IL-12Rβ1 Deficiency: Mutation Update and Description of the<i>IL12RB1</i>Variation Database

Vosse, Esther van de; Haverkamp, Margje H.; Ramírez-Alejo, Noé; Martínez‐Gallo, Mónica; Blancas-Galicia, Lizbeth; Metìn, Ayşe; Garty, Ben Zion; Sun-Tan, Çağman; Broides, Arnon; Paus, Roelof A. de; Keskin, Özlem; Çağdaş, Deniz; Tezcan, İlhan; Lopez-Ruzafa, Encarna; Aróstegui, Juan I.; Levy, Jacov; Espinosa-Rosales, Francisco; Sanal, Özden; Santos-Argumedo, Leopoldo; Casanova, Jean‐Laurent; Boisson–Dupuis, Stéphanie; Dissel, Jaap T. van; Bustamante, Jacinta

doi:10.1002/humu.22380

Cited by 86 publications

(78 citation statements)

References 82 publications

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“…Previous analysis of patients with IL12RB1 mutations demonstrated deficient IL12/JAK/STAT signaling (as could be confirmed for the patient analyzed here), lack of resulting IFNg production by T and NK cells as well as deficient IL23 signaling and low levels of IL17-producing T cells. 45 A similar phenotype is described for targeted IL12RB1 knockout mice. 46 In humans the clinical penetrance of IL12RB1 mutations varies.…”

Section: Discussionmentioning

confidence: 81%

Deregulation of Fas ligand expression as a novel cause of autoimmune lymphoproliferative syndrome-like disease

et al. 2015

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© F e r r a t a S t o r t i F o u n d a t i o nFor instance, forced expression of the Fas regulating miR146a caused an immune disorder similar to ALPS in transgenic mice. 22 One factor known to regulate expression of both Fas and FasL is interleukin-12 (IL12). [23][24][25][26][27][28][29][30] This cytokine mediates its effects via binding to a heterodimeric receptor composed of the IL12 receptors β1 (IL12RB1) and β2 (IL12RB2) and subsequent activation of JAK/STAT signaling. 31 The IL12 receptor is mainly expressed on T lymphocytes and natural killer (NK) cells. IL12RB1 deficiency is associated with Mendelian susceptibility to mycobacterial diseases. [32][33][34][35] These diseases predispose affected individuals to mycobacterial infections (tuberculosis) due to disturbance of IL12/IL23/IFNg signaling. IL12RB1 also associates with IL23R to form the IL23 receptor. Phagocytic cells release both IL12 and IL23 in response to non-viral infections to induce the secretion of interferon (IFN)g by T and NK cells. This in turn stimulates phagocytes to eliminate intracellular pathogens and activation of IFNg−secreting T helper cells. The IL12 signaling pathway is known to regulate FasL expression on activated T cells and knockout of IL12RB2 predisposes mice to spontaneous autoimmunity, lymphoproliferation and B-cell malignancies. 36 In the present study we identified a patient with a classical ALPS phenotype that was associated with a truncating nonsense mutation in IL12RB1 and loss of IL12/IL23-mediated signaling. Methods Study cohorts and DNA isolationTwenty-six ALPS patients, relatives and healthy controls were enrolled in the study. Written informed consent was obtained from all participants. Experiments were approved by the Ethical Review Boards of Hadassah, the Israeli Ministry of Health and the local Ethics committee of the University of Düsseldorf. Mononuclear cells were derived from peripheral blood by Ficoll (Biochrom, Berlin, Germany) density centrifugation. DNT cells were magnetically selected employing the double-negative T-cell isolation kit (Miltenyi, Bergisch-Gladbach, Germany). Genomic DNA was isolated from whole blood or DNT cells using the DNA blood kit (Qiagen, Hilden, Germany). Whole-exome sequencing and data analysisAfter exclusion of mutations in known ALPS-associated genes by targeted Sanger sequencing (Online Supplementary Methods, Online Supplementary Table S1) whole-exome sequencing was carried out as described elsewhere. 37 In brief, sequencing libraries of 350 bp fragments were generated from sheared genomic DNA. Exome capture was performed using the SeqCap EZ Exome Library 2.0 kit (Roche/Nimblegen, Madison, WI, USA). One hundred base-pair, single-read sequencing was performed on a HiSeq2000 (Illumina, San Diego, CA, USA).Sequencing data were aligned against the human reference genome hg19 (GRCh37, statistics provided in Online Supplementary Table S2) and converted using Samtools. 38 Variation calls were obtained employing GATK, HapMap, OmniArray and dbSNP134 datasets (The Broad Institu...

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Section: Discussionmentioning

confidence: 81%

Deregulation of Fas ligand expression as a novel cause of autoimmune lymphoproliferative syndrome-like disease

et al. 2015

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“…As recently and extensively reviewed by van de Vosse et al (70), multiple IL12RB1 polymorphisms confer susceptibility to mycobacterial infection. The importance of these IL12RB1 polymorphisms on IL-12 signaling and T H 1 development has historically been interpreted in the context of human IL12R␤1, which, relative to IL12R␤1⌬TM, is better studied since its cloning by Chua et al (71).…”

Section: Discussionmentioning

confidence: 87%

IL12Rβ1ΔTM Is a Secreted Product ofil12rb1That Promotes Control of Extrapulmonary Tuberculosis

et al. 2015

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bIL12RB1 is a human gene that is important for resistance to Mycobacterium tuberculosis infection. IL12RB1 is expressed by multiple leukocyte lineages, and encodes a type I transmembrane protein (IL12R␤1) that associates with IL12p40 and promotes the development of host-protective T H 1cells. Recently, we observed that il12rb1-the mouse homolog of IL12RB1-is alternatively spliced by leukocytes to produce a second isoform (IL12R␤1⌬TM) that has biological properties distinct from IL12R␤1. Although the expression of IL12R␤1⌬TM is elicited by M. tuberculosis in vivo, and its overexpression enhances IL12p40 responsiveness in vitro, the contribution of IL12R␤1⌬TM to controlling M. tuberculosis infection has not been tested. Here, we demonstrate that IL12R␤1⌬TM represents a secreted product of il12rb1 that, when absent from mice, compromises their ability to control M. tuberculosis infection in extrapulmonary organs. Furthermore, elevated M. tuberculosis burdens in IL12R␤1⌬TM-deficient animals are associated with decreased lymph node cellularity and a decline in T H 1 development. Collectively, these data support a model wherein IL12R␤1⌬TM is a secreted product of il12rb1 that promotes resistance to M. tuberculosis infection by potentiating T H cells response to IL-12.

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“…These patients are also susceptible to Salmonella, Candida and M. tuberculosis species 2,3 . Nine disease-causing genes have been described, including three genes controlling the response to IFN-γ (IFNGR1, IFNGR2, STAT1), four involved in IFN-γ production (IL12B, IL12RB1, NEMO,ISG15), one involved in the IFN-γ dependent induction of IL-12 (IRF8) and another gene controlling the macrophage respiratory burst, which can be triggered by IFN-γ (CYBB) 2,[4][5][6][7][8] . The considerable allelic heterogeneity at some of these loci has resulted in the definition of up to 18 different inborn errors of immunity 2 .…”

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confidence: 99%

“…IL-12Rb1 is a common receptor chain of the IL-12 and the IL-23 receptors and deficiency of IL-12Rb1 causes a profound defect in both IL-12 and IL-23 signaling 2,7,8,9 . IL-12 is an important cytokine for the development of IFN-γ producing T cells and also induces IFN-γ production by Natural killer (NK) and Natural Killer T (NKT) cells 9 .…”

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confidence: 99%

Clinical and genetic features of IL12Rb1 deficiency: Single center experience of 18 patients

et al. 2016

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In all patients the percentage of activated lymphocytes with surface expression of IL12Rb1 was <1% indicating that it is an effective method for the screening of these patients. Three recurrent mutations were responsible for 85% of our families. Prognosis was good in patients, in whom specific antimicrobial therapy was given before dissemination occurs, as well as prophylactic antimicrobial treatment when needed and IFN-γ therapy for severe infectious episodes.

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IL-12Rβ1 Deficiency: Mutation Update and Description of theIL12RB1Variation Database

Cited by 86 publications

References 82 publications

Deregulation of Fas ligand expression as a novel cause of autoimmune lymphoproliferative syndrome-like disease

Deregulation of Fas ligand expression as a novel cause of autoimmune lymphoproliferative syndrome-like disease

IL12Rβ1ΔTM Is a Secreted Product ofil12rb1That Promotes Control of Extrapulmonary Tuberculosis

Clinical and genetic features of IL12Rb1 deficiency: Single center experience of 18 patients

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