Microvascular Injury in the Pulmonary Fibrosis of Collagen Vascular Disease
We encountered 16 patients with connective tissue disease in whom pulmonary fibrosis developed. Routine light microscopic, ultrastructural, and direct immunofluorescent analyses were conducted, and circulating antibodies, including those of endothelial cell derivation, were assessed using indirect immunofluorescence and Western blot assays. Underlying diseases were dermatomyositis, scleroderma, mixed connective tissue disease, sclerodermatomyositis, Sjögren syndrome, rheumatoid arthritis, and anti-Ro–associated systemic lupus erythematosus. Antibodies to one or more Ro, RNP, Jo 1, OJ, and/or nucleolar antigens were seen in all cases and antiphospholipid antibodies in half. All biopsies revealed microvascular injury in concert with intraparenchymal fibrosis; in some cases, there were corroborative ultrastructural findings of microvascular injury. Patterns of fibroplasia represented nonspecific interstitial pneumonitis and usual interstitial pneumonitis. We noted IgG, IgA, and/or complement in the septal microvasculature. In 6 cases with available serum samples, indirect immunofluorescent endothelial cell antibody studies were positive and Western blot studies showed reactivity of serum samples to numerous endothelial cell lysate–derived proteins.

Pulmonary fibrosis, a recognized complication of systemic connective tissue disease, develops in connective tissue disease syndromes with pathogenetically established immune-based microvascular injury at other sites. A similar mechanism of antibody-mediated endothelial cell injury may be the basis of the tissue injury and fibrosing reparative response.

Connective tissue diseases (CTDs) represent a heterogeneous group of disorders of unknown cause that are accompanied by circulating autoantibodies that may evoke tissue injury. The pathogenetic dilemma associated with CTDs in general includes the following issues: (1) The mechanisms resulting in autoantibody formation are not clear. (2) There is no clear explanation for the specificity of the organ-specific cellular targets of the antibodies. (3) The pathogenetic consequence of these antibodies are unknown.

Pulmonary fibrosis (PF) is among the most serious sequelae associated with collagen vascular disease, defining an important cause of morbidity and mortality. There are select CTD syndromes in which this complication is more likely to develop, namely those conditions associated with multiorgan immune-based microvascular injury. These entities encompass scleroderma, dermatomyositis, mixed connective tissue disease (MCTD), sclerodermatomyositis, anti-Ro–associated systemic lupus erythematosus (anti-Ro SLE), and rheumatoid arthritis (RA). In fact, the incidence of PF is particularly high in the setting of scleroderma; up to 70% of patients with scleroderma manifest some degree of parenchymal fibrosis. As expected, one of the main causes of death in patients with dermatomyositis-polymyositis, MCTD, and scleroderma is respiratory dysfunction, reflecting relentless, progressive intrapulmonary fibroplasia.

Although there is substantial literature linking PF to underlying collagen vascular disease, the basis of the fibrosis is undetermined. In contrast, the mechanism of extrapulmonary tissue injury in these conditions is better elucidated. Given the ubiquitous nature of the autoimmune-based microvascular injury operative in other organ sites such as the skin and muscle and the presence of circulating anti–endothelial cell antibodies in these various syndromes, we hypothesized that these antibodies are an inciting trigger to PF.

Studies support the hypothesis that immune-based microvascular injury may be important in the propagation of PF. In particular, endothelial cell injury has been linked to idiopathic PF (IPF) and fibrosis developing in the setting of scleroderma. We found that patients with IPF and scleroderma who developed PF manifested deposition of complement and immunoglobulin within the septal microvasculature; there was also serologic evidence of circulating anti–endothelial cell antibodies. In regards to the latter point, Western blot studies showed reactivity to endothelial cell lysates of serum from patients with IPF and scleroderma. In support of this finding, Fujita and coworkers demonstrated reactivity of serum from patients with IPF and collagen vascular disease with cytokeratin 19, an important and unique constituent of pulmonary microvascular endothelial cells. Moreover, Ihn and coworkers showed a direct association between anti–endothelial cell antibodies and the development and severity of PF.

This article describes the clinical and pathologic findings in 16 patients with connective tissue disease syndromes in whom lung biopsy showed PF. By using direct (DIF) and indirect (IIF) immunofluorescence, electron microscopy, Western blot analysis, and serologic studies to assess for vascular cofactors, we explored a role for autoimmune-based microvascular injury.