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Principal Investigator: Jessica A Hamerman
Organization: BENAROYA RESEARCH INST AT VIRGINIA MASON
Fiscal Year: 2020
Award: $253,182
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by the presence
of circulating autoantibodies to nucleic acids and to proteins with which they associate. Signaling through the
nucleic acid sensing TLRs, TLR7 and TLR9, is critical in SLE pathogenesis, and dysregulated TLR signaling
can promote lupus in humans and in mouse models. Plasmacytoid dendritic cells (pDC) and B cells both
express these nucleic acid sensing TLR and are important in SLE pathogenesis. Autoreactive B cells produce
pathogenic autoantibodies in SLE, and B cell antibody production is promoted by TLR7 and TLR9 signaling.
pDC use TLR7 and TLR9 to respond to nucleic acids in immune complexes resulting in the secretion of large
quantities of type I IFN cytokines, which have pleiotropic effects on the immune response, including enhancing
dendritic cell (DC) maturation, plasma cell formation, and T cell responses, all of which can promote a feed
forward loop of immune activation. Therefore, understanding the mechanisms by which TLR7 and TLR9
signaling are regulated in these two critical cell types is important for understanding the pathogenesis of SLE
and in defining therapeutic targets for this disease. We have identified the signaling adapter B cell adapter for
PI3-kinase (BCAP) as a key modulator of TLR signaling in multiple immune lineages. First, we found that in
macrophages BCAP inhibits TLR-induced inflammatory cytokine production via activation of PI3-kinase. We
recently showed that BCAP promotes pDC IFNα, but not IL-6, secretion. We have also begun to examine how
BCAP regulates B cell TLR7/9 responses, an understudied area. Our preliminary data show that BCAP is a
key regulator of B cell TLR7/9 responses in all B cell subsets, with a particularly striking decrease in
proliferation and IgG secretion from splenic marginal zone B cells. Additionally, we have found that BCAP-
deficiency protects the TLR7.1 mouse lupus model from disease. Together, our findings show an important
role of BCAP in endosomal TLR signaling in pDC and B cells, both important in SLE pathogenesis. Given the
importance of TLR7 and TLR9 signaling in both B cells and pDC in SLE, the premise of this application is that
BCAP regulation of pDC and B cell TLR7/9 signaling is critical in the development of lupus-like disease.
Specifically, we will 1) determine the mechanism by which BCAP regulates TLR7/9-induced IFNα production in
pDCs, 2) determine the mechanism by which BCAP regulates B cell TLR7/9 responses, and 3) determine the
relative contribution of BCAP in pDCs and B cells to lupus-like disease using two mouse models.
Terms: <1-Phosphatidylinositol 3-Kinase><2019 novel coronavirus><2019-nCoV><7S Gamma Globulin><ARDS><Ab response><Acute><Acute Respiratory Distress><Acute Respiratory Distress Syndrome><Acute respiratory failure><Adult ARDS><Adult RDS><Adult Respiratory Distress Syndrome><Alferon><Antibody Formation><Antibody Production><Antigen-Antibody Complex><Area><Aspirate><Aspirate substance><Autoantibodies><Autoimmune Diseases><Automobile Driving><B blood cells><B cell><B cells><B-Cell Subsets><B-Cells><B-Lymphocyte Subsets><B-Lymphocytes><B-cell><Blood Coagulation Disorders><Blood Plasma><Blood Plasma Cell><Blood Sample><Blood Serum><Blood monocyte><Blood specimen><Body Tissues><COVID-19><COVID19><Case Study><Cell Body><Cell Communication and Signaling><Cell Maturation><Cell Signaling><Cells><Cessation of life><Chemotactic Cytokines><Clinical><Clinical Markers><Coagulation Disorder><Coagulopathy><Communicable Diseases><Complex><Complication><Control Groups><Critical Care><Cytotoxic cell><Da Nang Lung><Data><Death><Dendritic Cells><Development><Disease><Disease Marker><Disease model><Disorder><ED visit><ER Positive><ER visit><ER+><Elderly><Emergency care visit><Emergency department visit><Emergency hospital visit><Emergency room visit><Encephalopathies><Estrogen receptor positive><Exhibits><Failure><Funding><Hepatosplenomegaly><History><Homologous Chemotactic Cytokines><Hospitals><Human><Human Resources><IFN><IFN Alpha><IFN-α><IFNa><IFNα><IgG><Immune><Immune Cell Activation><Immune Complex><Immune response><Immunes><Immunoglobulin G><Immunologic Subtyping><Immunological response><Immunophenotyping><In Vitro><Individual><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Inflammation><Inflammatory><Inflammatory Response><Inpatients><Institution><Intercrines><Interferon Alfa-n3><Interferon-alpha><Interferon-α><Interferons><Intracellular Communication and Signaling><K lymphocyte><Lead><Leukocyte Interferon><Life><Link><Lung><Lung Respiratory System><Lupus><Lupus Erythematosus Disseminatus><Lymphoblast Interferon><Lymphoblastoid Interferon><Macrophage Activation><Manpower><Marrow monocyte><Measures><Medical center><Mice><Mice Mammals><Modern Man><Murine><Mus><NK Cells><Natural Killer Cells><Nucleic Acids><Out-patients><Outpatients><PBMC><PI-3 Kinase><PI-3K><PI3-Kinase><Pathogenesis><Pathogenicity><Pathology><Patients><Pb element><Peripheral Blood Mononuclear Cell><Phenotype><Phosphatidylinositol 3-Kinase><Phosphatidylinositol-3-OH Kinase><Phosphoinositide 3-Hydroxykinase><Plasma><Plasma Cells><Plasma Serum><Plasmacytes><Pneumonia><Process><Production><Proteins><PtdIns 3-Kinase><Publishing><Recording of previous events><Regulation><Research Institute><Research Resources><Research Specimen><Resources><Reticuloendothelial System, Serum, Plasma><Role><SARS-CoV-2><SARS-CoV2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related coronavirus 2><SIS cytokines><SLE><Sampling><Sepsis><Serum><Severe acute respiratory syndrome coronavirus 2><Severities><Severity of illness><Shock Lung><Signal Transduction><Signal Transduction Systems><Signaling><Specialist><Specimen><Stiff lung><Swab><Syndrome><Systemic Lupus Erythematosus><Systemic Lupus Erythematous><Systemic Lupus Erythmatosus><T cell response><T-Cells><T-Lymphocyte><TLR7><TLR7 gene><Testing><Time><Tissues><Toll-Like Receptor 7><Type I Phosphatidylinositol Kinase><Type III Phosphoinositide 3-Kinase><Veiled Cells><Viral><Viral Diseases><Virginia><Virus><Virus Diseases><Work><Wuhan coronavirus><advanced age><antibody biosynthesis><autoimmune antibody><autoimmune disorder><autoreactive B cell><biological signal transduction><bleeding disorder><blood infection><bloodstream infection><case report><cell type><chemoattractant cytokine><chemokine><clotting disorder><cohort><corona virus disease 2019><coronavirus disease 2019><cytokine><cytokine release syndrome><cytokine storm><cytopenia><developmental><disease severity><disorder model><disseminated lupus erythematosus><driving><early biomarkers><early detection biomarkers><early detection markers><elders><endotracheal><experience><experiment><experimental research><experimental study><familial hemophagocytic lymphohistiocytosis><geriatric><heavy metal Pb><heavy metal lead><hemophagocytic lymphohistiocytosis><host response><immune activation><immunoglobulin biosynthesis><immunophenotype><immunoresponse><late life><later life><lupus-like><macrophage><monocyte><mouse model><murine model><older adult><older person><patient subgroups><patient subpopulations><patient subsets><patient subtypes><personnel><plasmocyte><pleiotropic effect><pleiotropism><pleiotropy><pulmonary><response><self reactive antibody><senior citizen><social role><systemic lupus erythematosis><therapeutic target><thymus derived lymphocyte><viral infection><virus infection><virus-induced disease><wet lung>