Antibodies are generated during early B cell development by random joining of immunoglobulin (Ig) gene segments. Ig gene recombination can result in the assembly of self-reactive antibodies or B cell receptors (BCR). B cells that develop self-reactive receptors can be silenced by one of three mechanisms: deletion, anergy; and receptor editing. Whereas deletion and anergy ultimately eliminate self-reactive B cells, receptor editing rescues them by replacing autoreactive antibodies. We analyzed how B cell tolerance was established in humans by following the evolution of autoantibody-producing B cells during B cell development. We found that 55-75% of early B cell precursors expressed self-reactive antibodies and that autoantibodyproducing B cells in healthy donors were removed from the population at two discrete checkpoints. The mechanisms that prevail in silencing these autoreactive B cells remain to be characterized, and little is known about the effect of antibody specificity and BCR signaling in regulating the balance between deletion, anergy, and receptor editing. However, defects in BCR signaling have been reported in B cells from patients with systemic lupus erythematosus and common variable immunodeficiency (CVID) who frequently develop autoimmunity suggesting that BCR signaling may play a role in counterselecting self-reactive B cells. The long range goal of the proposed research is to elucidate the role of BCR in the regulation of B cell tolerance by analyzing primary immunodeficient patient B cells with altered BCR signaling. The working hypothesis is that BCR signaling is essential in establishing B cell tolerance and when it is affected, autoreactive B cells are not silenced and can migrate to the periphery.
The first aim of the project will consist of cloning antibodies from single B cells from the blood of X-linked agammaglobulinemia patients and determine whether modified threshold of BCR signaling in btk gene-deficient B cells impacts B cell tolerance mechanisms. The second part of the project will analyze how BCR co-receptors such as CD40 influence the establishment and the maintenance of B cell tolerance in hyper-IgM patients. The third part of the project will study B cell tolerance in CVID patients. These studies have significant implications for understanding how self-reactive B cells may be produced with or without maintaining self-tolerance.
| Nair, Shiny; Sng, Joel; Boddupalli, Chandra Sekhar et al. (2018) Antigen-mediated regulation in monoclonal gammopathies and myeloma. JCI Insight 3: |
| Mayor, Paul C; Eng, Kevin H; Singel, Kelly L et al. (2018) Cancer in primary immunodeficiency diseases: Cancer incidence in the United States Immune Deficiency Network Registry. J Allergy Clin Immunol 141:1028-1035 |
| 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 : |
| Shan, Meimei; Carrillo, Jorge; Yeste, Ada et al. (2018) Secreted IgD Amplifies Humoral T Helper 2 Cell Responses by Binding Basophils via Galectin-9 and CD44. Immunity 49:709-724.e8 |
| Casanova, Jean-Laurent; Abel, Laurent (2018) Human genetics of infectious diseases: Unique insights into immunological redundancy. Semin Immunol 36:1-12 |
| Gernez, Yael; Freeman, Alexandra F; Holland, Steven M et al. (2018) Autosomal Dominant Hyper-IgE Syndrome in the USIDNET Registry. J Allergy Clin Immunol Pract 6:996-1001 |
Showing the most recent 10 out of 189 publications
