Yipp, BryanKubes, PaulKim, Jung Hwan2018-01-252018-01-252018-01-17Kim, J. H. (2018). The Role of B-cells in Regulating Pulmonary Neutrophils in vivo (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.http://hdl.handle.net/1880/106313Neutrophils, the major innate immune cell, are short-lived and typically considered as pro-inflammatory. As such, its pre-dominant role is to clear infections via the release of cytotoxic granules and phagocytosis. The production of neutrophils is regulated in the bone marrow, which generates about 1011 neutrophils per day in humans. Newly produced neutrophils circulate and transit through all organs receiving blood flow, seeking out infections and inflammatory signals. During homeostasis, neutrophils age overtime and are thought to be cleared from the system by macrophages in lymphoid organs. However, despite t extensive research, a complete life-cycle of neutrophils, including the aging process and regulation of neutrophil clearance, remains poorly understood. Interestingly, the pulmonary vasculature contains a significant amount of retained neutrophils that are higher concentration than their circulating counterpart. These marginated neutrophils were described to be retained within the pulmonary vasculature via CXCR4, a marker that is up-regulated on aged neutrophils. Therefore, we hypothesized that margination of neutrophils in the lung might represent a key intermediate step in the regulation and elimination of neutrophils. In this body of work, we discovered lung neutrophils display an aged phenotype where they express a higher level of CD18 and CXCR4 than the peripheral pool. Interestingly, these aged neutrophils bind pulmonary circulating B-cells via CD18. Moreover, such intercellular interaction between the two cells induces apoptosis in neutrophils that also depends on CD18, leading to the removal of subsequent apoptotic neutrophils by macrophages. B-cell depletion resulted in neutrophil inflammation leading to interstitial lung disease (ILD), and was attenuated by B-cell adoptive transfer or neutrophil depletion. During a model of rheumatoid arthritis (RA), B-cell sufficient animals were protected from neutrophil pulmonary inflammation; however, CD19-deficient mice, which have defective B-cell populations and response regulation, developed lung neutrophilic inflammation in addition to arthritis. Thus, we have defined a new regulatory role of B-cells to control neutrophils in pulmonary capillaries and found that the lung is a key site for neutrophil life-cycle.enUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.ImmunologyNeutrophilsB-cellsLung diseaseImmunologydoctoral thesis10.11575/PRISM/5394