Document text
Principal Investigator: Eva Maria Carmona Porquera
Organization: MAYO CLINIC ROCHESTER
Fiscal Year: 2019
Award: $79,500
Funding agency: National Heart Lung and Blood Institute
PROJECT SUMMARY/ABSTRACT
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.
Terms: <3-10C><AMCF-I><Address><Alveolar><Antibody-Producing Cells><Atrophic Arthritis><Automobile Driving><Award><B blood cells><B cell><B cell differentiation factor><B cell stimulating factor 2><B cells><B-Cell Activation><B-Cell Attracting Chemokine 1><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><B-Cells><B-Lymphocyte Chemoattractant><B-Lymphocytes><B-cell><BALT><BCA1><BCDF><BLC gene><BLC protein><BSF-2><BSF2><Besnier-Boeck Disease><Beta Proprotein Interleukin 1><Bleo><Bleomycin><Blood Neutrophil><Blood Polymorphonuclear Neutrophil><Blood monocyte><Body Tissues><Boeck's Sarcoid><Bronchus-Associated Lymphoid Tissue><CCL20><CCL20 gene><CRG-2><CXCL10><CXCL10 gene><CXCL13><CXCL13 gene><CXCL8><Cell Body><Cell Growth in Number><Cell Isolation><Cell Multiplication><Cell Proliferation><Cell Segregation><Cell Separation><Cell Separation Technology><Cells><Cellular Proliferation><Cessation of life><Chemokine, CC Motif, Ligand 20><Chemokine, CXC Motif, Ligand 13><Chemotactic Cytokines><Chemotaxis><Chronic><Clinical><D-Galactoside-Binding Lectin><Data><Death><Dendritic Cells><Development><Disease><Disease model><Disorder><Drugs><Effector Cell><Exodus 1><FK506 Binding Protein 12-Rapamycin Associated Protein 1><FKBP12 Rapamycin Complex Associated Protein 1><FRAP1><FRAP1 gene><FRAP2><Fibroblasts><Fibrosis><Foundations><Fungal Antigens><Future><GCP1><Galactose Binding Lectin><Galaptins><Galectins><Goals><HPGF><Health><Hepatocyte-Stimulating Factor><Homologous Chemotactic Cytokines><Human><Hybridoma Growth Factor><IFI10><IFN-beta 2><IFNB2><IL-1 beta><IL-1 β><IL-1-b><IL-1β><IL-6><IL-8><IL1-Beta><IL1-β><IL1B Protein><IL1F2><IL1β><IL6 Protein><IL8><IL8 gene><INP10><IP-10><Immune><Immunes><Immunoglobulin-Producing Cells><Infection><Inflammation Mediators><Inflammatory><Inflammatory Response><Injury><Intercrines><Interleukin 1beta><Interleukin-1 beta><Interleukin-1β><Interleukin-6><Investigation><K60><LARC><LUCT><LYNAP><Ligands><Link><Lung><Lung Grafting><Lung Inflammation><Lung Parenchyma><Lung Respiratory System><Lung Tissue><Lung Transplantation><Lung damage><Lung diseases><MDNCF><MGI-2><MIP3A><MMP-7><MOB-1><MONAP><Macrophage Inflammatory Protein 3-Alpha><Marrow Neutrophil><Marrow monocyte><Matrilysin><Matrin><Matrix Metalloproteinase-7><Mechanistic Target of Rapamycin><Medication><Messenger RNA><Metallopeptidases><Metalloproteases><Metalloproteinases><Mice><Mice Mammals><Modern Man><Molecular><Murine><Mus><Myeloid Differentiation-Inducing Protein><Neutrophilic Granulocyte><Neutrophilic Leukocyte><PUMP-1><Pathogenesis><Pathway interactions><Patients><Pattern recognition receptor><Pharmaceutic Preparations><Pharmaceutical Preparations><Phenotype><Plasmacytoma Growth Factor><Play><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Preinterleukin 1 Beta><Process><Publishing><Pulmonary Diseases><Pulmonary Disorder><Pulmonary Fibrosis><RAFT1><Reaction><Regulation><Research><Respiratory Disease><Respiratory Failure><Respiratory System Disease><Respiratory System Disorder><Rheumatoid Arthritis><Role><S-Type Lectins><SCYA20><SCYB10><SCYB13><SCYB8><SIS cytokines><Sarcoidosis><Schaumann's Disease><Small Inducible Cytokine Subfamily A, Member 20><Small Inducible Cytokine Subfamily B, Member 13><Smoke><Source><Structure of parenchyma of lung><System><T-Cells><T-Lymphocyte><TSG-1><Techniques><Testing><Tissues><Vaccine Adjuvant><Veiled Cells><Work><b-ENAP><base><beta-D-Galactosyl-Specific Lectin><beta-Galactoside Binding Lectin><beta-Glucans><cell sorting><chemoattractant cytokine><chemokine><curative intervention><curative therapeutic><curative therapy><curative treatments><cytokine><design><designing><developmental><diffuse interstitial pulmonary fibrosis><disease of the lung><disorder model><disorder of the lung><driving><drug/agent><environmental agent><expectation><experiment><experimental research><experimental study><gIP-10><healing><idiopathic pulmonary fibrosis><inflammatory mediator><injury and repair><innovate><innovation><innovative><insight><interferon beta 2><laser capture microdissection><lung development><lung disorder><lung fibrosis><lung injury><lung transplant><mRNA><mTOR><mammalian target of rapamycin><microbial antigen><microorganism antigen><migration><monocyte><mouse model><murine model><neutrophil><new drug target><new drug treatments><new druggable target><new drugs><new pharmacotherapy target><new therapeutic target><new therapeutics><new therapy><new therapy target><next generation therapeutics><novel><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmacotherapy target><novel therapeutic target><novel therapeutics><novel therapy><novel therapy target><pathogen><pathway><patient subgroups><patient subpopulations><patient subsets><patient subtypes><pulmonary><pulmonary failure><recruit><respiratory insufficiency/failure><response><rheumatic arthritis><social role><syndecan-4><thymus derived lymphocyte><β-Glucans>