Combined immunodeficiency with CD4 lymphopenia and sclerosing cholangitis caused by a novel loss-of-function mutation affecting IL21R

Combined immunodeficiency with CD4 lymphopenia and sclerosing cholangitis caused by a novel loss-of-function mutation affecting IL21RCombined immunodeficiencies (CIDs) comprise a heterogeneous group of monogenic disorders manifesting with lymphocyte defects, recurrent infections and dysregulated immune response.Recently, we and others have described clinical and molecular features of the combined immunodeficiency syndromes caused by IL21 or IL21R loss-of-function mutations in humans.To date, only one homozygous mutation in the IL21 and five distinct homozygous mutations in the IL21R gene were identified, however only three have been published so far.1,2 Accordingly, comprehensive clinical and immunological data characterizing this novel type of CID are lacking.Here we report a novel homozygous frame-shift mutation in the IL21R gene of a patient presenting with T-, B-and natural killer (NK)-cell lymphopenia.The patient had eosinophilic duodenitis, sclerosing cholangitis, tinea corporis and otitis media, but no increased frequency of respiratory infections, as described in other IL21R-deficient patients.3 Thus, our report expands on the clinical and functional characteristics of the IL21R deficiency, which may aid early diagnosis leading to improved treatment options.The cytokine IL21 regulates T-and B-cell proliferation and activation, 4,5 and promotes NK-cell cytotoxicity.6 IL21 binds to the IL21R, primarily expressed by lymphocyte populations and other hematopoietic cells, but it can also be found on non-hematopoietic cells including fibroblasts, keratinocytes and intestinal epithelial cells.7,8 IL21R and the interleukin-2 receptor common gamma-chain (IL2RG) form a heterodimer complex which upon IL21 binding initiates downstream signaling by activating Janus kinase 1, 3 (JAK1, JAK3) and inducing signal transducer and activator