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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI071087-08
Application #
8586459
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Peyman, John A
Project Start
2006-07-01
Project End
2016-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
8
Fiscal Year
2014
Total Cost
$416,250
Indirect Cost
$166,250
Name
Yale University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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 137:889-898.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
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
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
Janssen, Erin; Morbach, Henner; Ullas, Sumana et al. (2014) Dedicator of cytokinesis 8-deficient patients have a breakdown in peripheral B-cell tolerance and defective regulatory T cells. J Allergy Clin Immunol 134:1365-74
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
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

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