B-cells are increasingly linked to a number of fibrotic lung diseases (FLD) and it is well recognized that they form aggregates, known as inducible bronchus associated lymphoid tissue (iBALTs) in the lung of many of these patients. Our studies demonstrate that when activated by microbial antigens through pattern recognition receptors (PRRs), B-cells are not just merely antibody producing cells but are also an important source of inflammatory mediators that participate in the recruitment of other immune effector cells. However, the role that B-cells and iBALTs play in the pathogenesis of FLD remains obscure. Our long-term goal is to dissect the mechanisms by which B-cells participate in the injury and repair of lung tissue in FLD, determine their role in the development of fibrosis and develop novel therapeutic strategies for these devastating diseases. The objective of this proposal is to investigate the participation of B-cells in lung fibrosis by characterizing the phenotype and function of circulating and tissue infiltrating B-cells in patients with FLD and murine models of fibrosis. The central hypothesis is that is that B-cells activated via PRRs release inflammatory mediators that regulate immune effector cells contributing to the inflammatory response and that dysregulation of B-cells contributes to the development of lung fibrosis. Our rationale is that identification of the mechanisms by which B-cells contribute to lung injury and repair in the setting of FLD will identify new therapeutic opportunities for these patients.
Our specific aims will test the following hypothesis:
(Aim 1) Activated B-cells contribute to lung injury and repair, by secreting CXCL10, CXCL13, CCL20 and galectins.
(Aim 2) Chronic Stimulation of PRRs promotes the persistence of iBALTs formation in FLD by stimulation of PRRs that drive mTOR-dependent and independent pathways involved in cell proliferation and cytokines/chemokine secretion.
(Aim 3) : iBALTs are disease specific and modulate the injury and repair mechanisms of the lung. This contribution is significant since it will advance our understanding of B-cell responses to PRRs ligands and decipher the mechanisms by which B-cells modulate healing processes in the lung and how they contribute to the development of fibrosis. The proposed research is innovative through novel investigation of the effect of B-cells activation in the regulation of inflammatory cell recruitment and iBALT formation. Insight into the molecular pathways that drive B-cell activation by PRRs will allow selective targeting with current available therapies.
Pulmonary fibrosis is an incurable disease that causes respiratory failure and death in the majority of patients, with lung transplant being the only curative option. While, B-cell aggregates are frequently found in the lung tissue of a subset of these patients, B-cell depleted therapies showed only variable clinical responses suggesting that better understanding of B-cells is needed to identify potential curative treatments. Upon conclusion of our studies, aimed at dissecting the main mechanisms by which B-cells contribute to the development of fibrosis, will aid in the identification of new targets for therapeutic exploitation in a selected group of patients with lung fibrosis.