Interstitial lung disease patients exhibit augmented germinal center responses in Lung Lymph nodes and increased serum reactivities to novel autoantigens

Abstract Interstitial lung disease (ILD), a group of disorders characterized by scarring of the lungs, often leads to fatal impairment of respiratory function. While some patients exhibit features of autoimmunity, the role of the immune system within this heterogeneous group of disorders remains a matter of debate. We previously reported the enlargement of lung-draining lymph nodes (LLN) correlates with decreased survival in ILD patients, suggesting that activation of the adaptive immune system may contribute to pathophysiology. To investigate the composition and functional state of cells in the enlarged LLN, we performed flow cytometry analysis of LLN cells from endstage ILD patients undergoing transplantation (n=53) and control organ donors (n=36). We found that T cells from the ILD LLN exhibit effector memory phenotypes and significantly upregulate activation molecules including HLA-DR, CD38, CD154 and CD137, which are indicative of an ongoing immune response. Analyses of CD4 T cells revealed that Foxp3+CD25− regulatory T cells are specifically increased in ILD LLN. Moreover, follicular helper T cells and germinal center (GC) B cells are highly enriched, suggesting that antibody responses are activated in ILD LLN. To test the hypothesis that autoantigens may drive the augmented GC response, we screened circulating antibodies from ILD patients at two medical centers against the entire human peptidome using phage immunoprecipitation sequencing. We defined novel and shared autoantigens and experimentally validated antibody bindings to 5 protein antigens. Collectively, our findings suggest that antigen-specific immune responses may be involved in the pathophysiology and identify novel autoantigens for subsets of ILD.