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J Allergy Clin Immunol. 2016 Apr;137(4):1189-1196.e2. doi: 10.1016/j.jaci.2015.07.053. Epub 2015 Nov 20.

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

Author information

1
Service of Medical Genetics, Lausanne University Hospital, Lausanne, Switzerland.
2
Immunology, Allergology and Rheumatology Unit, Department of Pediatrics, Lausanne University Hospital, Lausanne, Switzerland.
3
Immunology and Allergy Unit, Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland.
4
Department of Immunology, University Hospital Zurich, Zurich, Switzerland.
5
Rheumatology Unit, Lausanne University Hospital, Lausanne, Switzerland.
6
Department of Dermatology, Lausanne University Hospital, Lausanne, Switzerland.
7
Infectious Diseases Unit, Department of Medicine, Lausanne University Hospital, Lausanne, Switzerland.
8
Hematology-Oncology Unit, Department of Pediatrics, Lausanne University Hospital, Lausanne, Switzerland.
9
Service of Medical Genetics, Lausanne University Hospital, Lausanne, Switzerland; Swiss Institute of Bioinformatics, Lausanne, Switzerland.
10
Immunology, Allergology and Rheumatology Unit, Department of Pediatrics, Lausanne University Hospital, Lausanne, Switzerland. Electronic address: Michael.Hofer@chuv.ch.

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.

KEYWORDS:

Adenosine deaminase 2; CECR1; IL17RA; chronic inflammation; chronic mucocutaneous candidiasis; immunodeficiency; vasculitis; whole-genome analyses

PMID:
26607704
DOI:
10.1016/j.jaci.2015.07.053
[Indexed for MEDLINE]

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