Extending the clinical and immunological phenotype of human interleukin-21 receptor deficiency

Stepensky, Polina; Keller, Baerbel; Abuzaitoun, Omar; Shaag, Avraham; Barak, Yaacov; Unger, Susanne; Seidl, Maximilian; Rizzi, Marta; Weintraub, Michael; Elpeleg, Orly; Warnatz, Klaus

doi:10.3324/haematol.2014.112508

Cited by 44 publications

(45 citation statements)

References 14 publications

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“…When we analysed follicular T-cell populations in the peripheral blood of the three IL-21R-deficient patients, we observed that the fractions of circulating CD4 + CXCR5 hi PD-1 hi Foxp3 − Tfh phenotype cells were within the broad range of healthy controls (Fig. 2f), which is consistent with previous observations1939. By contrast, the percentages of CD4 + CXCR5 hi PD-1 hi CD127 lo Foxp3 + Tfr phenotype cells in the peripheral blood of IL-21R-deficient patients were elevated relative to healthy controls (Fig.…”

Section: Resultssupporting

confidence: 91%

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IL-21 restricts T follicular regulatory T cell proliferation through Bcl-6 mediated inhibition of responsiveness to IL-2

et al. 2017

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T follicular regulatory (Tfr) cells control the magnitude and specificity of the germinal centre reaction, but how regulation is contained to ensure generation of high-affinity antibody is unknown. Here we show that this balance is maintained by the reciprocal influence of interleukin (IL)-2 and IL-21. The number of IL-2-dependent FoxP3+ regulatory T cells is increased in the peripheral blood of human patients with loss-of-function mutations in the IL-21 receptor (IL-21R). In mice, IL-21:IL-21R interactions influence the phenotype of T follicular cells, reducing the expression of CXCR4 and inhibiting the expansion of Tfr cells after T-cell-dependent immunization. The negative effect of IL-21 on Tfr cells in mice is cell intrinsic and associated with decreased expression of the high affinity IL-2 receptor (CD25). Bcl-6, expressed in abundance in Tfr cells, inhibits CD25 expression and IL-21-mediated inhibition of CD25 is Bcl-6 dependent. These findings identify a mechanism by which IL-21 reinforces humoral immunity by restricting Tfr cell proliferation.

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Section: Resultssupporting

confidence: 91%

“…CD25 hi CD4 + T cells in peripheral blood were previously shown to be similar between IL-21R-deficient patients and healthy controls1939, and our findings are consistent with these observations. By contrast, dual expressing FoxP3 + CD25 hi Treg cells were increased by IL21R deficiency.…”

Section: Discussionsupporting

confidence: 92%

IL-21 restricts T follicular regulatory T cell proliferation through Bcl-6 mediated inhibition of responsiveness to IL-2

et al. 2017

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“…Several IL-21(R)-deficient patients were initially diagnosed with CVID, before the onset of opportunistic infections 55 57. However, over time it has become evident that IL-21 and IL-21R deficiencies represent forms of CID rather than CVID 54–58…”

Section: Genes Associated With Monogenic Forms Of Cvidmentioning

confidence: 99%

Genes associated with common variable immunodeficiency: one diagnosis to rule them all?

et al. 2016

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Common variable immunodeficiency (CVID) is a primary antibody deficiency characterised by hypogammaglobulinaemia, impaired production of specific antibodies after immunisation and increased susceptibility to infections. CVID shows a considerable phenotypical and genetic heterogeneity. In contrast to many other primary immunodeficiencies, monogenic forms count for only 2-10% of patients with CVID. Genes that have been implicated in monogenic CVID include ICOS, TNFRSF13B (TACI), TNFRSF13C (BAFF-R), TNFSF12 (TWEAK), CD19, CD81, CR2 (CD21), MS4A1 (CD20), TNFRSF7 (CD27), IL21, IL21R, LRBA, CTLA4, PRKCD, PLCG2, NFKB1, NFKB2, PIK3CD, PIK3R1, VAV1, RAC2, BLK, IKZF1 (IKAROS) and IRF2BP2. With the increasing number of disease genes identified in CVID, it has become clear that CVID is an umbrella diagnosis and that many of these genetic defects cause distinct disease entities. Moreover, there is accumulating evidence that at least a subgroup of patients with CVID has a complex rather than a monogenic inheritance. This review aims to discuss current knowledge regarding the molecular genetic basis of CVID with an emphasis on the relationship with the clinical and immunological phenotype

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“…Furthermore, in western paediatric populations, primary immunodeficiency affecting T-cell function have been implicated, including mutations in genes that result in severe combined immunodeficiency (SCID) syndrome such as IL2RG and adenosine deaminase deficiency (ADA) mutations. Cases have also been reported in hyper IgE syndrome with autosomal dominant mutations in STAT3 [12] as well as in mutations in IL21R which can signal via STAT3 [13, 14]. A list of reported mutations in humans and supportive studies in murine models of infection are listed in Table I.…”

Section: Current Epidemiology Of Pneumocystis Infectionmentioning

confidence: 99%

New advances in understanding the host immune response to Pneumocystis

Hoving

Kolls

2017

Current Opinion in Microbiology

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Pneumocystis jirovecii causes clinical pneumonia in immunocompromised hosts. Despite this, the inability to cultivate this organism in vitro has likely hindered the field in ascertaining the true impact of Pneumocystis in human infection. However the recent release of the genome as well as in advances in understanding host genetics, and other risk factors for infection and robust experimental models of disease have shed new light on the impact of this fungal pathogen as to better define populations at risk. This review will highlight these recent advances as well as highlight future needed areas of research.

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Extending the clinical and immunological phenotype of human interleukin-21 receptor deficiency

Cited by 44 publications

References 14 publications

IL-21 restricts T follicular regulatory T cell proliferation through Bcl-6 mediated inhibition of responsiveness to IL-2

IL-21 restricts T follicular regulatory T cell proliferation through Bcl-6 mediated inhibition of responsiveness to IL-2

Genes associated with common variable immunodeficiency: one diagnosis to rule them all?

New advances in understanding the host immune response to Pneumocystis

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