title: IL-17 receptor A and adenosine deaminase 2 deficiency in siblings with recurrent infections and chronic inflammation.
abstract: BACKGROUND
  Data on patients affected by chronic mucocutaneous candidiasis underscore the preponderant role of IL-17 receptor A (IL-17RA) in preserving mucocutaneous immunity. Little is known about the role of adenosine deaminase (ADA) 2 in regulation of immune responses, although recent reports linked ADA2 deficiency with inflammation and vasculitis.
  
  
  OBJECTIVE
  We sought to investigate the mechanisms of chronic inflammation and vasculitis in a child lacking IL-17RA and ADA2 to identify therapeutic targets.
  
  
  METHODS
  We report a family with 2 siblings who have had recurrent mucocutaneous infections with Candida albicans and Staphylococcus aureus and chronic inflammatory disease and vasculitis since early childhood, which were refractory to classical treatments. Array-based comparative genomic hybridization analysis showed that both siblings are homozygous for a 770-kb deletion on chr22q11.1 encompassing both IL17RA and cat eye critical region 1 (CECR1). Immunologic studies were carried out by means of flow cytometry, ELISA, and RIA.
  
  
  RESULTS
  As expected, in the affected child we found a lack of IL-17RA expression, which implies a severe malfunction in the IL-17 signaling pathway, conferring susceptibility to recurrent mucocutaneous infections. Surprisingly, we detected an in vitro and in vivo upregulation of proinflammatory cytokines, notably IL-1β and TNF-α, which is consistent with the persistent systemic inflammation.
  
  
  CONCLUSIONS
  This work emphasizes the utility of whole-genome analyses combined with immunologic investigation in patients with unresolved immunodeficiency. This approach is likely to provide an insight into immunologic pathways and mechanisms of disease. It also provides molecular evidence for more targeted therapies. In addition, our report further corroborates a potential role of ADA2 in modulating immunity and inflammation.
authors.affiliation: Service of Medical Genetics, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: Florence
authors.initials: F
authors.lastname: Fellmann
authors.affiliation: Immunology, Allergology and Rheumatology Unit, Department of Pediatrics, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: Federica
authors.initials: F
authors.lastname: Angelini
authors.affiliation: Immunology, Allergology and Rheumatology Unit, Department of Pediatrics, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Wassenberg
authors.affiliation: Immunology and Allergy Unit, Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Perreau
authors.affiliation: Department of Immunology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Natalia
authors.initials: N
authors.lastname: Arenas Ramirez
authors.affiliation: Rheumatology Unit, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: Gregoire
authors.initials: G
authors.lastname: Simon
authors.affiliation: Department of Immunology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Onur
authors.initials: O
authors.lastname: Boyman
authors.affiliation: Department of Dermatology, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: Olivier
authors.initials: O
authors.lastname: Demaria
authors.affiliation: Department of Dermatology, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Christen-Zaech
authors.affiliation: Department of Dermatology, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Hohl
authors.affiliation: Service of Medical Genetics, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: Marco
authors.initials: M
authors.lastname: Belfiore
authors.affiliation: Immunology, Allergology and Rheumatology Unit, Department of Pediatrics, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: Annette
authors.initials: A
authors.lastname: von Scheven-Gete
authors.affiliation: Department of Dermatology, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: Michel
authors.initials: M
authors.lastname: Gilliet
authors.affiliation: Infectious Diseases Unit, Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Bochud
authors.affiliation: Immunology, Allergology and Rheumatology Unit, Department of Pediatrics, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Perrin
authors.affiliation: Hematology-Oncology Unit, Department of Pediatrics, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: Maya
authors.initials: M
authors.lastname: Beck Popovic
authors.affiliation: Immunology and Allergy Unit, Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: Pierre-Alexandre
authors.initials: PA
authors.lastname: Bart
authors.affiliation: Service of Medical Genetics, Lausanne University Hospital, Lausanne, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland.
authors.forename: Jacques S
authors.initials: JS
authors.lastname: Beckmann
authors.affiliation: Service of Medical Genetics, Lausanne University Hospital, Lausanne, Switzerland.
authors.forename: Danielle
authors.initials: D
authors.lastname: Martinet
authors.affiliation: Immunology, Allergology and Rheumatology Unit, Department of Pediatrics, Lausanne University Hospital, Lausanne, Switzerland. Electronic address: Michael.Hofer@chuv.ch.
authors.forename: Michaël
authors.initials: M
authors.lastname: Hofer
mesh_terms: D000243:Adenosine Deaminase / Q000172:deficiency* / Q000235:genetics* / Q000276:immunology; D000293:Adolescent; D002178:Candidiasis, Chronic Mucocutaneous / Q000150:complications / Q000235:genetics* / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D002908:Chronic Disease; D055028:Comparative Genomic Hybridization; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007249:Inflammation / Q000150:complications / Q000235:genetics* / Q000276:immunology; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000235:genetics* / Q000276:immunology; D053722:Receptors, Interleukin-17 / Q000172:deficiency* / Q000235:genetics* / Q000276:immunology; D017384:Sequence Deletion; D035781:Siblings; D014657:Vasculitis / Q000150:complications / Q000235:genetics* / Q000276:immunology
chemical_list: C109985:IL17RA protein, human; D036341:Intercellular Signaling Peptides and Proteins; D053722:Receptors, Interleukin-17; C408373:ADA2 protein, human; D000243:Adenosine Deaminase
keywords: Adenosine deaminase 2; CECR1; IL17RA; chronic inflammation; chronic mucocutaneous candidiasis; immunodeficiency; vasculitis; whole-genome analyses