Deficiency in the dedicator of cytokinesis-8 (DOCK8) gene, a guanine nucleotide exchange factor, results in autosomal recessive Hyper-IgE syndrome characterized by recurrent pulmonary infections, eczema, cutaneous viral infections, elevated serum IgE levels, food allergy, low numbers of T cells, and deficient antibody responses. We have found that DOCK8 deficient patients have impaired IgG antibody responses, lack of memory B cells, reduced numbers of marginal zone (MZ)-like B cells and of follicular helper (TFH) cells. Unlike normal subjects, they make IgE antibodies to pneumococcal antigens. We also made the novel observation that DOCK8 functions downstream of TLR9 in B cells, and is essential for TLR9-induced activation of STAT3, which plays an important role in the differentiation of B cells into antibody producing cells, and demonstrated that DOCK8 associates with MyD88 and the tyrosine kinase Pyk2 in B cells, undergoes phosphorylation by Pyk2 and is critical for the activation of a Lyn-Syk-STAT3 cascade following TLR9 ligation in human and mouse B cells. We propose to test the overall hypothesis that DOCK8 is a key regulator of B cell activity. We will take advantage of our access to a large population of DOCK8 deficient patients, of newly constructed Dock8-/- mice whose B cells phenocopy the defects in the patients, and of mice that carry a conditional (floxed) Dock8 allele, to test the hypothesis tht DOCK8 promotes protective T dependent (TD) and type II T independent (TI) Ab. responses, but inhibits allergic IgE Ab. responses by mechanisms both intrinsic and extrinsic to B cells. We will 1) Test the hypothesis that ligand binding to TLR9 in B cells recruits and activates the tri- molecular MyD88/DOCK8/Pyk2 complex, resulting in STAT3 activation and B cell differentiation. 2) Test the hypothesis that DOCK8 cells plays a critical role in IgG antibody responses by mediating TLR9 signaling, promoting T follicular helper cell function and driving the development of MZ B cells. 3) Test the hypothesis that DOCK8 is a regulator of IgE antibody production and that IgE antibodies to microbial antigens enhance the susceptibility to infection in DOCK8 deficiency. A deeper knowledge of the role of DOCK8 in B cell function will further our understanding of the susceptibility of DOCK8 patients to infection. Since DOCK8 deficiency predisposes to autoimmunity, allergy and cancer, its study is likely to provide novel and important insights into the pathogenesis of these common conditions.

Public Health Relevance

Autosomal recessive Hyper-IgE syndrome is a primary immunodeficiency diseases caused by mutations in the dedicator of cytokinesis-8 (DOCK8) gene. We propose to examine the role of DOCK8 in promoting protective IgG antibody responses, and inhibiting harmful IgE antibody responses. A deeper knowledge of the role of DOCK8 in B cell function will further our understanding of the susceptibility of DOCK8 patients to infection. Since DOCK8 deficiency predisposes to autoimmunity, allergy and cancer, its study is also likely to provide novel and important insights into the pathogenesis of these common conditions.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01AI100315-02
Application #
8639460
Study Section
Cellular and Molecular Immunology - B Study Section (CMIB)
Program Officer
Johnson, David R
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Children's Hospital Boston
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02115
Turvey, Stuart E; Durandy, Anne; Fischer, Alain et al. (2014) The CARD11-BCL10-MALT1 (CBM) signalosome complex: Stepping into the limelight of human primary immunodeficiency. J Allergy Clin Immunol 134:276-84
Keles, Sevgi; Jabara, Haifa H; Reisli, Ismail et al. (2014) Plasmacytoid dendritic cell depletion in DOCK8 deficiency: rescue of severe herpetic infections with IFN-? 2b therapy. J Allergy Clin Immunol 133:1753-5.e3
Al-Zahrani, Daifulah; Raddadi, Ali; Massaad, Michel et al. (2014) Successful interferon-alpha 2b therapy for unremitting warts in a patient with DOCK8 deficiency. Clin Immunol 153:104-8
Janssen, Erin; Tsitsikov, Erdyni; Al-Herz, Waleed et al. (2014) Flow cytometry biomarkers distinguish DOCK8 deficiency from severe atopic dermatitis. Clin Immunol 150:220-4
Pai, Sung-Yun; de Boer, Helen; Massaad, Michel J et al. (2014) Flow cytometry diagnosis of dedicator of cytokinesis 8 (DOCK8) deficiency. J Allergy Clin Immunol 134:221-3
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