Impaired immune functions leading to primary immunodeficiencies often correlate with paradoxical autoimmune complications. Patients with primary immunodeficiencies 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 pathways in patients lacking functional BTK, CD19, or molecules mediating TLR signaling such as IRAK4, MyD88, and UNC93B result in a defective central checkpoint and a failure to counterselect developing autoreactive B cells (1, 2). Indeed, the binding of self-antigens to autoreactive BCRs and TLRs fail to induce tolerance mechanisms due to increase receptor signaling thresholds in all these patients'B cells and autoreactive B cells leaks from the bone marrow into the periphery (1, 2). Our latest investigations revealed that central B cell tolerance defects are primary to many autoimmune diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and type 1 diabetes (T1D) and result from genetic factors segregating with autoimmunity and which encode variants interfering with BCR signaling (3-5). However, we recently found that patients with multiple sclerosis (MS) only displayed peripheral B cell tolerance defects whereas central B cell tolerance was often established normally. Similar observations were observed in CD40L- and MHC class II-deficient patients, who pointed to a potential role for regulatory T (Treg) cells and serum B-cell activating factor (BAFF) in the removal of developing autoreactive B cells in the periphery (6). Interestingly, Treg cell functions have been reported to be defective in MS patients. Hence, Treg cells as second axis controlling the establishment and the maintenance of B cell tolerance in the periphery is proposed to be analyzed in this R21 application by studying immune deficiency, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) and autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) patients, who display a defective Treg cell compartment and suffer from autoimmune condition and the secretion of many self-reactive antibodies. The long range goal of the proposed research is to determine the mechanisms that regulate peripheral B cell tolerance in healthy humans but may be defective in IPEX and APECED patients. The working hypothesis is that genetic defects impacting Treg cell functions not only interfere with the removal of autoreactive B cells in the periphery but may lead to their activation, thereby potentially favoring the development of autoimmunity. Similarly to CD40L-deficient patients, we expect to find that FOXP3- and AIRE-deficient patients with abnormal Treg cell functions will display normal central yet defective peripheral B cell tolerance checkpoints. We will also assess the mechanisms by which Treg cells may induce autoreactive B cell death and contribute to B cell homeostasis regulation. Altogether, the proposed study intends to demonstrate a role for Treg cells in the restraining autoreactive B cells in the periphery.

Public Health Relevance

This proposal intends to demonstrate a role for Treg cells in the peripheral removal of autoreactive B cells by analyzing Foxp3- and AIRE-deficient patients with altered Treg cell frequencies and functions, and assessing mechanisms by which Treg cells may prevent autoreactive B cell expansion in the periphery.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI095848-01A1
Application #
8302578
Study Section
Special Emphasis Panel (ZRG1-IMM-N (52))
Program Officer
Johnson, David R
Project Start
2012-03-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
1
Fiscal Year
2012
Total Cost
$248,750
Indirect Cost
$98,750
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
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
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

Showing the most recent 10 out of 25 publications