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Principal Investigator: John J. Erickson
Organization: CINCINNATI CHILDRENS HOSP MED CTR
Fiscal Year: 2024
Award: $193,212
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
TITLE: Maternal B cells enforce fetal tolerance
GOALS/OBJECTIVES: The overall goal of this five-year proposal for a Mentored Clinical Scientist Research
Career Development Award (K08) is for me to develop into a productive, independent academic investigator in
the field of reproductive immunology. My prior training has provided me expertise regarding T cell and antibody
mediated host defense. Through this proposal I will gain additional experience in B cell biology,
glycoimmunology and fetal tolerance. The long-term goal of this research is to improve pregnancy outcomes,
which will lead to healthier pregnancies and neonates. I graduated from the American Board of Pediatrics
Accelerated Research Pathway for Residency in General, and I completed my Fellowship in Neonatal-
Perinatal Medicine at Cincinnati Children’s Hospital (CCHMC). I joined the faculty of CCHMC and the
University of Cincinnati as an Attending Physician and Research Assistant Professor in the Division of
Neonatology. My mentor for this award, Dr. Sing Sing Way, is a physician-scientist with a longstanding track
record of scientific innovation and providing exceptional training to mentees at all levels. As an internationally
recognized expert in the immunology of pregnancy, microchimerism, commensalism and neonatal sepsis, Dr.
Way’s work highly complements my own. My mentorship committee brings needed expertise to the areas of
antigen-specific B cell responses (Dr. Justin Taylor), B cell interactions with N-linked glycans (Dr. Shiv Pillai),
placental immunology (Dr. Tamara Tilburgs), transgenic lymphocytes (Dr. Koichi Araki) and maternal-fetal
immunology (Dr. Hitesh Deshmukh). I am also extremely fortunate to have the unfettered support of CCHMC
and the Perinatal Institute, whose combined resources are unmatched.
Scientifically, this proposal focuses on deepening our understanding of mechanisms of fetal tolerance. The
field currently focuses on immune suppressive CD4+ Foxp3+ regulatory T cells (Treg) as the key mediators of
tolerance. This is based on observations that maternal Treg expand throughout pregnancy and are blunted in
pregnancy complications associated with fetal intolerance (e.g., preeclampsia, stillbirth). However, there is
growing appreciation that Treg do not work in isolation, and often require support from other cell types, including
regulatory B cells (Breg). Activation of B cells is tightly regulated by the inhibitory receptor CD22, which binds to
sialic acid present at the terminal position of certain glycoproteins. There remain numerous gaps in knowledge
regarding the role of maternal B cells in mediating fetal tolerance, factors affecting their activation, and
modification of fetal antigens. Additionally, whether these maternal B cells work independently or
synergistically with maternal Treg remains to be determined. My central hypothesis is that CD22 impairs
maternal B cell immune regulatory functions, preventing B cells from upholding fetal tolerance. This is based on
very interesting preliminary data showing that CD22 blockade reverses pregnancy complications and fetal loss
when maternal Treg are depleted or functionally impaired by infection. The aims of this proposal will establish:
1) how maternal B cell immune suppression is counter-regulated though antigen recognition and CD22, as well
as 2) how maternal B cells enforce fetal tolerance through IL10-mediated inhibition of maternal T cells with
fetal-specificity.
The scientific rigor of this proposal is supported by numerous career development objectives that will help
enable a transition to a successful independent research program. I will work closely with my mentor, Sing
Sing Way, and mentoring committee to gain expertise in reproductive immunology, fetal tolerance, spectral
flow cytometry, characterization of rare antigen-specific B cells, placental immunology, glycobiology and
genetic manipulation of antigen-specific B cells. Coursework, seminars, scientific conferences and hand-on
training in laboratories of collaborators/mentors will add additional layers of expertise. Overall, this mentored
career development award will broaden my scientific acumen to include reproductive immunology with a focus
on B cell biology and glycobiology. As pregnancy complications remain the leading cause of infant and
childhood mortality, results of these studies will potentially lead to novel B cell-directed therapies aimed at
improving outcomes for pregnant mothers and their children.
Terms: <0-11 years old><0-4 weeks old><Acceleration><Adoptive Transfer><Affect><Allogenic><American><Antibodies><Antigens><Area><Award><B blood cells><B cell><B cell depletion therapy><B cell differentiation><B cell directed therapy><B cell receptor><B cell targeted therapy><B cell therapies><B cell therapy><B cells><B lymphocyte differentiation><B-Cell Activation><B-Cell Antigen CD22><B-Cell Antigen Receptor><B-Cell Subsets><B-Cells><B-Lymphocyte Subsets><B-Lymphocytes><B-cell><B3 antigen><Binding><Blocking Antibodies><Body Tissues><CD22><CD22 antigen><CD22 gene><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CRISPR approach><CRISPR based approach><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><CSIF><CSIF-10><Career Development Awards><Career Development Awards and Programs><Career Development Programs K-Series><Cas nuclease technology><Cell Body><Cell Communication><Cell Communication and Signaling><Cell Interaction><Cell Signaling><Cell-to-Cell Interaction><Cells><Cells Placenta-Tissue><Cellular Immunology><Cellular biology><Child><Child Youth><Childhood><Children (0-21)><Children's Hospital><Clinical><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Complex><Cytokine Synthesis Inhibitory Factor><Data><Developing fetus><Disparate><Doctor's Assistants><EPH Gestosis><Effector Cell><Equilibrium><FOXP3><FOXP3 gene><Faculty><Fellowship><Fetal Death><Fetal Development><Fetal Tissues><Fetus><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Forkhead Box P3><Functional impairment><Genes><Genetic><Genetic Diversity><Genetic Variation><Gestation><Glycans><Glycobiology><Glycoproteins><Goals><Hand><Host Defense><IL-10><IL-10 receptor><IL10><IL10A><Immune><Immune Cell Suppression><Immune Tolerance><Immune system><Immunes><Immunity><Immunochemical Immunologic><Immunologic><Immunologic Tolerance><Immunological><Immunologically><Immunologics><Immunology><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Impairment><Infant><Infection><Interleukin 10 Precursor><Interleukin-10><International><Intracellular Communication and Signaling><Investigators><JM2><K-Awards><K-Series Research Career Programs><Knowledge><Laboratories><Ligands><Link><Lymphatic cell><Lymphocyte><Lymphocytic><Maternal Health><Measures><Mediating><Mediator><Mentors><Mentorship><Metabolic Glycosylation><Mice><Mice Mammals><Microchimerism><Modification><Molecular Interaction><Mothers><Murine><Mus><N-Acetylneuraminic Acids><Neonatal><Neonatal Mortality><Neonatology><Newborn Infant><Newborns><Normal Placentoma><Ovalbumin><Pathway interactions><Pediatric Hospitals><Pediatrics><Perinatal><Peripartum><Physician Assistants><Physicians><Physicians' Extenders><Placenta><Placenta Embryonic Tissue><Placentome><Polysaccharides><Position><Positioning Attribute><Pre-Eclampsia><Predisposition><Preeclampsia><Pregnancy><Pregnancy Complications><Pregnancy Outcome><Pregnancy Toxemias><Pregnant Women><Premature Birth><Prematurely delivering><Preterm Birth><Productivity><Proliferating><Property><Proteinuria-Edema-Hypertension Gestosis><Receptor Protein><Receptor Signaling><Regulation><Regulatory T-Lymphocyte><Reporter><Reproduction Immunology><Reproductive Immunology><Research><Research Assistant><Research Career Program><Research Personnel><Research Resources><Researchers><Residencies><Resources><Role><SCURFIN><SIGLEC2><Scientist><Sialic Acid-Binding Immunoglobulin-Like Lectin 2><Sialic Acids><Signal Transduction><Signal Transduction Systems><Signaling><Specificity><Susceptibility><Symbiosis><T-Cells><T-Lymphocyte><T8 Cells><T8 Lymphocytes><Teff cell><Tissues><Training><Transgenic Mice><Transgenic Organisms><Treg><Universities><Work><activated B cells><balance><balance function><biological signal transduction><career><career development><cell biology><cell type><commensalism><complications during pregnancy><conference><convention><death among neonates><death among newborns><death in neonates><death in newborn><effector T cell><embryo/fetus antigen><expectant mother><expecting mother><experience><experiment><experimental research><experimental study><experiments><fetal><fetal antigen><fetal loss><fetus death><fetus loss><fetus tissue><flow cytophotometry><gene editing method><gene editing methodology><gene editing strategy><gene editing techniques><gene manipulation><gene-editing approach><genetic manipulation><genetically manipulate><genetically perturb><glycosylation><hands><healthy pregnancy><immune suppression><immune suppressive activity><immune suppressive function><immune system tolerance><immune unresponsiveness><immunogen><immunological paralysis><immunosuppressive activity><immunosuppressive function><immunosuppressive response><improved><improved outcome><innovate><innovation><innovative><interleukin-10 receptor><kids><loss of function><lymph cell><lymph organ><lymphatic organ><lymphoid organ><male><maternal immune system><maternal morbidity><mortality><mortality among neonates><mortality among newborns><mortality in neonates><mortality in newborns><mother immune system><mouse model><murine model><neonatal death><neonatal demise><neonatal immunity><neonatal morbidity><neonatal outcome><neonatal sepsis><neonate><newborn child><newborn children><newborn death><newborn morbidity><newborn mortality><novel><offspring><pathway><pediatric><perinatal medicine><pre-eclamptic><pregnancy immunology><pregnancy toxemia/hypertension><pregnancy-related complications><pregnant mothers><premature childbirth><premature delivery><preterm delivery><prevent><preventing><professor><programs><receptor><receptor binding><receptor bound><receptor expression><regulatory T-cells><reproductive><response><sialylation><social role><stillbirth><stillborn><summit><symposia><symposium><thymus derived lymphocyte><tool><transgenic><translational goal><translational mission><youngster>