Microbial exposure and autoimmunity in the etiopathogenesis of Sarcoidosis

Abstract

Abstract Sarcoidosis is an enigmatic inflammatory disease affecting multiple organs such as the lungs, lymph nodes, brain, heart, and skin. It is characterized by the occurrence of multiple non-caseating granulomas comprised of macrophages, giant cells, and CD4 T cells. Although genetic and environmental factors increase the risk for sarcoidosis, the etiology remains unknown. Recent studies have shown that HLA-DR3+ sarcoidosis patients harbor CD4+ T cells reactive with a vimentin peptide 424–443. However, whether autoimmunity is a cause or consequence of the disease is not known. This study was undertaken to investigate the mechanisms responsible for activation of vimentin reactive T cells and determine their pathogenic role in sarcoidosis. For this purpose, we immunized the NOD-DR3 mice with the vimentin peptide 424–443 and induced a robust T cell response against the peptide. Fine epitope mapping using T cell hybridomas reactive with the peptide showed that both N-terminal and C-terminal amino acids were critical for T cell activation. Homology searches of microbial protein database identified a 100% homologous sequence in a protein from Klebsiella pneumoniae. Immunization of mice with this peptide, followed by intravenous transfer of peptide-coupled agarose beads induced granulomatous lesions in the lungs. Immunohistochemical analysis of these lesions showed the presence of CD4+ T cells, macrophages, and an upregulated MHC-II expression. In summary, our data demonstrate for the first time that autoimmunity is involved in the pathogenesis of sarcoidosis. Furthermore, the demonstration of molecular mimicry between a lung infecting microbe and vimentin might explain the role of microbial exposures as a risk factor for sarcoidosis.