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.
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.
|Gaschignard, Jean; Levy, Corinne; Chrabieh, Maya et al. (2014) Invasive pneumococcal disease in children can reveal a primary immunodeficiency. Clin Infect Dis 59:244-51|
|Gutzeit, Cindy; Nagy, Noemi; Gentile, Maurizio et al. (2014) Exosomes derived from Burkitt's lymphoma cell lines induce proliferation, differentiation, and class-switch recombination in B cells. J Immunol 192:5852-62|
|Maglione, Paul J; Ko, Huaibin M; Beasley, Mary B et al. (2014) Tertiary lymphoid neogenesis is a component of pulmonary lymphoid hyperplasia in patients with common variable immunodeficiency. J Allergy Clin Immunol 133:535-42|
|Castiello, Maria Carmina; Bosticardo, Marita; Pala, Francesca et al. (2014) Wiskott-Aldrich Syndrome protein deficiency perturbs the homeostasis of B-cell compartment in humans. J Autoimmun 50:42-50|
|Al-Herz, Waleed; Bousfiha, Aziz; Casanova, Jean-Laurent et al. (2014) Primary immunodeficiency diseases: an update on the classification from the international union of immunological societies expert committee for primary immunodeficiency. Front Immunol 5:162|
|Magri, Giuliana; Miyajima, Michio; Bascones, Sabrina et al. (2014) Innate lymphoid cells integrate stromal and immunological signals to enhance antibody production by splenic marginal zone B cells. Nat Immunol 15:354-64|
|Maglione, Paul J; Overbey, Jessica R; Radigan, Lin et al. (2014) Pulmonary radiologic findings in common variable immunodeficiency: clinical and immunological correlations. Ann Allergy Asthma Immunol 113:452-9|
|Keller, M; Glessner, J; Resnick, E et al. (2014) Burden of copy number variation in common variable immunodeficiency. Clin Exp Immunol 177:269-71|
|Gutzeit, Cindy; Magri, Giuliana; Cerutti, Andrea (2014) Intestinal IgA production and its role in host-microbe interaction. Immunol Rev 260:76-85|
|Menard, Laurence; Cantaert, Tineke; Chamberlain, Nicolas et al. (2014) Signaling lymphocytic activation molecule (SLAM)/SLAM-associated protein pathway regulates human B-cell tolerance. J Allergy Clin Immunol 133:1149-61|
Showing the most recent 10 out of 70 publications