Molecular mechanisms of mucocutaneous immunity against Candida and Staphylococcus species
2012; Elsevier BV; Volume: 130; Issue: 5 Linguagem: Inglês
10.1016/j.jaci.2012.09.011
ISSN1097-6825
AutoresLászló Maródi, Sophie Cypowyj, Beáta Tóth, Л.И. Чернышова, Anne Puel, Jean‐Laurent Casanova,
Tópico(s)Pediatric health and respiratory diseases
ResumoSignal transducer and activator of transcription (STAT) proteins are key components of the innate and adaptive immune responses to pathogenic microorganisms. Recent research on primary immunodeficiency disorders and the identification of patients carrying germline mutations in STAT1, STAT3, and STAT5B have highlighted the role of human STATs in host defense against various viruses, bacteria, and fungi. Mutations in STAT1 and STAT3 disrupt various cytokine pathways that control mucocutaneous immunity against Candida species, especially Candida albicans, and Staphylococcus species, especially Staphylococcus aureus. Here we consider inborn errors of immunity arising from mutations in either STAT1 or STAT3 that affect mucocutaneous immunity to Candida and Staphylococcus species. Signal transducer and activator of transcription (STAT) proteins are key components of the innate and adaptive immune responses to pathogenic microorganisms. Recent research on primary immunodeficiency disorders and the identification of patients carrying germline mutations in STAT1, STAT3, and STAT5B have highlighted the role of human STATs in host defense against various viruses, bacteria, and fungi. Mutations in STAT1 and STAT3 disrupt various cytokine pathways that control mucocutaneous immunity against Candida species, especially Candida albicans, and Staphylococcus species, especially Staphylococcus aureus. Here we consider inborn errors of immunity arising from mutations in either STAT1 or STAT3 that affect mucocutaneous immunity to Candida and Staphylococcus species. Information for Category 1 CME CreditCredit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions.Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted.Date of Original Release: November 2012. Credit may be obtained for these courses until October 31, 2014.Copyright Statement: Copyright © 2012-2014. All rights reserved.Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease.Target Audience: Physicians and researchers within the field of allergic disease.Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates these educational activities for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity.List of Design Committee Members: László Maródi, MD, PhD, Sophie Cypowyj, PhD, Beáta Tóth, PhD, Liudmyla Chernyshova, MD, PhD, Anne Puel, PhD, and Jean-Laurent Casanova, MD, PhDActivity Objectives1.To identify primary immunodeficiencies associated with signal transducer and activator of transcription (STAT)–mediated signaling pathways.2.To identify how molecular defects associated with specific primary immunodeficiency diseases predispose affected subjects to an increased risk of Candida and Staphylococcus species mucocutaneous infections.Recognition of Commercial Support: This CME activity has not received external commercial support.Disclosure of Significant Relationships with Relevant CommercialCompanies/Organizations: S. Cypowyj has received research support from the Axa Fellowship. J.-L. Casanova has received research support from the National Center for Research Resources and the National Center for Advancing Sciences (National Institutes of Health) and the St Giles Foundation and has received consultancy fees from Pfizer, GlaxoSmithKline, NovImmune, Merck, and Sanofi. The rest of the authors declare that they have no relevant conflicts of interest. Credit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions. Method of Physician Participation in Learning Process: The core material for these activities can be read in this issue of the Journal or online at the JACI Web site: www.jacionline.org. The accompanying tests may only be submitted online at www.jacionline.org. Fax or other copies will not be accepted. Date of Original Release: November 2012. Credit may be obtained for these courses until October 31, 2014. Copyright Statement: Copyright © 2012-2014. All rights reserved. Overall Purpose/Goal: To provide excellent reviews on key aspects of allergic disease to those who research, treat, or manage allergic disease. Target Audience: Physicians and researchers within the field of allergic disease. Accreditation/Provider Statements and Credit Designation: The American Academy of Allergy, Asthma & Immunology (AAAAI) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AAAAI designates these educational activities for a maximum of 1 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity. List of Design Committee Members: László Maródi, MD, PhD, Sophie Cypowyj, PhD, Beáta Tóth, PhD, Liudmyla Chernyshova, MD, PhD, Anne Puel, PhD, and Jean-Laurent Casanova, MD, PhD Activity Objectives1.To identify primary immunodeficiencies associated with signal transducer and activator of transcription (STAT)–mediated signaling pathways.2.To identify how molecular defects associated with specific primary immunodeficiency diseases predispose affected subjects to an increased risk of Candida and Staphylococcus species mucocutaneous infections. Recognition of Commercial Support: This CME activity has not received external commercial support. Disclosure of Significant Relationships with Relevant Commercial Companies/Organizations: S. Cypowyj has received research support from the Axa Fellowship. J.-L. Casanova has received research support from the National Center for Research Resources and the National Center for Advancing Sciences (National Institutes of Health) and the St Giles Foundation and has received consultancy fees from Pfizer, GlaxoSmithKline, NovImmune, Merck, and Sanofi. The rest of the authors declare that they have no relevant conflicts of interest. Many cases of primary immunodeficiencies (PIDs) are the results of defects in hematopoietic cell differentiation or abnormal functioning of leukocytes and in turn the consequences of gene mutations encoding cell-surface or intracellular receptors or receptor-mediated signal transduction pathway proteins.1Maródi L. Notarangelo L.D. Immunological and genetic bases of new primary immunodeficiencies.Nat Rev Immunol. 2007; 7: 851-861Crossref PubMed Scopus (80) Google Scholar, 2Casanova J.-L. Abel L. 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The JAK-STAT pathway at twenty.Immunity. 2012; 36: 503-514Abstract Full Text Full Text PDF PubMed Scopus (1042) Google Scholar STAT-mediated signaling is the transmission of signals from various receptors of cytokines and growth factors after ligand binding. STAT proteins are present in the cytoplasm as inactive monomers and typically form homodimers or heterodimers after being phosphorylated by receptor-associated JAKs. These phosphorylated STAT dimers translocate to the nucleus, where they act as activators of transcription; nuclear binding of STAT dimers promotes the expression of a variety of genes important for cell survival, differentiation, proliferation, and migration and for efficient host responses to various pathogens. STAT1 proteins can be phosphorylated and activated on binding of IFN-α/β, IFN-γ, IFN-λ, and IL-27 to their receptors, and STAT3 is primarily phosphorylated and activated on binding of IL-6, IL-10, and numerous other molecules.17Casanova J.-L. Holland S.M. Notarangelo L.D. Inborn errors of human JAKs and STATs.Immunity. 2012; 36: 515-528Abstract Full Text Full Text PDF PubMed Scopus (244) Google Scholar, 36O'Shea J.J. Lahesmaa R. Vahedi G. Laurence A. Kanno Y. Genomic views of STAT function in CD4+ T helper cell differentiation.Nat Rev Immunol. 2011; 11: 239-250Crossref PubMed Scopus (221) Google Scholar STAT3 has been implicated in host defenses against extracellular bacteria, including S aureus, and fungi, including C albicans, by recent investigations of patients with autosomal dominant hyper-IgE syndrome (AD-HIES).38Ma C.S. Chew G.Y. Simpson N. Priyadarshi A. Wong M. Grimbacher B. et al.Deficiency of Th17 cells in hyper IgE syndrome due to mutations in STAT3.J Exp Med. 2008; 205: 1551-1557Crossref PubMed Scopus (568) Google Scholar, 39Milner J.D. Brenchley J.M. Laurence A. Freeman A.F. Hill B.J. 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Autosomal dominant STAT3 deficiency and hyper-IgE syndrome: molecular, cellular, and clinical features from a French National Survey.Medicine. 2012; 91: 1-19Crossref PubMed Scopus (245) Google Scholar Recent research has revealed that the IL-17–producing CD4+ TH lymphocytes are central to the host defense against skin and lung infections by producing IL-17 and IL-22 cytokines, which in turn recruit neutrophils and bind to and stimulate epidermal or epithelial cells to induce the release of bactericidal peptides (Fig 2).47Minegishi Y. Saito M. Nagasawa M. Takada H. Hara T. Tsuchiya S. et al.Molecular explanation for the contradiction between systemic Th17 defect and localized bacterial infection in hyper-IgE syndrome.J Exp Med. 2009; 206: 1291-1301Crossref PubMed Scopus (204) Google Scholar In some patients with AD-HIES, naive CD4+ T cells might not differentiate into IL-17–producing T cells because of dominant negative mutations of STAT3; almost all such mutations affect the DNA-binding domain (DNA-BD), Src homology (SH) 2 domain, or transactivation domain of STAT3 (Fig 3, A). DNA-BD and transactivation domain mutations might prevent binding of STAT3 homodimers and STAT3-STAT1 heterodimers to promoter sequences in genomic DNA. Indeed, the electrophoretic mobility shift assay showed that even in the presence of normal levels of phosphorylated STAT3, binding of STAT3 to DNA was undetectable in T cells from patients with HIES in contrast to that seen in T cells from healthy subjects.39Milner J.D. Brenchley J.M. Laurence A. Freeman A.F. Hill B.J. Elias K.M. et al.Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome.Nature. 2008; 452: 773-776Crossref PubMed Scopus (954) Google Scholar, 42Minengishi Y. Saito M. Tsuchiya A. Tsuge I. Takada H. Hara T. et al.Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome.Nature. 2007; 448: 1058-1062Crossref PubMed Scopus (838) Google Scholar These findings clearly suggest that STAT3 mutations in patients with AD-HIES are dominant negative. Mutations in the SH2 domain might interfere with dimerization of STAT3 proteins. The severe depletion of IL-17–producing T cells in patients with AD-HIES has led to the suggestion that STAT3-dependent immunity is required to control infections by pathogens residing on body surfaces.38Ma C.S. Chew G.Y. Simpson N. Priyadarshi A. Wong M. Grimbacher B. et al.Deficiency of Th17 cells in hyper IgE syndrome due to mutations in STAT3.J Exp Med. 2008; 205: 1551-1557Crossref PubMed Scopus (568) Google Scholar, 39Milner J.D. Brenchley J.M. Laurence A. Freeman A.F. Hill B.J. Elias K.M. et al.Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome.Nature. 2008; 452: 773-776Crossref PubMed Scopus (954) Google Scholar, 40de Beaucoudrey L. Puel A. Filipe-Santos O. Cobat A. Ghandil P. Chrabieh M. et al.Mutations in STAT3 and IL12RB1 impair the development of human IL-17-producing T cells.J Exp Med. 2008; 205: 1543-1550Crossref PubMed Scopus (378) Google Scholar Release of IL-17 and IL-22 by T cells in dermal tissue and mucous membranes probably initiates the secretion of CXC chemokines and granulocyte colony-stimulating factor by epithelial cells, and these agents might then recruit neutrophils on the body surfaces and eliminate bacteria and fungi (Fig 2). Another important and relevant role of IL-17 cytokines is to promote the release of bactericidal peptides, including defensins.48Conti H.R. Gaffen S.L. Host responses to Candida albicans: Th17 cells and mucosal candidiasis.Microbes Infect. 2010; 12: 518-527Crossref PubMed Scopus (115) Google ScholarFig 2In 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.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Fig 3Representation 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
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