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

Kreins, Alexandra; Ciancanelli, Michael J.; Okada, Satoshi; Kong, Xiao‐Fei; Ramírez-Alejo, Noé; Kılıç, Sara Şebnem; Baghdadi, Jamila El; Nonoyama, Shigeaki; Mahdaviani, Seyed Alireza; Ailal, Fatima; Bousfiha, Aziz; Mansouri, Davood; Nievas, Elma; Cindy, S.; Rao, Geetha; Bernasconi, Andrea; Kuehn, Hye Sun; Niemela, Julie E.; Stoddard, Jennifer; Deveau, Paul; Cobat, Aurélie; Azbaoui, Safa El; Sabri, Ayoub; Lim, Che Kang; Sundin, Mikael; Avery, Danielle T.; Halwani, Rabih; Grant, Audrey V.; Boisson, Bertrand; Bogunovic, Dusan; Itan, Yuval; Moncada-Vélez, Marcela; Martı́nez-Barricarte, Rubén; Migaud, Mélanie; Deswarte, Caroline; Alsina, Laia; Kotlarz, Daniel; Klein, Christoph; Müller-Fleckenstein, Ingrid; Fleckenstein, Bernhard; Cormier‐Daire, Valérie; Rose-John, Stefan; Pïcard, Capucine; Hammarström, Lennart; Puel, Anne; Al‐Muhsen, Saleh; Abel, Laurent; Chaussabel, Damien; Rosenzweig, Sergio D.; Minegishi, Yoshiyuki; Tangye, Stuart G.; Bustamante, Jacinta; Casanova, Jean‐Laurent; Boisson–Dupuis, Stéphanie

doi:10.1084/jem.20140280

Cited by 305 publications

(374 citation statements)

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“…Multiple other cytokine receptors also signal through combinations of four JAKs and seven STAT proteins, for example, JAK1 is also used in signalling by IL-2, IL-4, IL-7, IL-9, IL-15, IL-21, IL-27, IL-6 family cytokines and IL-10 family cytokines4. To date, germline mutations in two out of the four known Janus kinases, JAK3 and TYK2, have been found in PID patients6789. Somatic mutations in JAK2 have also been shown to cause clonal myeloproliferative disorders, for example, polycythemia vera and idiopathic erythrocytosis1011, whereas somatic JAK1 mutations have been associated with gynaecologic cancers12.…”

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confidence: 99%

Biallelic JAK1 mutations in immunodeficient patient with mycobacterial infection

et al. 2016

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Mutations in genes encoding components of the immune system cause primary immunodeficiencies. Here, we study a patient with recurrent atypical mycobacterial infection and early-onset metastatic bladder carcinoma. Exome sequencing identified two homozygous missense germline mutations, P733L and P832S, in the JAK1 protein that mediates signalling from multiple cytokine receptors. Cells from this patient exhibit reduced JAK1 and STAT phosphorylation following cytokine stimulations, reduced induction of expression of interferon-regulated genes and dysregulated cytokine production; which are indicative of signalling defects in multiple immune response pathways including Interferon-γ production. Reconstitution experiments in the JAK1-deficient cells demonstrate that the impaired JAK1 function is mainly attributable to the effect of the P733L mutation. Further analyses of the mutant protein reveal a phosphorylation-independent role of JAK1 in signal transduction. These findings clarify JAK1 signalling mechanisms and demonstrate a critical function of JAK1 in protection against mycobacterial infection and possibly the immunological surveillance of cancer.

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confidence: 99%

Biallelic JAK1 mutations in immunodeficient patient with mycobacterial infection

et al. 2016

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“…Autosomal recessive TYK2 deficiency causes a disease with characteristic features, at least in some patients, of both hyper-IgE syndrome (HIES) and susceptibility to mycobacterial disease (following BCG vaccination). Other patients instead developed neurobrucellosis and viral ( herpes zoster ) infections but did not show any signs of atopy, asthma, or fungal skin infections [16–18]. …”

Section: Jaks-associated Diseasesmentioning

confidence: 99%

Small molecules to the rescue: Inhibition of cytokine signaling in immune-mediated diseases

Gadina

Gazaniga

Vian

et al. 2017

Journal of Autoimmunity

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Cytokines are small, secreted proteins associated with the maintenance of immune homeostasis but also implicated with the pathogenesis of several autoimmune and inflammatory diseases. Biologic agents blocking cytokines or their receptors have revolutionized the treatment of such pathologies. Nonetheless, some patients fail to respond to these drugs or do not achieve complete remission. The signal transduction originating from membrane-bound cytokine receptors is an intricate network of events that lead to gene expression and ultimately regulate cellular functionality. Our understanding of the intracellular actions that molecules such as interleukins, inteferons (IFNs) and tumor necrosis factor (TNF) set into motion has greatly increased in the past few years, making it possible to interfere with cytokines’ signaling cascades. The Janus kinase (JAK)/signal transducer and activator of transcription (STAT), the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), the mitogen activated protein kinase (MAPK) and the Phosphatidylinositol-3’-kinases (PI3K) pathways have all been intensively studied and key steps as well as molecules have been identified. These research efforts have led to the development of a new generation of small molecule inhibitors. Drugs capable of blocking JAK enzymatic activity or interfering with the proteasome-mediated degradation of intermediates in the NF-kB pathway have already entered the clinical arena confirming the validity of this approach. In this review, we have recapitulated the biochemical events downstream of cytokine receptors and discussed some of the drugs which have already been successfully utilized in the clinic. Moreover, we have highlighted some of the new molecules that are currently being developed for the treatment of immune-mediated pathologies and malignancies.

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“…However, recently, seven new Tyk2-deficient patients were identified, all with normal IgE, calling into question the classification of Tyk2 deficiency as a hyper-IgE syndrome. 22 …”

Section: Clinical Presentation Of Dock8 Deficiencymentioning

confidence: 99%

Current Status of Dedicator of Cytokinesis-Associated Immunodeficiency

Dimitrova

Freeman

2017

Dermatologic Clinics

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Synopsis DOCK8 deficiency is an autosomal recessive combined immunodeficiency disease associated with elevated IgE, atopy, recurrent sinopulmonary and cutaneous viral infections, and malignancy. The DOCK8 protein is critical for cytoskeletal organization, and deficiency impairs dendritic cell transmigration, T cell survival, and NK cell cytotoxicity. Early hematopoietic stem cell transplant is gaining prominence as a definitive treatment given the potential for severe complications and mortality in this disease. Recently, DOCK2 deficiency has been identified in several patients with early-onset invasive bacterial and viral infections.

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

Abstract: Kreins et al. report the identification and immunological characterization of a group of TYK2-deficient patients.

Cited by 305 publications

References 103 publications

Biallelic JAK1 mutations in immunodeficient patient with mycobacterial infection

Biallelic JAK1 mutations in immunodeficient patient with mycobacterial infection

Small molecules to the rescue: Inhibition of cytokine signaling in immune-mediated diseases

Current Status of Dedicator of Cytokinesis-Associated Immunodeficiency

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