Molecular mechanisms of mucocutaneous immunity against Candida and Staphylococcus species László Maródi, MD, PhD, Sophie Cypowyj, PhD, Beáta Tóth, PhD,

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Presentation transcript:

Molecular mechanisms of mucocutaneous immunity against Candida and Staphylococcus species László Maródi, MD, PhD, Sophie Cypowyj, PhD, Beáta Tóth, PhD, Liudmyla Chernyshova, MD, PhD, Anne Puel, PhD, Jean-Laurent Casanova, MD, PhD Journal of Allergy and Clinical Immunology Volume 130, Issue 5, Pages 1019-1027 (November 2012) DOI: 10.1016/j.jaci.2012.09.011 Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 A and B, Submental staphylococcal abscess (Fig 1, A, circle) in a 7-month-old girl and nail candidiasis (Fig 1, B) in her mother from a family with AD-HIES and the R382W mutation in STAT3. C, Cold staphylococcal abscess in a 10-year-old female patient with AD-HIES and the H332Y amino acid substitution in STAT3. D, Severe eczema and typical facial characteristics in a 9-year-old boy with sporadic AD-HIES and the R382W mutation in STAT3. Journal of Allergy and Clinical Immunology 2012 130, 1019-1027DOI: (10.1016/j.jaci.2012.09.011) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 In human subjects, IL-6 and IL-1 are the major cytokines inducing IL-17 T-cell differentiation from naive CD4 T cells, which can also differentiate into regulatory T (TREG), follicular TH (TFH), TH1, and TH2 cells. Dendritic cell (DC)–derived IL-23 reinforces and maintains IL-17 T-cell differentiation. In mice TH17 cell differentiation can also be amplified by the release of IL-21. The IL-17 T-cell differentiation involves upregulation of retinoic acid orphan receptor γt (RORγt). STAT3 plays critical role in signaling by both IL-21 and IL-23. TH17-derived cytokines induce secretion of chemokines, colony-stimulating factors, and antimicrobial peptides by epithelial cells. TH17- and TH22-derived cytokines induce the accumulation of phagocytes at the site of pathogen invasion. EC, Epithelial cells; G-CSF, granulocyte colony-stimulating factor; PMN, polymorphonuclear neutrophil granulocyte. Journal of Allergy and Clinical Immunology 2012 130, 1019-1027DOI: (10.1016/j.jaci.2012.09.011) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Representation of the domains of STAT3 (A) and STAT1 (B) proteins and disease-causing mutations. Currently, 75 different disease-causing mutations of STAT3 have been reported. Fourteen morbid mutations in the CC domain and 7 mutations affecting the DNA-BD, SH2 domain, and transactivation domain of STAT1 have been described. Roman numerals, Coding exons; bold bars, cDNA regions corresponding to various domains together with their amino acid boundaries; N, NH2 terminal; C, COOH terminal. *Recessive mutation associated with partial STAT1 deficiency. Journal of Allergy and Clinical Immunology 2012 130, 1019-1027DOI: (10.1016/j.jaci.2012.09.011) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 The IFN-γ/IL-12/IL-23 circuit and its role in regulation of innate immunity. After stimulation by IFN-γ and JAK-STAT1–mediated signaling, mononuclear phagocytes (MNPs) and dendritic cells (DCs) produce IL-12 and IL-23. These cytokines induce the production of IFN-γ by natural killer (NK) and T cells. IFN-γ binds to its receptor, resulting in dimerization of the 2 receptor subunits and phosphorylation of JAK1 and JAK2. The activated JAKs phosphorylate IFN-γ receptor 1 (IFN-γR1), leading to recruitment and activation of STAT1 proteins that translocate to the nucleus and bind to responsive elements of IFN-γ–inducible genes that are then transcribed. GAF, γ-Interferon activation factor; GAS, γ-interferon activated sequence; ISRE, interferon-stimulated response elements. Journal of Allergy and Clinical Immunology 2012 130, 1019-1027DOI: (10.1016/j.jaci.2012.09.011) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Severe clinical manifestation of the STAT1 CC-D mutation. Hippocratic nails (nail clubbing), oral mucositis, total alopecia, and blepharoconjunctivitis in a 19-year-old man with the D165G mutation of STAT1 underlying CMC is shown. The severity of the clinical phenotype is unique in this patient and contrasts with the much milder phenotypes in most patients with STAT1 CC-D mutations. Journal of Allergy and Clinical Immunology 2012 130, 1019-1027DOI: (10.1016/j.jaci.2012.09.011) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions