Genomic Spectrum and Phenotypic Heterogeneity of Human IL-21 Receptor Deficiency.
Deniz CagdasDaniel MayrSafa BarisLisa WorleyDavid B LangleyAyse MetinElif Soyak AytekinRaziye AtanNurhan KasapSevgi Köstel BalJasmin DmytrusRaul Jimenez HerediaGulsun KarasuSelda Hancerli TorunMuge ToyranElif Karakoc-AydinerDaniel ChristBaris KuskonmazDuygu Uçkan-ÇetinkayaAysegul UnerFelicitas OberndorferAna-Iris SchieferGulbu UzelElissa K DeenickBaerbel KellerKlaus WarnatzBénédicte NevenAnne DurandyOzden SanalCindy S MaAhmet ÖzenPolina StepenskyIlhan TezcanKaan BoztugStuart G TangyePublished in: Journal of clinical immunology (2021)
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.
Keyphrases
- end stage renal disease
- newly diagnosed
- ejection fraction
- chronic kidney disease
- peritoneal dialysis
- endothelial cells
- cardiovascular disease
- oxidative stress
- cell proliferation
- optical coherence tomography
- chronic obstructive pulmonary disease
- single cell
- smoking cessation
- autism spectrum disorder
- acute myeloid leukemia
- dna methylation
- sars cov
- patient reported outcomes
- lung function
- free survival
- soft tissue