Impaired immune functions leading to primary immunodeficiency diseases (PID) often correlate with paradoxical autoimmune complications. PID patients provide rare opportunities to study the impact of specific defective genes on the regulation of B cell tolerance and the removal of developing autoreactive B cells in humans. Alterations in B cell receptor (BCR) signaling in patients lacking functional BTK, CDI 9, or molecules mediating Toll-like receptor (TLR) signaling such as IRAK-4, MyD88, and UNC-93B result in a defective central checkpoint and a failure to counterselect developing autoreactive B cells. Indeed, the binding of self-antigens to autoreactive BCRs and TLRs fail to induce tolerance mechanisms in all these patients'developing B cells and autoreactive B cells leaks from the bone marrow into the periphery. Our recent work demonstrates that mutations in the gene encoding the transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) whose functions involve MyD88, also affect early B cell tolerance checkpoints. In addition, we identified a major and previously unsuspected role for activation-induced cytidine deaminase (AID), an enzyme required for class switch recombination (CSR) and somatic hypermutation (SHM), in the removal of developing autoreactive B cells in humans. Finally, mutations in CDI 9, TACI and IRAK4 genes also alter the production of some memory B cells yet their involvement in the selection of activated B cell clones in humans remained to be determined. The long range goal ofthe proposed research is to further determine the mechanisms that regulate B cell tolerance in healthy humans but may be defective in PID patients. The working hypothesis is that TACI, intertwined with TLR7,TLR9, and MyD88 as well as AID, whose expression is induced in immature B cells after BCR, TLR9 and/or TACI triggering, play essential roles in the removal of developing autoreactive B cells. In addition, we will focus on the analysis ofthe mechanisms involving TLRs, TACI, MyD88 and AID and by which developing mutating clones are selected in the memory B cell compartments.

Public Health Relevance

Understanding the mechanisms that prevent or account for the production of autoreactive B cells may suggest new approaches to control disease and design more specific and sustained therapies. In addition, anti-B cell therapies effective at blocking autoimmune disease progression may be useful for delaying or preventing the development of other disorders potentially affecting patients with primary immune deficiency.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI061093-10
Application #
8525311
Study Section
Special Emphasis Panel (ZAI1-PA-I)
Project Start
Project End
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
10
Fiscal Year
2013
Total Cost
$497,328
Indirect Cost
$117,266
Name
Icahn School of Medicine at Mount Sinai
Department
Type
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Uzzan, Mathieu; Ko, Huaibin M; Mehandru, Saurabh et al. (2016) Gastrointestinal Disorders Associated with Common Variable Immune Deficiency (CVID) and Chronic Granulomatous Disease (CGD). Curr Gastroenterol Rep 18:17
Chorny, Alejo; Casas-Recasens, Sandra; Sintes, Jordi et al. (2016) The soluble pattern recognition receptor PTX3 links humoral innate and adaptive immune responses by helping marginal zone B cells. J Exp Med 213:2167-85
Massaad, Michel J; Zhou, Jia; Tsuchimoto, Daisuke et al. (2016) Deficiency of base excision repair enzyme NEIL3 drives increased predisposition to autoimmunity. J Clin Invest 126:4219-4236
Scott, Eric M; Halees, Anason; Itan, Yuval et al. (2016) Characterization of Greater Middle Eastern genetic variation for enhanced disease gene discovery. Nat Genet 48:1071-6
Cols, Montserrat; Rahman, Adeeb; Maglione, Paul J et al. (2016) Expansion of inflammatory innate lymphoid cells in patients with common variable immune deficiency. J Allergy Clin Immunol 137:1206-1215.e6
Lee, Alison Joanne; Moncada-Vélez, Marcela; Picard, Capucine et al. (2016) Severe Mycobacterial Diseases in a Patient with GOF IκBα Mutation Without EDA. J Clin Immunol 36:12-5
Cantaert, Tineke; Schickel, Jean-Nicolas; Bannock, Jason M et al. (2016) Decreased somatic hypermutation induces an impaired peripheral B cell tolerance checkpoint. J Clin Invest 126:4289-4302
Kuehn, Hye Sun; Boisson, Bertrand; Cunningham-Rundles, Charlotte et al. (2016) Loss of B Cells in Patients with Heterozygous Mutations in IKAROS. N Engl J Med 374:1032-43
Bonilla, Francisco A; Barlan, Isil; Chapel, Helen et al. (2016) International Consensus Document (ICON): Common Variable Immunodeficiency Disorders. J Allergy Clin Immunol Pract 4:38-59
Morbach, Henner; Schickel, Jean-Nicolas; Cunningham-Rundles, Charlotte et al. (2016) CD19 controls Toll-like receptor 9 responses in human B cells. J Allergy Clin Immunol 137:889-898.e6

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