A role for B cells in autoimmune diseases is now clearly established both with mouse models as well as in humans by successful treatment of rheumatoid arthritis (RA) and other autoimmune diseases with anti-CD20 monoclonal antibodies that eliminate B cells. However, the underlying mechanisms by which B cells may promote the development of autoimmune diseases remain poorly understood. We previously demonstrated that untreated active RA patients, patients with systemic lupus erythematosus, and patients with type 1 diabetes display abnormal early B cell tolerance checkpoints resulting in the accumulation of large numbers of autoreactive naove B cells in their blood. We recently established that these early B cell tolerance defects were primary to these autoimmune diseases and can be induced in asymptomatic donors by risk alleles such as PTPN22, which interfere with B cell receptor (BCR) signaling and the establishment of central B cell tolerance. In addition, anergy, one of the central B cell tolerance mechanisms, seems to be favored in some RA patients as illustrated by the increased frequency of peripheral unresponsive autoreactive B cells, which do not express the complement receptor 2/CD21 and are refractory to BCR and CD40 triggering. Hence, increased numbers of naove autoreactive B cells in patients with RA may favor disease development but it remains to be determined what pathways and mechanisms break B cell tolerance. The long range goal of the proposed research is to continue to characterize the mechanisms that regulate B cell tolerance in healthy humans but are defective in RA patients. The working hypothesis is that RA B cells suffer from intrinsic defects caused by associated risk alleles, which impinge on sensing self-antigens and result in an altered induction/regulation of central B cell tolerance mechanisms. Hence, receptor editing and deletion fail to be properly regulated in RA patients whereas anergy also contributes to the increased numbers of autoreactive B cells reaching the periphery where inflammatory conditions such as in the synovium may lead the activation of these autoreactive B cells and promote disease development. In addition, 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.
This proposal intends to demonstrate how genetic predispositions alter the induction and the regulation of B cell tolerance mechanisms in rheumatoid arthritis. In addition, we will study the activation of autoreactive B cells that infiltrate the synovium of RA patients and potentially promote disease pathogenesis.
|Schickel, Jean-Nicolas; Glauzy, Salomé; Ng, Yen-Shing et al. (2017) Self-reactive VH4-34-expressing IgG B cells recognize commensal bacteria. J Exp Med 214:1991-2003|
|Borsotti, Chiara; Danzl, Nichole M; Nauman, Grace et al. (2017) HSC extrinsic sex-related and intrinsic autoimmune disease-related human B-cell variation is recapitulated in humanized mice. Blood Adv 1:2007-2018|
|Glauzy, Salomé; Boccitto, Marco; Bannock, Jason M et al. (2017) Accumulation of Antigen-Driven Lymphoproliferations in Complement Receptor 2/CD21-/low B Cells From Patients With Sjögren's Syndrome. Arthritis Rheumatol :|
|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|
|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 137:889-98.e6|
|Chamberlain, Nicolas; Massad, Christopher; Oe, Tyler et al. (2016) Rituximab does not reset defective early B cell tolerance checkpoints. J Clin Invest 126:282-7|
|Cantaert, Tineke; Schickel, Jean-Nicolas; Bannock, Jason M et al. (2015) Activation-Induced Cytidine Deaminase Expression in Human B Cell Precursors Is Essential for Central B Cell Tolerance. Immunity 43:884-95|
|Berkowska, Magdalena A; Schickel, Jean-Nicolas; Grosserichter-Wagener, Christina et al. (2015) Circulating Human CD27-IgA+ Memory B Cells Recognize Bacteria with Polyreactive Igs. J Immunol 195:1417-26|
|Pala, Francesca; Morbach, Henner; Castiello, Maria Carmina et al. (2015) Lentiviral-mediated gene therapy restores B cell tolerance in Wiskott-Aldrich syndrome patients. J Clin Invest 125:3941-51|
|Romberg, Neil; Virdee, Manmeet; Chamberlain, Nicolas et al. (2015) TNF receptor superfamily member 13b (TNFRSF13B) hemizygosity reveals transmembrane activator and CAML interactor haploinsufficiency at later stages of B-cell development. J Allergy Clin Immunol 136:1315-25|
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