SEMINAR: Unravelling the molecular and cell-mediated pathways in fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive form of interstitial lung disease (ILD) of unknown aetiology. Analysis of the molecular and cellular mechanisms underlying IPF have led to the discovery that gp130-mediated Jak/STAT signalling potentiates fibrosis in response to Blm-induced damage. Using knockout and mutant mouse models, with heightened Jak/STAT signalling but deficient in B and T cells we have implicated immune cells in the development of fibrosis. Our current research in human cells and tissues has demonstrated that IPF is associated with prominent lymphoid aggregates of CD3+ T cells and CD20+ B cells within the lung tissue located near sites of active fibrosis. We have examined peripheral blood and lung tissue samples from a cohort of clinically diagnosed IPF patients and aged match healthy controls to examine B cell populations and the presence of chemokines and auto antibodies. A subset of IPF patients displayed elevated levels of CXCL13 and BAFF in serum, and auto antibodies to nuclear antigens (30%), dsDNA (13%) and/or anti Rheumatoid factor Abs (30%). The presence of circulating autoantibodies suggests that these IPF patients have experienced a breakdown in self- tolerance to systemic antigens a finding consistent with other ILDs. Immunophenotyping of peripheral blood samples has revealed differences in immune cell subsets and this may be helpful in the future to better stratify patients to identify those who may benefit from targeted immunotherapy to arrest disease progression.