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01-08-2021 | Cholangitis | Original Article

Genomic Spectrum and Phenotypic Heterogeneity of Human IL-21 Receptor Deficiency

Authors: Deniz Cagdas, Daniel Mayr, Safa Baris, Lisa Worley, David B. Langley, Ayse Metin, Elif Soyak Aytekin, Raziye Atan, Nurhan Kasap, Sevgi Köstel Bal, Jasmin Dmytrus, Raul Jimenez Heredia, Gulsun Karasu, Selda Hancerli Torun, Muge Toyran, Elif Karakoc-Aydiner, Daniel Christ, Baris Kuskonmaz, Duygu Uçkan-Çetinkaya, Aysegul Uner, Felicitas Oberndorfer, Ana-Iris Schiefer, Gulbu Uzel, Elissa K. Deenick, Baerbel Keller, Klaus Warnatz, Bénédicte Neven, Anne Durandy, Ozden Sanal, Cindy S. Ma, Ahmet Özen, Polina Stepensky, Ilhan Tezcan, Kaan Boztug, Stuart G. Tangye

Published in: Journal of Clinical Immunology | Issue 6/2021

Abstract

Biallelic inactivating mutations in IL21R causes a combined immunodeficiency that is often complicated by cryptosporidium infections. While eight IL-21R-deficient patients have been reported previously, the natural course, immune characteristics of disease, and response to hematopoietic stem cell transplantation (HSCT) remain to be comprehensively examined. In our study, we have collected clinical histories of 13 patients with IL-21R deficiency from eight families across seven centers worldwide, including five novel patients identified by exome or NGS panel sequencing. Eight unique mutations in IL21R were identified in these patients, including two novel mutations. Median age at disease onset was 2.5 years (0.5–7 years). The main clinical manifestations were recurrent bacterial (84.6%), fungal (46.2%), and viral (38.5%) infections; cryptosporidiosis-associated cholangitis (46.2%); and asthma (23.1%). Inflammatory skin diseases (15.3%) and recurrent anaphylaxis (7.9%) constitute novel phenotypes of this combined immunodeficiency. Most patients exhibited hypogammaglobulinemia and reduced proportions of memory B cells, circulating T follicular helper cells, MAIT cells and terminally differentiated NK cells. However, IgE levels were elevated in 50% of IL-21R-deficient patients. Overall survival following HSCT (6 patients, mean follow-up 1.8 year) was 33.3%, with pre-existing organ damage constituting a negative prognostic factor. Mortality of non-transplanted patients (n = 7) was 57.1%. Our detailed analysis of the largest cohort of IL-21R-deficient patients to date provides in-depth clinical, immunological and immunophenotypic features of these patients, thereby establishing critical non-redundant functions of IL-21/IL-21R signaling in lymphocyte differentiation, humoral immunity and host defense against infection, and mechanisms of disease pathogenesis due to IL-21R deficiency. Outcome following HSCT depends on prior chronic infections and organ damage, which should thus be considered as early as possible following molecular diagnosis.

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Title: Genomic Spectrum and Phenotypic Heterogeneity of Human IL-21 Receptor Deficiency
Authors: Deniz Cagdas
Daniel Mayr
Safa Baris
Lisa Worley
David B. Langley
Ayse Metin
Elif Soyak Aytekin
Raziye Atan
Nurhan Kasap
Sevgi Köstel Bal
Jasmin Dmytrus
Raul Jimenez Heredia
Gulsun Karasu
Selda Hancerli Torun
Muge Toyran
Elif Karakoc-Aydiner
Daniel Christ
Baris Kuskonmaz
Duygu Uçkan-Çetinkaya
Aysegul Uner
Felicitas Oberndorfer
Ana-Iris Schiefer
Gulbu Uzel
Elissa K. Deenick
Baerbel Keller
Klaus Warnatz
Bénédicte Neven
Anne Durandy
Ozden Sanal
Cindy S. Ma
Ahmet Özen
Polina Stepensky
Ilhan Tezcan
Kaan Boztug
Stuart G. Tangye
Publication date: 01-08-2021
Publisher: Springer US
Keyword: Cholangitis
Published in: Journal of Clinical Immunology / Issue 6/2021
Print ISSN: 0271-9142
Electronic ISSN: 1573-2592
DOI: https://doi.org/10.1007/s10875-021-01031-5

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