 day after implantation in both wild-type and PAI-1(-/-) mice. The pattern of connective tissue invasion also differed: cells in wild-type mice infiltrated as individually penetrating cells whereas in PAI-1(-/-) mice they did so as a well-demarcated advancing front. Providing an alternative provisional matrix by impregnating sponges with a low concentration of collagen before implantation corrected the changes induced by PAI-1 deficiency. In conclusion, PAI-1 deficiency appears to affect fibrotic tissue formation in part by altering the provisional matrix that forms soon after tissue injury.