Common variable immunodeficiency and natural killer cell lymphopenia caused by Ets-binding site mutation in the IL-2 receptor γ (IL2RG) gene promoter.
Ontology highlight
ABSTRACT:
SUBMITTER: Chandra A
PROVIDER: S-EPMC4774944 | biostudies-literature | 2016 Mar
REPOSITORIES: biostudies-literature
Publications
Common variable immunodeficiency and natural killer cell lymphopenia caused by Ets-binding site mutation in the IL-2 receptor γ (IL2RG) gene promoter.
Chandra Anita A Zhang Fang F Gilmour Kimberly C KC Webster David D Plagnol Vincent V Kumararatne Dinakantha S DS Burns Siobhan O SO Nejentsev Sergey S Thrasher Adrian J AJ
The Journal of allergy and clinical immunology 20151031 3
Similar Datasets
Project description:PurposeIdiopathic CD4 lymphopenia constitutes a heterogeneous group of immunodeficiencies with characteristically low CD4+ T-cell counts with largely unknown genetic etiology. We here sought to determine the underlying molecular cause in an index family with two patients suffering from combined immunodeficiency that evolved into predominant CD4+ lymphopenia. The more severely affected index patient also presented with selective antibody deficiency against bacterial polysaccharide antigens.MethodsFor the genetic analysis, we used combined homozygosity mapping and exome sequencing. Functional assays included immunoblot analysis, flow cytometry and TCR Vβ spectratyping.ResultsA novel homozygous missense mutation was revealed in the kinase domain of JAK3 (c.T3196C, p.Cys1066Arg). Further analysis showed revertant chimerism in CD8+ T-cells in both patients. The additional presence of revertant CD4+ T-cells was associated with a milder clinical and immunological phenotype in the second patient, although the role somatic chimerism plays in amelioration of disease phenotype is uncertain, as presence of revertant cells had no effect on residual CD4 cell JAK3 signaling function. Residual activity of JAK3-dependent STAT3 and STAT5 signaling was also found in immortalized B-cell lines indicating a hypomorphic nature of the described mutation which likely contributes to the milder clinical phenotype.ConclusionsWe here present the first case of revertant mosaicism in JAK3 deficiency, manifesting as combined immunodeficiency evolving into predominant CD4+ lymphopenia. Revertant chimerism or hypomorphic mutations in genes typically associated with more severe T-cell deficiency should be considered when assessing patients with milder forms of combined immunodeficiencies.
| S-EPMC4220108 | biostudies-literature
Project description:Hypomorphic IL2RG mutations may lead to milder phenotypes than X-SCID, named variably as atypical X-SCID or X-CID. We report an 11-year-old boy with a novel c. 172C>T;p.(Pro58Ser) mutation in IL2RG, presenting with atypical X-SCID phenotype. We also review the growing number of hypomorphic IL2RG mutations causing atypical X-SCID. We studied the patient's clinical phenotype, B, T, NK, and dendritic cell phenotypes, IL2RG and CD25 cell surface expression, and IL-2 target gene expression, STAT tyrosine phosphorylation, PBMC proliferation, and blast formation in response to IL-2 stimulation, as well as protein-protein interactions of the mutated IL2RG by BioID proximity labeling. The patient suffered from recurrent upper and lower respiratory tract infections, bronchiectasis, and reactive arthritis. His total lymphocyte counts have remained normal despite skewed T and B cells subpopulations, with very low numbers of plasmacytoid dendritic cells. Surface expression of IL2RG was reduced on his lymphocytes. This led to impaired STAT tyrosine phosphorylation in response to IL-2 and IL-21, reduced expression of IL-2 target genes in patient CD4+ T cells, and reduced cell proliferation in response to IL-2 stimulation. BioID proximity labeling showed aberrant interactions between mutated IL2RG and ER/Golgi proteins causing mislocalization of the mutated IL2RG to the ER/Golgi interface. In conclusion, IL2RG p.(Pro58Ser) causes X-CID. Failure of IL2RG plasma membrane targeting may lead to atypical X-SCID. We further identified another carrier of this mutation from newborn SCID screening, lost to closer scrutiny.
| S-EPMC7142052 | biostudies-literature
Project description:Most patients with primary immune deficiency suffer from recurrent infections; however, paradoxical autoimmune phenomena can also manifest. The aim of this study was to identify immunological markers of autoimmune phenomena associated with common variable immunodeficiency (CVID). The study included 33 adults with CVID divided into two groups: (1) those with noninfectious autoimmune complications (CVID-C (n = 24)) and (2) those with only infectious symptoms (CVID-OI (n = 9)). Flow cytometry of peripheral blood was performed and compared with systemic lupus erythematosus (SLE) patients (n = 17) and healthy controls (n = 20). We found that all lymphocytes were lower in CVID-C and SLE. NK cells were lowest in CVID-C. Th17 cells were significantly reduced in CVID-C and SLE. Tregs were significantly lower in CVID-C and SLE. Bregs did not significantly differ between any groups. Class-switched memory B cells were significantly lower in CVID-C and CVID-OI. Lastly, plasmablasts were significantly higher in SLE. Among the T cell subsets, CVID-C patients had lower naive and recent thymic emigrant CD4+ T cells. In conclusion, reduced Treg, Th17, and NK cells are features of CVID with autoimmune complications, and class-switched memory B cells can help distinguish patients with different causes of autoimmunity. Future studies are needed to confirm whether reductions of Treg, Th17, and NK cells might be a biomarker of more complicated CVID cases.
| S-EPMC8348468 | biostudies-literature
Project description:E26 transformation-specific sequence 1 (Ets-1), the prototype of the ETS family of transcription factors, is critical for the expression of IL-2 by murine Th cells; however, its mechanism of action is still unclear. Here we show that Ets-1 is also essential for optimal production of IL-2 by primary human Th cells. Although Ets-1 negatively regulates the expression of Blimp1, a known suppressor of IL-2 expression, ablation of B lymphocyte-induced maturation protein 1 (Blimp1) does not rescue the expression of IL-2 by Ets-1-deficient Th cells. Instead, Ets-1 physically and functionally interacts with the nuclear factor of activated T-cells (NFAT) and is required for the recruitment of NFAT to the IL-2 promoter. In addition, Ets-1 is located in both the nucleus and cytoplasm of resting Th cells. Nuclear Ets-1 quickly exits the nucleus in response to calcium-dependent signals and competes with NFAT proteins for binding to protein components of noncoding RNA repressor of NFAT complex (NRON), which serves as a cytoplasmic trap for phosphorylated NFAT proteins. This nuclear exit of Ets-1 precedes rapid nuclear entry of NFAT and Ets-1 deficiency results in impaired nuclear entry, but not dephosphorylation, of NFAT proteins. Thus, Ets-1 promotes the expression of IL-2 by modulating the activity of NFAT.
| S-EPMC3785780 | biostudies-literature
Project description:Common variable immunodeficiency (CVID) is the most prevalent symptomatic primary immunodeficiency in adults. CVID patients often present changes in the frequency and function of B lymphocytes, reduced number of Treg cells, chronic immune activation, recurrent infections, high incidence of autoimmunity and increased risk for malignancies. We hypothesized that the frequency of B10 cells would be diminished in CVID patients because these cells play an important role in the development of Treg cells and in the control of T cell activation and autoimmunity. Therefore, we evaluated the frequency of B10 cells in CVID patients and correlated it with different clinical and immunological characteristics of this disease. Forty-two CVID patients and 17 healthy controls were recruited for this study. Cryopreserved PBMCs were used for analysis of T cell activation, frequency of Treg cells and characterization of B10 cells by flow cytometry. IL-10 production by sorted B cells culture and plasma sCD14 were determined by ELISA. We found that CVID patients presented decreased frequency of IL-10-producing CD24hiCD38hi B cells in different cell culture conditions and decreased frequency of IL-10-producing CD24hiCD27+ B cells stimulated with CpG+PIB. Moreover, we found that CVID patients presented lower secretion of IL-10 by sorting-purified B cells when compared to healthy controls. The frequency of B10 cells had no correlation with autoimmunity, immune activation and Treg cells in CVID patients. This work suggests that CVID patients have a compromised regulatory B cell compartment which is not correlated with clinical and immunological characteristics presented by these individuals.
| S-EPMC4798727 | biostudies-literature
Project description:The SHP-1 protein encoded by the Ptpn6 gene has been extensively studied in hematopoietic cells in the context of inflammation. A point mutation in this gene (Ptpn6spin) causes spontaneous inflammation in mice, which has a striking similarity to neutrophilic dermatoses in humans. Recent findings highlighted the role of signaling adapters and kinases in promoting inflammation in Ptpn6spin mice; however, the underlying transcriptional regulation is poorly understood. Here, we report that SYK is important for driving neutrophil infiltration and initiating wound healing responses in Ptpn6spin mice. Moreover, we found that deletion of the transcription factor Ets2 in myeloid cells ameliorates cutaneous inflammatory disease in Ptpn6spin mice through transcriptional regulation of its target inflammatory genes. Furthermore, Ets-2 drives IL-1α-mediated inflammatory signaling in neutrophils of Ptpn6spin mice. Overall, in addition to its well-known role in driving inflammation in cancer, Ets-2 plays a major role in regulating IL-1α-driven Ptpn6spin-mediated neutrophilic dermatoses. Model for the role of ETS-2 in neutrophilic inflammation in Ptpn6spin mice. Mutation of the Ptpn6 gene results in SYK phosphorylation which then sequentially activates MAPK signaling pathways and activation of ETS-2. This leads to activation of ETS-2 target genes that contribute to neutrophil migration and inflammation. When Ets2 is deleted in Ptpn6spin mice, the expression of these target genes is reduced, leading to the reduced pathology in neutrophilic dermatoses.
| S-EPMC8245632 | biostudies-literature
Project description:Natural Killer (NK) cells have been shown to exert antiviral and antitumoural activities. Nevertheless most available data are derived from mouse models and functions of these cells in human remain unclear. To evaluate the impact of low circulating NK cell counts and to provide some clues to the role of NK cells in natural conditions, we studied a large cohort of patients with common variable immunodeficiency (CVID) included in a multicenter cohort of patients with primary hypogammaglobulinaemia. Patients were classified into three groups on the basis of their NK cell counts: severe and mild NK cell lymphopenia (<50 and 50-99×10(6)/L respectively), and normal NK cell counts (>100×10(6)/L). Clinical events were analyzed and compared between these three groups of patients. During study period, 457 CVID patients were included: 99 (21.7%) with severe NK cell lymphopenia, 118 (25.8%) with mild NK cell lymphopenia and 240 (52.5%) with normal NK cell counts. Non-infectious complications (57% vs. 36% and 35%), and, particularly, granulomatous complications (25.3% vs. 13.6% and 8.8%), were more frequent in patients with severe NK cell lymphopenia than in other groups. Invasive infections (68.7% vs. 60.2% and 48.8%), including bacteraemia (22.2% vs. 5.9% and 8.3%) and infectious pneumonia (63.6% vs. 59.3% and 44.2%), were also more frequent in this population. However, no difference was observed for viral infections and neoplasms. Low circulating NK cell counts are associated with more severe phenotypes of CVID, which may indicate a protective role of these immune cells against severe bacterial infections and other complications and non-redundant immune functions when the adaptive immune response is not optimal.
| S-EPMC4856746 | biostudies-literature
Project description:Ras-related C3 botulinum toxin substrate 2 (RAC2), through interactions with reduced NAD phosphate oxidase component p67 phox , activates neutrophil superoxide production, whereas interactions with p21-activated kinase are necessary for fMLF-induced actin remodeling. We identified 3 patients with de novo RAC2[E62K] mutations resulting in severe T- and B-cell lymphopenia, myeloid dysfunction, and recurrent respiratory infections. Neutrophils from RAC2[E62K] patients exhibited excessive superoxide production, impaired fMLF-directed chemotaxis, and abnormal macropinocytosis. Cell lines transfected with RAC2[E62K] displayed characteristics of active guanosine triphosphate (GTP)-bound RAC2 including enhanced superoxide production and increased membrane ruffling. Biochemical studies demonstrated that RAC2[E62K] retains intrinsic GTP hydrolysis; however, GTPase-activating protein failed to accelerate hydrolysis resulting in prolonged active GTP-bound RAC2. Rac2+/E62K mice phenocopy the T- and B-cell lymphopenia, increased neutrophil F-actin, and excessive superoxide production seen in patients. This gain-of-function mutation highlights a specific, nonredundant role for RAC2 in hematopoietic cells that discriminates RAC2 from the related, ubiquitous RAC1.
| S-EPMC6497516 | biostudies-literature
Project description:Mutations of the IL2RG gene, which encodes for the interleukin-2 receptor common gamma chain (γC, CD132), can lead to X-linked severe combined immunodeficiency (X-SCID) associated with a T-B+NK- phenotype as a result of dysfunctional γC-JAK3-STAT5 signaling. Lately, hypomorphic mutations of the IL2RG gene have been described causing atypical SCID with a milder phenotype. Here, we report three brothers with low-normal lymphocyte counts and susceptibility to recurrent respiratory infections and cutaneous warts. The clinical presentation combined with dysgammaglobulinemia suspected an inherited immunity disorder, which has been proven by Next Generation Sequencing as a novel c.458T > C; p.Ile153Thr IL2RG missense-mutation. Subsequent functional characterization revealed impaired T-cell proliferation, low TREC levels and a skewed TCR Vβ repertoire in all three patients. Interestingly, investigation of various subpopulations showed normal expression of CD132 but with partially impaired STAT5 phosphorylation compared to healthy controls. Additionally, we performed precise genetic analysis of subpopulations revealing spontaneous somatic reversion, predominately in lymphoid derived CD3+, CD4+ and CD8+ T cells. Our data demonstrate that the atypical SCID phenotype noticed in these three brothers is due to the combination of hypomorphic IL-2RG function and somatic reversion.
| S-EPMC8774591 | biostudies-literature
Project description:Severe combined immunodeficiency (SCID) encompasses a range of inherited disorders that lead to a profound deterioration of the immune system. Among the pivotal genes associated with SCID, RAG1 and IL2RG play crucial roles. IL2RG is essential for the development, differentiation, and functioning of T, B, and NK cells, while RAG1 critically contributes to adaptive immunity by facilitating V(D)J recombination during the maturation of lymphocytes. Animal models carrying mutations in these genes exhibit notable deficiencies in their immune systems. Non-human primates (NHPs) are exceptionally well-suited models for biomedical research due to their genetic and physiological similarities to humans. Cytosine base editors (CBEs) serve as powerful tools for precisely and effectively modifying single-base mutations in the genome. Their successful implementation has been demonstrated in human cells, mice, and crop species. This study outlines the creation of an immunodeficient monkey model by deactivating both the IL2RG and RAG1 genes using the CBE4max system. The base-edited monkeys exhibited a severely compromised immune system characterized by lymphopenia, atrophy of lymphoid organs, and a deficiency of mature T cells. Furthermore, these base-edited monkeys were capable of hosting and supporting the growth of human breast cancer cells, leading to tumor formation. In summary, we have successfully developed an immunodeficient monkey model with the ability to foster tumor growth using the CBE4max system. These immunodeficiency monkeys show tremendous potential as valuable tools for advancing biomedical and translational research.
| S-EPMC10475462 | biostudies-literature