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Principal Investigator: Momoko Yoshimoto
Organization: WESTERN MICHIGAN UNIV SCHOOL OF MEDICINE
Fiscal Year: 2024
Award: $191,364
Funding agency: National Institute of Allergy and Infectious Diseases
Abstract
IgA is the most abundant immunoglobulin produced in the lamina propria (LP) of the intestine and protects the
host against microbial invasions into intestinal mucosa by coating and excluding them. Selective IgA deficiency
is the most common immunodeficiency, and more than 50% of patients are asymptomatic. However, other
patients develop various diseases such as inflammatory bowel diseases, allergies, autoimmune diseases, and
recurrent infections. Despite the essential roles of IgA, it still remains unknown what causes the different clinical
manifestations of this disease. One of the barriers to understanding the pathology of selective IgA deficiency is
a gap of knowledge about the heterogeneity of developmental origin of the IgA-secreting cells. Our long-term
goal is to fill this knowledge gap and to determine the roles of IgA+ cells of different origins in the mucosal
immunity.
There are two known pathways in producing IgA secreting cells: T-cell independent (TI) and T-cell dependent
(TD) pathways. TI-IgA is a low-affinity polyclonal antibody that coats bacteria and maintains the microbiome
homeostasis, while TD-IgA undergoes somatic hypermutation and reacts against specific antigens. The
precursors of these TI- and TD-IgA have been controversial, but it has recently been demonstrated that TI IgA+
cells are derived from peritoneal B-1b cells while TD IgA+ cells are from germinal center B-2 cells. It is generally
considered that these B-1b and B-2 cells are ultimately produced by hematopoietic stem cells (HSCs) that reside
in the bone marrow (BM). However, our and others' prior work has shown that B-1b cells are also produced by
HSC-independent fetal progenitors during embryonic development. Our lineage tracing data indicated that IgA+
cells in the lamina propria (LP) are derived from embryonic day (E) 7.5 endothelial cells (ECs), three days before
the first HSC production in the embryo. Our lineage tracing system using EC-derived (Cdh5CreERT2) and HSC-
derived (Fgd5CreERT2) enables us to segregate IgA+ cells in the LP of different origins. Thus, the central
hypothesis of this project is that IgA+ cells in the LP consists of cells with different origins: fetal (EC)- and HSC-
derived and that IgA+ cells of different origins have different roles against gut injury and infections. To test our
hypothesis, in Aim1, we will examine TI- and TD- class switching of fetal- and HSC-derived B cells. We will also
visualize these fetal- and HSC-derived TI- and TD- IgA+ cells using scRNA-sequencing and BCR repertoire-
sequencing and will display the molecular differences of these cells. In Aim 2, we will examine the protective
roles of fetal- and HSC-derived IgA+ cells against GI infection with C. rodentium.
The results obtained from this proposal will establish a new paradigm of the developmental origin of IgA+ cells
and their functions in the gut homeostasis and infections.
Terms: <21+ years old><Adult><Adult Human><Affinity><Allergy><Antibodies><Antigens><Autoimmune Diseases><Autoregulation><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><B-cell receptor repertoire sequencing><B-cell receptor sequencing><BCR repertoire sequencing><BCR seq><BCR sequencing><BCRseq><Bacteria><Binding><Blood Precursor Cell><Bone Marrow><Bone Marrow Reticuloendothelial System><C rodentium><C. rodentium><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><Cell Body><Cell Function><Cell Lineage><Cell Physiology><Cell Process><Cell secretion><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cellular Secretion><Characteristics><Chromium><Citrobacter freundii Biotype 4280><Citrobacter rodentium><Class Switching><Class Switchings><Clinical><Cr element><Data><Defect><Development><Disease><Disorder><Embryo><Embryo Development><Embryogenesis><Embryonic><Embryonic Development><Endothelial Cells><Endothelium><Exclusion><Fetal Liver><Gene Expression><Genetic><Germinal Center><Goals><HSC production><Hematopoietic Cell Production><Hematopoietic Progenitor Cells><Hematopoietic stem cells><Heterogeneity><Homeostasis><Hypersensitivity><Ig Somatic Hypermutation><IgA><IgA deficiency syndrome><Immune><Immune Globulins><Immunes><Immunity><Immunoglobulin A><Immunoglobulin Class Switching><Immunoglobulin Class Switchings><Immunoglobulin Somatic Hypermutation><Immunoglobulins><Infection><Infection prevention><Inflammatory Bowel Diseases><Inflammatory Bowel Disorder><Injury><Intestinal><Intestinal Mucosa><Intestines><Invaded><Investigation><Isotype Switching><Isotype Switchings><Knowledge><Lamina Propria><Lycopersicon esculentum><Lymphopoiesis><Mice><Mice Mammals><Molecular><Molecular Interaction><Mucosal Immunity><Mucous body substance><Mucus><Murine><Mus><Pathology><Pathway interactions><Patients><Peritoneal><Physiological Homeostasis><Play><Position><Positioning Attribute><Predisposition><Prevent infection><Production><Reaction><Reporting><Role><Selective IgA Immunodeficiency><Selective IgA deficiency><Solanum lycopersicum><Spleen><Spleen Reticuloendothelial System><Structure of germinal center of lymph node><Subcellular Process><Susceptibility><Symptoms><System><T-Cell Depletion><T-Cells><T-Lymphocyte><T-cell depletion therapy><T-lymphocyte depletion therapy><T4 Cells><T4 Lymphocytes><Testing><Tomatoes><Transplantation><Visualization><Work><adulthood><autoimmune condition><autoimmune disorder><autoimmunity disease><base><bases><blood cell progenitor><blood progenitor><blood stem cell><blood-forming stem cell><bowel><developmental><enteral infection><enteric infection><enteric pathogen infection><enteropathogen infection><enteropathogenic infection><fetal><fetal infection><fetal progenitor><fetal stem cell><gastrointestinal homeostasis><gut homeostasis><hematopoietic progenitor><hematopoietic stem cell production><hematopoietic stem progenitor cell><hemopoietic progenitor><hemopoietic stem cell><hypoimmunity><immune deficiency><immunodeficiency><immunogen><immunoglobin a deficiency 1><in vivo><infected with enteropathogen><infection recurrence><inflammatory disease of the intestine><inflammatory disorder of the intestine><injuries><intestinal autoinflammation><intestinal homeostasis><intestinal infection><intestine infection><lymphocytopoiesis><microbial><microbial consortia><microbial flora><microbial homeostasis><microbiome><microbiota><microflora><mouse model><mucous><multispecies consortia><murine model><pathogen><pathway><polyclonal antibody><prevent><preventing><progenitor><recurrent infection><recurring infection><response><scRNA-seq><segregation><selective deficiency of Immunoglobulin a><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><somatic hypermutation><thymus derived lymphocyte><transplant>