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

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dc.contributor.authorÖZEN, AHMET OĞUZHAN
dc.contributor.authorsCagdas, Deniz; Mayr, Daniel; Baris, Safa; Worley, Lisa; Langley, David B.; Metin, Ayse; Aytekin, Elif Soyak; Atan, Raziye; Kasap, Nurhan; Bal, Sevgi Koestel; Dmytrus, Jasmin; Heredia, Raul Jimenez; Karasu, Gulsun; Torun, Selda Hancerli; Toyran, Muge; Karakoc-Aydiner, Elif; Christ, Daniel; Kuskonmaz, Baris; Uckan-Cetinkaya, Duygu; Uner, Aysegul; Oberndorfer, Felicitas; Schiefer, Ana-Iris; Uzel, Gulbu; Deenick, Elissa K.; Keller, Baerbel; Warnatz, Klaus; Neven, Benedicte; Durandy, Anne; Sanal, Ozden; Ma, Cindy S.; Ozen, Ahmet; Stepensky, Polina; Tezcan, Ilhan; Boztug, Kaan; Tangye, Stuart G.
dc.date.accessioned2022-03-14T09:59:13Z
dc.date.available2022-03-14T09:59:13Z
dc.date.issued2021-08
dc.description.abstractBiallelic 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.
dc.identifier.doi10.1007/s10875-021-01031-5
dc.identifier.eissn1573-2592
dc.identifier.issn0271-9142
dc.identifier.pubmed33929673
dc.identifier.urihttps://hdl.handle.net/11424/243827
dc.identifier.wosWOS:000645896900001
dc.language.isoeng
dc.publisherSPRINGER/PLENUM PUBLISHERS
dc.relation.ispartofJOURNAL OF CLINICAL IMMUNOLOGY
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectIL-21
dc.subjectIL-21R signaling
dc.subjectT follicular helper cells
dc.subjectB cell differentiation
dc.subjectSTAT3
dc.titleGenomic Spectrum and Phenotypic Heterogeneity of Human IL-21 Receptor Deficiency
dc.typearticle
dspace.entity.typePublication
local.avesis.id5deb75a7-3dec-4912-9491-7e944a741155
local.import.packageSS16
local.indexed.atWOS
local.indexed.atSCOPUS
local.indexed.atPUBMED
local.journal.numberofpages19
oaire.citation.endPage1290
oaire.citation.issue6
oaire.citation.startPage1272
oaire.citation.titleJOURNAL OF CLINICAL IMMUNOLOGY
oaire.citation.volume41
relation.isAuthorOfPublication3e9c297b-e636-4836-8f61-dc9c8b7c29cf
relation.isAuthorOfPublication.latestForDiscovery3e9c297b-e636-4836-8f61-dc9c8b7c29cf

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