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Human TYK2 deficiency: Mycobacterial and viral infections without hyper-IgE syndrome.

ABSTRACT: Autosomal recessive, complete TYK2 deficiency was previously described in a patient (P1) with intracellular bacterial and viral infections and features of hyper-IgE syndrome (HIES), including atopic dermatitis, high serum IgE levels, and staphylococcal abscesses. We identified seven other TYK2-deficient patients from five families and four different ethnic groups. These patients were homozygous for one of five null mutations, different from that seen in P1. They displayed mycobacterial and/or viral infections, but no HIES. All eight TYK2-deficient patients displayed impaired but not abolished cellular responses to (a) IL-12 and IFN-α/β, accounting for mycobacterial and viral infections, respectively; (b) IL-23, with normal proportions of circulating IL-17(+) T cells, accounting for their apparent lack of mucocutaneous candidiasis; and (c) IL-10, with no overt clinical consequences, including a lack of inflammatory bowel disease. Cellular responses to IL-21, IL-27, IFN-γ, IL-28/29 (IFN-λ), and leukemia inhibitory factor (LIF) were normal. The leukocytes and fibroblasts of all seven newly identified TYK2-deficient patients, unlike those of P1, responded normally to IL-6, possibly accounting for the lack of HIES in these patients. The expression of exogenous wild-type TYK2 or the silencing of endogenous TYK2 did not rescue IL-6 hyporesponsiveness, suggesting that this phenotype was not a consequence of the TYK2 genotype. The core clinical phenotype of TYK2 deficiency is mycobacterial and/or viral infections, caused by impaired responses to IL-12 and IFN-α/β. Moreover, impaired IL-6 responses and HIES do not appear to be intrinsic features of TYK2 deficiency in humans.

SUBMITTER: Kreins AY

PROVIDER: S-EPMC4577846 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Human TYK2 deficiency: Mycobacterial and viral infections without hyper-IgE syndrome.

Kreins Alexandra Y AY Ciancanelli Michael J MJ Okada Satoshi S Kong Xiao-Fei XF Ramírez-Alejo Noé N Kilic Sara Sebnem SS El Baghdadi Jamila J Nonoyama Shigeaki S Mahdaviani Seyed Alireza SA Ailal Fatima F Bousfiha Aziz A Mansouri Davood D Nievas Elma E Ma Cindy S CS Rao Geetha G Bernasconi Andrea A Sun Kuehn Hye H Niemela Julie J Stoddard Jennifer J Deveau Paul P Cobat Aurelie A El Azbaoui Safa S Sabri Ayoub A Lim Che Kang CK Sundin Mikael M Avery Danielle T DT Halwani Rabih R Grant Audrey V AV Boisson Bertrand B Bogunovic Dusan D Itan Yuval Y Moncada-Velez Marcela M Martinez-Barricarte Ruben R Migaud Melanie M Deswarte Caroline C Alsina Laia L Kotlarz Daniel D Klein Christoph C Muller-Fleckenstein Ingrid I Fleckenstein Bernhard B Cormier-Daire Valerie V Rose-John Stefan S Picard Capucine C Hammarstrom Lennart L Puel Anne A Al-Muhsen Saleh S Abel Laurent L Chaussabel Damien D Rosenzweig Sergio D SD Minegishi Yoshiyuki Y Tangye Stuart G SG Bustamante Jacinta J Casanova Jean-Laurent JL Boisson-Dupuis Stéphanie S

The Journal of experimental medicine 20150824 10

Autosomal recessive, complete TYK2 deficiency was previously described in a patient (P1) with intracellular bacterial and viral infections and features of hyper-IgE syndrome (HIES), including atopic dermatitis, high serum IgE levels, and staphylococcal abscesses. We identified seven other TYK2-deficient patients from five families and four different ethnic groups. These patients were homozygous for one of five null mutations, different from that seen in P1. They displayed mycobacterial and/or vi ...[more]

PMID: 26304966

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Project description:Introduction: Hyper-IgE Syndrome (HIES) is a rare inborn error of immunity (IEI) characterized by a constellation of symptoms related to susceptibility to Staphylococcal skin and pulmonary infections, eczema, raised serum IgE (>2,000 IU/ml), craniofacial anomalies, and recurrent bone fractures. Data on HIES from the Indian subcontinent is scarce and restricted to small case series and case reports. This is the first compilation of national data on HIES. Materials and Methods: A total 103 cases clinically diagnosed and treated as HIES were analyzed from nine centers. Cases with clinical and/or molecular diagnosis of DOCK8 deficiency were not included. Patients were divided into two groups: group I for whom a heterozygous rare variant of STAT3 was identified, and group II, with clinical features similar to those of AD STAT3 deficiency, but without any genetic diagnosis. Results: Genetic diagnosis was available in 27 patients (26.2%) and all harbored rare variants in the STAT3 gene. Majority of these STAT3 HIES patients presented with recurrent skin abscesses (77.7%) or pneumonia (62.9%) or both (59.2%). Other features included eczema (37%), candidiasis (55.5%), facial dysmorphism (55.5%), recurrent fractures (11.1%), and retained primary teeth (7.4%). Mycobacterial infections were seen in a significant 18.5%. Mortality was seen in three subjects (11.1%). A similar trend in the clinical presentation was observed when all the 103 patients were analyzed together. Twenty percent of patients without a rare variant in the STAT3 gene had an NIH score of ≥40, whereas, 51.9% of STAT3 HIES subjects had scores below the cut off of ≥40. TH17 cell numbers were low in 10/11 (90.9%) STAT3 HIES tested. Rare variants observed were 8 in exon 21; 8 in exon 13; 3 in exon 10; 2 in exon 15, and one each in exon 6, 16, 17, 19, 22, and splice site downstream of exon 12. Seven variants were novel and included F174S, N567D, L404Sfs*8, G419 =, M329K, T714I, R518X, and a splice site variant downstream of exon 12. Conclusions: The report includes seven novel STAT3 variants, including a rare linker domain nonsense variant and a CC domain variant. Mycobacterial diseases were more frequent, compared to western literature.

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Human TYK2 deficiency: Mycobacterial and viral infections without hyper-IgE syndrome.

Publications

Human TYK2 deficiency: Mycobacterial and viral infections without hyper-IgE syndrome.

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