Blocks to B cell memory: Dr. Charlotte Cunningham-Rundles: Common variable immune deficiency (CVID) is a primary antibody deficiency disease in which B cell development, including isotype switch, somatic hypermutation, differentiation into plasma cells and secretion of immunoglobulins is impaired. Due to prevalence, complications, and need for lifelong immunoglobulin therapy, CVID is one of the most clinically important primary immune defects. While the genetic causes of B cell dysfunction in CVID are unknown for most subjects, a growing number of autosomal recessive and more recently, dominant genes have been identified. About 8-10% of CVID subjects have mutations in the B cell receptor transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI). In addition to hypogammaglobulinemia, these subjects have striking lymphoid hyperplasia, splenomegaly and autoimmunity. TACI is highly expressed on marginal zone and CD27+ (memory) B cells, which secrete T cell independent (TI) Ab to carbohydrate antigens, essential in defense against bacterial disease. Unlike mice, human B cells have two TACI isoforms, a long and a short version; our data suggest that only the latter drives plasma cell differentiation, revealing additional complexity in this receptor system. Our group showed that TACI requires the cytoplasmic adaptor MyD88, and more recently that cytoplasmic TACI co-localizes with TLR9, MyD88, and the TNF receptor associated (TRAF) TRAF2 and TRAF6 in the endocytic compartment, suggesting intimate cytoplasmic cooperation between the TACI receptor and innate endosomal TLR pathways. Project 1 uses naturally occurring mutations in TACI, MyD88 and IRAK4, newly described defects in TRAF-interacting protein (TIFA) and members of the linear ubiquitination chain assembly complex, HOIL, HOIP, to explore how TACI isoforms are involved in the control of B cell growth, differentiation and the production of biologically important antibodies in humans. This project is closely linked to the study of tolerance in Project 2, marginal zone biology, bacterial defense, and the production of IgA in mucosal immunity in Project 3, and our progress in identifying new genetic defects leading to loss of B cell function and impaired antibody production to carbohydrate antigens, the topic of Project 4. These projects use naturally-occurring genetic immune defects to probe how normal human B cells are activated and controlled, knowledge essential for understanding how humans are efficiently immunized to produce protective antibodies and how the immune system achieves antibody memory while avoiding autoimmunity.

Public Health Relevance

Primary immune deficiencies (PIDs) are natural experiments of nature that can help us to better understand the regulation and function of human immune responses. In this project we are examining how antibody producing cells make antibody to pathogenic bacteria. The proposed studies will provide scientists and physicians with better understand of how normal antibodies are made and offer clues about how these cells are prevented from producing autoantibodies.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program Projects (P01)
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Special Emphasis Panel (ZAI1)
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Icahn School of Medicine at Mount Sinai
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Gutzeit, Cindy; Chen, Kang; Cerutti, Andrea (2018) The enigmatic function of IgD: some answers at last. Eur J Immunol 48:1101-1113
Gies, Vincent; Schickel, Jean-Nicolas; Jung, Sophie et al. (2018) Impaired TLR9 responses in B cells from patients with systemic lupus erythematosus. JCI Insight 3:
Bousfiha, Aziz; Jeddane, Leïla; Picard, Capucine et al. (2018) The 2017 IUIS Phenotypic Classification for Primary Immunodeficiencies. J Clin Immunol 38:129-143
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Ho, Hsi-En; Byun, Minji; Cunningham-Rundles, Charlotte (2018) Disseminated Cutaneous Warts in X-Linked Hyper IgM Syndrome. J Clin Immunol 38:454-456
Schwab, Charlotte; Gabrysch, Annemarie; Olbrich, Peter et al. (2018) Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4-insufficient subjects. J Allergy Clin Immunol 142:1932-1946
Smith, Tukisa D; Cunningham-Rundles, Charlotte (2018) Detection of anti-glutamic acid decarboxylase antibodies in immunoglobulin products. J Allergy Clin Immunol Pract 6:260-261
Petersheim, Daniel; Massaad, Michel J; Lee, Saetbyul et al. (2018) Mechanisms of genotype-phenotype correlation in autosomal dominant anhidrotic ectodermal dysplasia with immune deficiency. J Allergy Clin Immunol 141:1060-1073.e3
Bucciol, Giorgia; Moens, Leen; Bosch, Barbara et al. (2018) Lessons learned from the study of human inborn errors of innate immunity. J Allergy Clin Immunol :

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