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Principal Investigator: Ottavia Delmonte
Organization: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
Fiscal Year: 2024
Award: $111,089
Funding agency: National Institute of Allergy and Infectious Diseases
During the Fiscal Year 2024 (October 23- August 24) I obtained the following results:
A) Molecular and cellular characterization of novel genetic defects leading to IEI.
This collaborative effort with scientist at the Imagine Institute in Paris (France) allowed us to describe a novel IEI due to mutations of the PTCRA gene, encoding for the invariant pre-TCR alpha chain of the pre-T cell receptor. Homozygous loss of function variants of the gene impair generation of T cells in the thymus and expression the TCR. On the other hand, hypomorphic variants of PTCRA are associated with increased risk of autoimmune disease (1).
In another collaborative effort, I provided TCR and BCR repertoire studies for the characterization of FLT3L deficiency (2). In collaboration with Dr. Rosenzweig’s group at the NIH, we have expanded the phenotype and molecular pathology of AIOLOS deficiency (3)
B) Studies on the immuno-pathogenesis leading to the broad clinical spectrum of known IEI
We have shown that genetic defects that affect the non canonical NF-kB signaling pathway (NFKB-2, REL deficiencies) in the thymic medulla are associated with production of anti-IFN-I antibodies (4), indicating an important role of central thymic tolerance in preventing this manifestation of immunopathology.
In another study at the NIH we shown that RAG deficiency is associated with perturbation of the diversity and composition of the skin microbiome (5).
Furthermore, we have described a new case and performed literature review of Mulibrey syndrome (6). We have also expanded the spectrum of PAX1 deficiency, which causes a developmental defect of the thymus and other cervical-cranial-facies structures (7). The overall status of knowledge of primary and secondary forms of human thymic defects and of IEI associated with EBV lymphoproliferation have been reviewed (8-9).
4) Development of novel therapeutic approaches for CID due to RAG deficiency associated with immunedysregulation
In a humanized mouse model of RAG2 deficiency, we have provided preclinical evidence that gene editing can rescue the T- and B-cell differentiation potential of RAG-mutated human hematopoietic stem and progenitor cells (HSPC) (10).
5) Evaluation of adaptive immune responses to SARS-CoV2 in patients with primary and secondary immunodeficiency.
We described TCR repertoire changes in diversity and composition in a cohort of pediatric and adult patients with PIRD defects (11), we also evaluated the anti-Spike IgG immune response in a cohort patients with primary and secondary immunodeficiencies (12). In collaboration with the Necker hospital in France we showed that rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19 (13) while in a multicenter national effort coordinated by the USIDNET registry for IEI we evaluated the importance of the COVID-19 Vaccination in patients with IEI (including PIRD) to reduce the risk of hospitalization and critical care needs in this group of patients (14).
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV vaccine><21+ years old><7S Gamma Globulin><Adult><Adult Human><Affect><Age><Antibodies><Autoimmune Diseases><Autoimmune Status><Autoimmunity><B blood cells><B cell><B cell differentiation><B cells><B lymphocyte differentiation><B-Cells><B-Lymphocytes><B-cell><Blood Precursor Cell><Booster Immunization><Burkitt Herpesvirus><Burkitt Lymphoma Virus><CD152><CD152 Antigen><CD152 Gene><COVID-19 vaccination><COVID-19 vaccine><COVID-19 virus><COVID19 virus><CTLA 4><CTLA-4 Gene><CTLA4><CTLA4 deficiency><CTLA4 gene><CTLA4 haploinsufficiency><CTLA4-TM><Caring><Cell Communication and Signaling><Cell Compartmentation><Cell Compartmentations><Cell Signaling><Cephalic><Cervical><Cessation of life><Clinical><CoV-2><CoV2><Collaborations><Consensus><Cranial><Critical Care><Cytokine Signal Transduction><Cytokine Signaling><Cytotoxic T-Lymphocyte Protein 4><Cytotoxic T-Lymphocyte-Associated Antigen 4><Cytotoxic T-Lymphocyte-Associated Protein 4><Cytotoxic T-Lymphocyte-Associated Serine Esterase-4><Data><Death><Defect><Development><Diagnosis><Differentiation and Growth><Disease><Disease Progression><Disorder><EB virus><EBV><Epstein Barr Virus><Evaluation><Evolution><FLT 3 Ligand><FLT3 ligand><FLT3L><FLT3LG><FLT3LG gene><FMS-Related Tyrosine Kinase 3 Ligand Gene><FMS-Related Tyrosine Kinase-3 Ligand><FOXP3><FOXP3 gene><Facies><Forkhead Box P3><France><Gene variant><Generations><Genes><Genetic Alteration><Genetic Change><Genetic defect><Genomics><Goals><HHV-4><HHV4><HSC transplantation><Hematopoietic Progenitor Cells><Hematopoietic Stem Cell Transplant><Hematopoietic Stem Cell Transplantation><Hematopoietic stem cells><Hospital Admission><Hospitalization><Hospitals><Human><Human Herpesvirus 4><IFN><IMiD><IgG><Immune><Immune Diseases><Immune Disorders><Immune Dysfunction><Immune Modulation Therapy><Immune System Diseases><Immune System Disorder><Immune System Dysfunction><Immune System and Related Disorders><Immune modulatory therapeutic><Immune response><Immunes><Immunity><Immunodeficiency and Immunosuppression Disorders><Immunoglobulin Enhancer-Binding Protein><Immunoglobulin G><Immunologic Diseases><Immunological Diseases><Immunological Dysfunction><Immunological System Dysfunction><Immunological response><Impairment><Infection><Infectious Mononucleosis Virus><Inflammation><Interferons><Intracellular Communication and Signaling><JM2><Knowledge><LYT-10 Gene><LYT10 Gene><Laboratories><Link><Longitudinal Studies><MHC Receptor><Major Histocompatibility Complex Receptor><Modern Man><Molecular><Morbidity><Morbidity - disease rate><Mutate><Mutation><NF-kB><NF-kB Signaling Pathway><NF-kappa B><NF-kappaB><NFKB><NFKB Signaling Pathway><NFKB2><NFKB2 gene><NIH><National Institutes of Health><Non-Malignant><Nuclear Factor kappa B><Nuclear Factor of Kappa Light Chain Gene Enhancer in B-Cells 2><Nuclear Transcription Factor NF-kB><Omenn syndrome><Organ><Outcome><Paris><Paris, France><Pathogenesis><Patients><Pattern><Pediatric cohort><Phenotype><Predisposition><Primary Immunodeficiency><Production><Publishing><QOL><Quality of life><RAG deficiency><RAG1 deficiency><Registries><Regulatory T-Lymphocyte><Review Literature><Risk><Risk Reduction><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 vaccination><SARS-CoV-2 vaccine><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 vaccine><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><SCURFIN><STAT1><STAT1 gene><STAT3><STAT3 GOF><STAT3 gain of function><STAT3 gene><STAT91><STK1-ligand><Scientist><Secondary Immunization><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV 2 vaccine><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 vaccination><Severe acute respiratory syndrome coronavirus 2 vaccine><Severe acute respiratory syndrome related corona virus 2><Severities><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Structure><Structure of thymic medulla><Susceptibility><Symptoms><Syndrome><T-Cell Antigen Receptors><T-Cell Receptor><T-Cells><T-Lymphocyte><T-cell receptor repertoire><TCR repertoire><Testing><Therapeutic><Thymus><Thymus Gland><Thymus Medulla><Thymus Proper><Thymus Reticuloendothelial System><Transcription Factor NF-kB><Treg><United States National Institutes of Health><Variant><Variation><Wuhan coronavirus><adaptive immune response><adulthood><ages><aggressive therapy><aggressive treatment><allele variant><allelic variant><assess effectiveness><autoimmune condition><autoimmune disorder><autoimmunity disease><biological signal transduction><blood cell progenitor><blood progenitor><blood stem cell><blood-forming stem cell><booster vaccination><causal allele><causal gene><causal mutation><causal variant><causative mutation><causative variant><cohort><congenital immune deficiency><congenital immunodeficiency><coronavirus disease 2019 vaccination><coronavirus disease 2019 vaccine><coronavirus disease 2019 virus><coronavirus disease-19 vaccine><coronavirus disease-19 virus><cutaneous microbiome><cytotoxic T-lymphocyte antigen 4><dermal microbiome><determine effectiveness><developmental><disability><effectiveness assessment><effectiveness evaluation><epidermal microbiome><evaluate effectiveness><examine effectiveness><flk2 ligand><flk2-flt3 ligand><flt3 ligand protein><genetic immune defect><genetic immune deficiency><genetic immunodeficiency><genetic variant><genome 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therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><thymus derived lymphocyte><treatment and outcome><vaccinate against COVID-19><vaccinate against SARS-CoV-2><vaccinate against coronavirus disease 2019><vaccinate against severe acute respiratory syndrome coronavirus 2><vaccination against COVID-19><vaccination against SARS-CoV-2><vaccination against Severe acute respiratory syndrome coronavirus 2><vaccination against coronavirus disease 2019><vaccine against 2019-nCov><vaccine against COVID-19><vaccine against SARS-CoV-2><vaccine against SARS-coronavirus-2><vaccine against Severe Acute Respiratory Syndrome CoV 2><vaccine against Severe acute respiratory syndrome coronavirus 2><vaccine candidates against SARS-CoV-2><vaccine for novel coronavirus><vaccines preventing COVID><vaccines to prevent COVID>