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 #
2R01AI071087-06
Application #
8237551
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
2011-12-01
Budget End
2012-11-30
Support Year
6
Fiscal Year
2012
Total Cost
$414,271
Indirect Cost
$164,271
Name
Yale University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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Kuehn, Hye Sun; Ouyang, Weiming; Lo, Bernice et al. (2014) Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4. Science 345:1623-7
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
Amara, Khaled; Steen, Johanna; Murray, Fiona et al. (2013) Monoclonal IgG antibodies generated from joint-derived B cells of RA patients have a strong bias toward citrullinated autoantigen recognition. J Exp Med 210:445-55
Romberg, Neil; Chamberlain, Nicolas; Saadoun, David et al. (2013) CVID-associated TACI mutations affect autoreactive B cell selection and activation. J Clin Invest 123:4283-93
Kinnunen, Tuure; Chamberlain, Nicolas; Morbach, Henner et al. (2013) Accumulation of peripheral autoreactive B cells in the absence of functional human regulatory T cells. Blood 121:1595-603
Durandy, Anne; Cantaert, Tineke; Kracker, Sven et al. (2013) Potential roles of activation-induced cytidine deaminase in promotion or prevention of autoimmunity in humans. Autoimmunity 46:148-56
Romberg, Neil; Morbach, Henner; Lawrence, Monica G et al. (2013) Gain-of-function STAT1 mutations are associated with PD-L1 overexpression and a defect in B-cell survival. J Allergy Clin Immunol 131:1691-3
Saadoun, D; Terrier, B; Bannock, J et al. (2013) Expansion of autoreactive unresponsive CD21-/low B cells in Sjögren's syndrome-associated lymphoproliferation. Arthritis Rheum 65:1085-96
Ombrello, Michael J; Remmers, Elaine F; Sun, Guangping et al. (2012) Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions. N Engl J Med 366:330-8

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