A primary immunodeficiency characterized by defective immunoglobulin class switch recombination and impaired DNA repair

Immunoglobulin class switch recombination (CSR) deficiencies are rare primary immunodeficiencies, characterized by a lack of switched isotype (IgG, IgA, or IgE) production, variably associated with abnormal somatic hypermutation (SHM). Deficiencies in CD40 ligand, CD40, activation-induced cytidine deaminase, and uracil-N-glycosylase may account for this syndrome. We previously described another Ig CSR deficiency condition, characterized by a defect in CSR downstream of the generation of double-stranded DNA breaks in switch (S) μ regions. Further analysis performed with the cells of five affected patients showed that the Ig CSR deficiency was associated with an abnormal formation of the S junctions characterized by microhomology and with increased cell radiosensitivity. In addition, SHM was skewed toward transitions at G/C residues. Overall, these findings suggest that a unique Ig CSR deficiency phenotype could be related to an as-yet-uncharacterized defect in a DNA repair pathway involved in both CSR and SHM events

Pathogenic Fungi Regulate Immunity by Inducing Neutrophilic Myeloid-Derived Suppressor Cells

Peer reviewedPublisher PD

The Wiskott-Aldrich syndrome protein is required for iNKT cell maturation and function

The Wiskott-Aldrich syndrome (WAS) protein (WASp) is a regulator of actin cytoskeleton in hematopoietic cells. Mutations of the WASp gene cause WAS. Although WASp is involved in various immune cell functions, its role in invariant natural killer T (iNKT) cells has never been investigated. Defects of iNKT cells could indeed contribute to several WAS features, such as recurrent infections and high tumor incidence. We found a profound reduction of circulating iNKT cells in WAS patients, directly correlating with the severity of clinical phenotype. To better characterize iNKT cell defect in the absence of WASp, we analyzed was−/− mice. iNKT cell numbers were significantly reduced in the thymus and periphery of was−/− mice as compared with wild-type controls. Moreover analysis of was−/− iNKT cell maturation revealed a complete arrest at the CD44+ NK1.1− intermediate stage. Notably, generation of BM chimeras demonstrated a was−/− iNKT cell-autonomous developmental defect. was−/− iNKT cells were also functionally impaired, as suggested by the reduced secretion of interleukin 4 and interferon γ upon in vivo activation. Altogether, these results demonstrate the relevance of WASp in integrating signals critical for development and functional differentiation of iNKT cells and suggest that defects in these cells may play a role in WAS pathology

Mutations in STAT3 and IL12RB1 impair the development of human IL-17–producing T cells

The cytokines controlling the development of human interleukin (IL) 17–producing T helper cells in vitro have been difficult to identify. We addressed the question of the development of human IL-17–producing T helper cells in vivo by quantifying the production and secretion of IL-17 by fresh T cells ex vivo, and by T cell blasts expanded in vitro from patients with particular genetic traits affecting transforming growth factor (TGF) β, IL-1, IL-6, or IL-23 responses. Activating mutations in TGFB1, TGFBR1, and TGFBR2 (Camurati-Engelmann disease and Marfan-like syndromes) and loss-of-function mutations in IRAK4 and MYD88 (Mendelian predisposition to pyogenic bacterial infections) had no detectable impact. In contrast, dominant-negative mutations in STAT3 (autosomal-dominant hyperimmunoglobulin E syndrome) and, to a lesser extent, null mutations in IL12B and IL12RB1 (Mendelian susceptibility to mycobacterial diseases) impaired the development of IL-17–producing T cells. These data suggest that IL-12Rβ1– and STAT-3–dependent signals play a key role in the differentiation and/or expansion of human IL-17–producing T cell populations in vivo

Peculiar hyper-IgM syndrome. Case report / Sindrom hiper-IgM atipic. Prezentare de caz

Autorii raportează cazul unui sugar de sex masculin diagnosticat, la vârsta de 10 luni, cu sindrom hiper-IgM în contextul infecțiilor severe cauzate de Streptococcus pneumoniae, Staphylococcus aureus și Candida albicans. În ciuda terapiei de substituție cu gamaglobulină umană, sugarul a continuat să prezinte frecvente episoade de otită medie supurată cauzate de Candida și pneumococ penicilino-rezistent și abces antebraț determinat de Staphylococcus aureus. În evoluție sugarul a dezvoltat cataractă ambii ochi, hepatită cronică și fractură cominutivă femur secundară demineralizării osoase. Pacientul nu a prezentat infecții cu germeni oportuniști comparativ cu pacienții cu deficiență CD40 Ligand. Spre deosebire de majoritatea bolnavilor cu fenotip hiper-IgM, pacientul a necesitat cantități reduse de gamaglobulină umană. Ca particularitate imunologică, în evoluție valoarea serica a IgM a crescut la valori foarte mari

Functional subsets of human primary antibody deficiencies as revealed by multiplexed phenotyping of in vitro activated B-cells

Bu çalışma, 05-09 Haziran 2010 tarihleri arasında London[İngiltere]’da düzenlenen 29. Congress of the European-Academy-of-Allergy-and-Clinical-Immunology (EAACI)’da bildiri olarak sunulmuştur.European Acad Allergy & Clin Immuno

The Wiskott-Aldrich syndrome protein is required for iNKT cell maturation and function.

The Wiskott-Aldrich syndrome (WAS) protein (WASp) is a regulator of actin cytoskeleton in hematopoietic cells. Mutations of the WASp gene cause WAS. Although WASp is involved in various immune cell functions, its role in invariant natural killer T (iNKT) cells has never been investigated. Defects of iNKT cells could indeed contribute to several WAS features, such as recurrent infections and high tumor incidence. We found a profound reduction of circulating iNKT cells in WAS patients, directly correlating with the severity of clinical phenotype. To better characterize iNKT cell defect in the absence of WASp, we analyzed was(-/-) mice. iNKT cell numbers were significantly reduced in the thymus and periphery of was(-/-) mice as compared with wild-type controls. Moreover analysis of was(-/-) iNKT cell maturation revealed a complete arrest at the CD44(+) NK1.1(-) intermediate stage. Notably, generation of BM chimeras demonstrated a was(-/-) iNKT cell-autonomous developmental defect. was(-/-) iNKT cells were also functionally impaired, as suggested by the reduced secretion of interleukin 4 and interferon gamma upon in vivo activation. Altogether, these results demonstrate the relevance of WASp in integrating signals critical for development and functional differentiation of iNKT cells and suggest that defects in these cells may play a role in WAS pathology

Genetic characteristics of eighty-seven patients with the Wiskott-Aldrich syndrome

WOS: 000287894600008PubMed ID: 21185603The Wiskott-Aldrich syndrome (WAS) is an X-linked recessive immune deficiency disorder characterized by thrombocytopenia, small platelet size, eczema, recurrent infections, and increased risk of autoimmune disorders and malignancies. WAS is caused by mutations in the WASP gene which encodes WASP, a 502-amino acid protein. WASP plays a critical role in actin cytoskeleton organization and signalling, and functions of immune cells. We present here the results of genetic analysis of patients with WAS from eleven Eastern and Central European (ECE) countries and Turkey. Clinical and haematological information of 87 affected males and 48 carrier females from 77 WAS families were collected. The WASP gene was sequenced from genomic DNA of patients with WAS, as well as their family members to identify carriers. In this large cohort, we identified 62 unique mutations including 17 novel sequence variants. The mutations were scattered throughout the WASP gene and included single base pair changes (17 missense and 11 nonsense mutations), 7 small insertions, 18 deletions, and 9 splice site defects. Genetic counselling and prenatal diagnosis were applied in four affected families. This study was part of the J Project aimed at identifying genetic basis of primary immunodeficiency disease in ECE countries. This report provides the first comprehensive overview of the molecular genetic and demographic features of WAS in ECE. (C) 2010 Elsevier Ltd. All rights reserved.Hungarian Research FundOrszagos Tudomanyos Kutatasi Alapprogramok (OTKA) [OTKA PD 72445]; European Social FundEuropean Social Fund (ESF) [4.2.1./B-09/1/KONV-2010-0007]We thank Drs. LD Notarangelo, J van Dongen, C Klein, A Jones, M Losekoot, E Remold-O'Donell, K Schwartz, and H Ochs for their help in analysing some of our patients and supporting molecular diagnostic work in their labs. We thank the Jeffrey Modell Foundation for their support of several laboratories to perform molecular genetic testing. This work was supported by grants from the Hungarian Research Fund (OTKA PD 72445) to ME, and the TAMOP 4.2.1./B-09/1/KONV-2010-0007 project implemented through the New Hungary Development Plan and co-financed by the European Social Fund