IL-17 receptor A and adenosine deaminase 2 deficiency in siblings with recurrent infections and chronic inflammation

• Published in: Journal of allergy and clinical immunology Vol. 137; no. 4; pp. 1189 - 1196.e2
• Main Authors: Fellmann, Florence, MD, PhD, Angelini, Federica, MD, PhD, Wassenberg, Jacqueline, MD, Perreau, Matthieu, PhD, Arenas Ramirez, Natalia, Simon, Gregoire, MSc, Boyman, Onur, MD, Demaria, Olivier, PhD, Christen-Zaech, Stephanie, MD, Hohl, Daniel, MD, Belfiore, Marco, PhD, von Scheven-Gete, Annette, MD, Gilliet, Michel, MD, Bochud, Pierre-Yves, MD, Perrin, Yannick, MD, Beck Popovic, Maya, MD, Bart, Pierre-Alexandre, MD, Beckmann, Jacques S., PhD, Martinet, Danielle, PhD, Hofer, Michaël, MD
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-04-2016; Elsevier Limited
• Subjects: Adenosine; Adenosine Deaminase - deficiency; Adenosine Deaminase - genetics; Adenosine Deaminase - immunology; Adenosine deaminase 2; Adolescent; Age; Allergy and Immunology; Bacterial infections; Biopsy; Blood; Bone marrow; Candida albicans; Candidiasis, Chronic Mucocutaneous - complications; Candidiasis, Chronic Mucocutaneous - genetics; Candidiasis, Chronic Mucocutaneous - immunology; CECR1; Child; Child, Preschool; Chronic Disease; chronic inflammation; chronic mucocutaneous candidiasis; Cloning; Comparative Genomic Hybridization; Cytokines; Dermatitis; Fatal Outcome; Female; Genealogy; Granulocytes; Humans; IL17RA; Immune system; immunodeficiency; Infections; Inflammation; Inflammation - complications; Inflammation - genetics; Inflammation - immunology; Intercellular Signaling Peptides and Proteins - deficiency; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - immunology; Laboratories; Lymphocytes; Mutation; Neutropenia; Neutrophils; Patients; Receptors, Interleukin-17 - deficiency; Receptors, Interleukin-17 - genetics; Receptors, Interleukin-17 - immunology; Sequence Deletion; Siblings; Staphylococcus aureus; vasculitis; Vasculitis - complications; Vasculitis - genetics; Vasculitis - immunology; whole-genome analyses; Sri Lanka; Adenosine deaminase 2; chronic mucocutaneous candidiasis; IL-17 receptor A; CECR1; Periodic fever, aphthous stomatitis, pharyngitis, and adenopathy; Fluorescence in situ hybridization; IL-17RA; Allophycocyanin; immunodeficiency; Cat eye critical region 1; Erythrocyte sedimentation rate; chronic inflammation; Array-CGH; Online Mendelian Inheritance in Man; vasculitis; ESR; OMIM; Adenosine deaminase; Panarteritis nodosa; IL17RA; whole-genome analyses; APC; PFAPA; FISH; PAN; Array-based comparative genomic hybridization; ADA
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2015.07.053

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.