Autoantibodies are a characteristic of most autoimmune diseases and appear in the serum many years before the onset of clinical disease, suggesting an early break in B cell tolerance. An important role for B cells in some autoimmune diseases has been supported by successful treatment of patients with anti-CD20 monoclonal antibodies that eliminate B cells. The underlying mechanisms that account for autoreactive B cell and autoantibody production in autoimmune diseases are poorly defined. We analyzed B cell tolerance in untreated active rheumatoid arthritis (RA) and type 1 diabetes (T1D) patients by testing the specificity of recombinant antibodies cloned from single new emigrant and mature naive B cells. RA and T1D patients exhibit defective central and peripheral B cell tolerance checkpoints that result in the accumulation of selfreactive mature naive B cells, likely contributing to pathogenesis. The long range goal of the proposed research is to determine the mechanisms that regulate B cell tolerance in healthy humans but may be defective in patients with autoimmune diseases. The working hypothesis is that developing autoreactive B cells in patients with autoimmune diseases surfer from intrinsic defects that impinge on their proper counterselection in the bone marrow. In addition, defects in regulatory T cell functions and elevated BAFF levels may alter peripheral B cell tolerance and result in the abnormal recruitment and activation of autoreactive B cell clones.
The first aim of the project will consist of determining whether B cell tolerance defects in T1D persist after B cell depletion and may therefore predict patients'relapse. The second part of the project will analyze the development and involvement of autoreactive B cells in primary Sjogren's syndrome. The third part of the project will characterize the molecular basis for early defects in B cell tolerance checkpoints by analyzing the impact of known polymorphism that are protective or associated to the development of autoimmune diseases.

Public Health Relevance

Understanding the mechanisms that prevent or account for the production of autoreactive B cells may suggest new approaches to control disease. In particular, anti-B cell therapies, that are effective at blocking disease progression and have already received FDA approval for use in RA, may be useful for delaying or preventing the development of other autoimmune diseases such as T1D, pSS, and IBD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI082713-05
Application #
8468105
Study Section
Special Emphasis Panel (ZAI1-QV-I)
Project Start
Project End
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
5
Fiscal Year
2013
Total Cost
$181,263
Indirect Cost
$64,698
Name
Yale University
Department
Type
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Hedl, Matija; Zheng, Shasha; Abraham, Clara (2014) The IL18RAP region disease polymorphism decreases IL-18RAP/IL-18R1/IL-1R1 expression and signaling through innate receptor-initiated pathways. J Immunol 192:5924-32
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
Hedl, Matija; Abraham, Clara (2014) A TNFSF15 disease-risk polymorphism increases pattern-recognition receptor-induced signaling through caspase-8-induced IL-1. Proc Natl Acad Sci U S A 111:13451-6
Look, Michael; Saltzman, W Mark; Craft, Joe et al. (2014) The nanomaterial-dependent modulation of dendritic cells and its potential influence on therapeutic immunosuppression in lupus. Biomaterials 35:1089-95
Hedl, Matija; Lahiri, Amit; Ning, Kaida et al. (2014) Pattern recognition receptor signaling in human dendritic cells is enhanced by ICOS ligand and modulated by the Crohn's disease ICOSLG risk allele. Immunity 40:734-46
Ruddle, Nancy H (2014) Lymphatic vessels and tertiary lymphoid organs. J Clin Invest 124:953-9
Vudattu, Nalini K; Waldron-Lynch, Frank; Truman, Lucy A et al. (2014) Humanized mice as a model for aberrant responses in human T cell immunotherapy. J Immunol 193:587-96
Wu, Xingxin; Lahiri, Amit; Haines 3rd, G Kenneth et al. (2014) NOD2 regulates CXCR3-dependent CD8+ T cell accumulation in intestinal tissues with acute injury. J Immunol 192:3409-18
Lahiri, Amit; Abraham, Clara (2014) Activation of pattern recognition receptors up-regulates metallothioneins, thereby increasing intracellular accumulation of zinc, autophagy, and bacterial clearance by macrophages. Gastroenterology 147:835-46
Sehgal, Kartik; Ragheb, Ragy; Fahmy, Tarek M et al. (2014) Nanoparticle-mediated combinatorial targeting of multiple human dendritic cell (DC) subsets leads to enhanced T cell activation via IL-15-dependent DC crosstalk. J Immunol 193:2297-305

Showing the most recent 10 out of 40 publications