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Understanding Immune Mechanisms Involved in Chronic Lung Diease Autoimmunity and Monoclonal Antibody Mediated-trogocytosis
By:Sladjana Skopelja-Gardner
Published on 2017 by

The work presented in this thesis explores two different scientific questions: 1) Autoimmunity and host-pathogen interactions in chronic Pseudomonas aeruginosa infections and 2) Differential effector functions of B cell targeting monoclonal antibodies in chronic lymphocytic leukemia (CLL), with the goal of understanding heterogeneity in cystic fibrosis (CF) pulmonary disease, as well as variable response to monoclonal antibody therapy in CLL, respectively. In the first analysis of autoimmunity in a United States CF cohort, we demonstrate that the autoantibody profile in CF patients differs from that found in rheumatoid arthritis, despite their similar associations with lung inflammation. In particular, this work examines the unique signature of autoimmunity in CF: autoantibodies to bactericidal permeability/increasing protein (BPI), a neutrophil derived anti-microbial protein and proposes a mechanism that might lead to the breaking of tolerance to BPI. We demonstrate that BPI undergoes cleavage as result of neutrophil extracellular trap formation (NETosis) in the presence of Pseudomonas elastase expressing P. aeruginosa strains. This cleavage generates a fragment corresponding to the protein C-terminus, which we identified as a target of anti-BPI autoantibodies. By expanding our studies to a non-cystic fibrosis bronchiectasis (non-CF BR) cohort, we demonstrate that anti-BPI autoimmunity is not specific to CF, but arises in other pulmonary inflammatory diseases and strongly associates with chronic Pseudomonas aeruginosa infection. Anti-BPI autoimmunity in both conditions is associated with diminished pulmonary function. Through these studies, we also identified a distinct autoantibody type in a subset of CF and non-CF BR patients: anti-carbamylated protein autoantibodies (ACarPA). ACarPA develop independently of anti-BPI autoantibodies and do not associate with chronic P. aeruginosa infection. As part of these studies, besides the differential effect of P. aeruginosa strains on BPI, we have also identified differences in host-pathogen interactions between wild type and LasR-deficient P. aeruginosa strains and neutrophils. We demonstrate that absence of LasR, a global regulator of virulence factors and quorum sensing in P. aeruginosa, leads to diminished NET induction by Pseudomonas aeruginosa, independent of bacterial motility. LasR appears to mediate NETosis via regulation of one or more virulence factors, including Pseudomonas elastase LasB. We propose that pathoadaptability of LasR-deficient P. aeruginosa strains, which are also known to develop in chronically infected CF patients, could at least partially be attributed to evasion of NET-mediated killing. Further studies are required to investigate this hypothesis. The second part of this thesis addresses a different clinical question: Does trogocytosis play a role in the treatment of CLL with a new generation anti-CD20 monoclonal antibody Obinutuzumab (GA101)? Trogocytosis has previously been identified in rituximab (RTX) treated cells as a process by which FcgR carrying cells (monocytes, PMNs) remove and endocytose RTX-bound CD20 molecules and surrounding proteins from B cell surface, which alters both the B cell phenotype and cytokine production. In a direct comparison with rituximab, we demonstrated that obinutuzumab undergoes more potent trogocytosis, as a result of differential engagement of the CD20 molecule, which leads to formation of homotypic adhesion (HA). Furthermore, this work uncovers a high degree of variability in GA101-mediated homotypic adhesion formation and the extent of trogocytosis. We identify that increased expression of zeta-chain-associated protein kinase 70 kDa (ZAP-70), a B-cell receptor-associated kinase, strongly correlates with the degree of HA formation and trogocytosis, which are subsequently diminished as a consequence of ZAP-70 dysregulation. These findings elucidate the differences in trogocytosis and HA formation mediated by anti-CD20 monoclonal antibodies RTX and GA101, as well as provide a novel link between ZAP-70 expression and these effector functions. These novel observations suggest that clinical features of CLL (ZAP-70 expression) could serve to predict anti-CD20 treatment outcomes, both as a single therapy and in combination with tyrosine kinase inhibitors, and thus to better inform treatment choice.

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