scholarly journals Somatic Reversion of a Novel IL2RG Mutation Resulting in Atypical X-Linked Combined Immunodeficiency

Genes ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 35
Author(s):  
Yujuan Hou ◽  
Hans Peter Gratz ◽  
Guillermo Ureña-Bailén ◽  
Paul G. Gratz ◽  
Karin Schilbach-Stückle ◽  
...  
Keyword(s):  
Respiratory Infections ◽  
Functional Characterization ◽  
Severe Combined Immunodeficiency ◽  
Interleukin 2 ◽  
Combined Immunodeficiency ◽  
Gamma Chain ◽  
Normal Expression ◽  
Somatic Reversion ◽  
Atypical Scid ◽  
Il2rg Gene

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.

scholarly journals Gene therapy improves immune function in preadolescents with X-linked severe combined immunodeficiency

Blood ◽  
2007 ◽  
Vol 110 (1) ◽  
pp. 67-73 ◽  
Author(s):  
Javier Chinen ◽  
Joie Davis ◽  
Suk See De Ravin ◽  
Beverly N. Hay ◽  
Amy P. Hsu ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Cell Function ◽  
Severe Combined Immunodeficiency ◽  
Marrow Transplant ◽  
Salvage Treatment ◽  
Combined Immunodeficiency ◽  
Gamma Chain ◽  
Gene Encoding ◽  
Il2rg Gene ◽  
The Common

Retroviral gene therapy can restore immunity to infants with X-linked severe combined immunodeficiency (XSCID) caused by mutations in the IL2RG gene encoding the common gamma chain (γc) of receptors for interleukins 2 (IL-2), −4, −7, −9, −15, and −21. We investigated the safety and efficacy of gene therapy as salvage treatment for older XSCID children with inadequate immune reconstitution despite prior bone marrow transplant from a parent. Subjects received retrovirus-transduced autologous peripherally mobilized CD34+ hematopoietic cells. T-cell function significantly improved in the youngest subject (age 10 years), and multilineage retroviral marking occurred in all 3 children.

scholarly journals Case Report: Interleukin-2 Receptor Common Gamma Chain Defect Presented as a Hyper-IgE Syndrome

2021 ◽  
Vol 12 ◽  
Author(s):  
Brahim Belaid ◽  
Lydia Lamara Mahammed ◽  
Aida Mohand Oussaid ◽  
Melanie Migaud ◽  
Yasmine Khadri ◽  
...  
Keyword(s):  
T Cell ◽  
Functional Characterization ◽  
Severe Combined Immunodeficiency ◽  
Interleukin 2 ◽  
Surface Expression ◽  
T Cell Subsets ◽  
Gamma Chain ◽  
Gene Encoding ◽  
Common Gamma Chain ◽  
Novel Therapeutic Strategies

X-linked severe combined immunodeficiency (X-SCID) is caused by mutations of IL2RG, the gene encoding the interleukin common gamma chain (IL-2Rγ or γc) of cytokine receptors for interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Hypomorphic mutations of IL2RG may cause combined immunodeficiencies with atypical clinical and immunological presentations. Here, we report a clinical, immunological, and functional characterization of a missense mutation in exon 1 (c.115G>A; p. Asp39Asn) of IL2RG in a 7-year-old boy. The patient suffered from recurrent sinopulmonary infections and refractory eczema. His total lymphocyte counts have remained normal despite skewed T cell subsets, with a pronounced serum IgE elevation. Surface expression of IL-2Rγ was reduced on his lymphocytes. Signal transducer and activator of transcription (STAT) phosphorylation in response to IL-2, IL-4, and IL-7 showed a partially preserved receptor function. T-cell proliferation in response to mitogens and anti-CD3/anti-CD28 monoclonal antibodies was significantly reduced. Further analysis revealed a decreased percentage of CD4+ T cells capable of secreting IFN-γ, but not IL-4 or IL-17. Studies on the functional consequences of IL-2Rγ variants are important to get more insight into the pathogenesis of atypical phenotypes which may lay the ground for novel therapeutic strategies.

scholarly journals Characterization of B-cell lines established from two X-linked severe combined immunodeficiency patients: interleukin-15 binds to the B cells but is not internalized efficiently

Blood ◽  
1995 ◽  
Vol 86 (4) ◽  
pp. 1428-1436 ◽  
Author(s):  
S Kumaki ◽  
HD Ochs ◽  
M Timour ◽  
K Schooley ◽  
M Ahdieh ◽  
...  
Keyword(s):  
B Cells ◽  
Cell Lines ◽  
Severe Combined Immunodeficiency ◽  
Interleukin 2 ◽  
Chain Gene ◽  
Combined Immunodeficiency ◽  
Normal Numbers ◽  
Gamma Chain ◽  
Barr Virus ◽  
Epstein Barr

X-linked severe combined immunodeficiency (XSCID) is characterized by absent or profoundly reduced numbers of T cells and normal numbers of B cells in the circulation. Affected patients have mutations of the interleukin-2 (IL-2) receptor gamma chain gene. Using Epstein-Barr virus-transformed B-lymphoblastoid cell lines (B-LCLs) established from two unrelated XSCID patients, we could show that neither expressed the IL-2 receptor gamma chain on the cell surface. A novel cytokine IL-15, which has biologic activities similar to those of IL-2, could bind to the XSCID B-LCLs in the absence of the gamma chain, although both the beta and gamma chains of the human IL-2 receptor were previously shown to be required for IL-15 binding by transfected COS cells. Furthermore, a significant reduction and delay of IL-15 internalization by B lymphoblasts from XSCID patients was observed when compared with that of normal control B-LCLs. These results show the existence of a novel IL-15-specific receptor component that contributes to IL-15 binding but is insufficient for IL-15 internalization in the absence of the IL-2 receptor gamma chain.

Clinical and immunologic consequences of a somatic reversion in a patient with X-linked severe combined immunodeficiency

Blood ◽  
2008 ◽  
Vol 112 (10) ◽  
pp. 4090-4097 ◽  
Author(s):  
Carsten Speckmann ◽  
Ulrich Pannicke ◽  
Elisabeth Wiech ◽  
Klaus Schwarz ◽  
Paul Fisch ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Severe Combined Immunodeficiency ◽  
Interleukin 2 ◽  
Intrinsic Defect ◽  
Combined Immunodeficiency ◽  
Gamma Chain ◽  
Cell Repertoire ◽  
Hematopoietic Stem ◽  
Susceptibility To Infection

Abstract X-linked severe combined immunodeficiency is a life-threatening disorder caused by mutations in the gene encoding the interleukin-2 receptor gamma chain (IL2RG). Hypomorphic mutations and reversion of mutations in subpopulations of cells can result in variant clinical phenotypes, making diagnosis and treatment difficult. We describe a 5-year-old boy with mild susceptibility to infection who was investigated for a mutation in IL2RG due to persistent natural killer (NK)– and T-cell lymphopenia. A functionally relevant novel T466C point mutation was found in B, NK, and epithelial cells, whereas α/β and γ/δ T cells showed the normal gene sequence, suggesting reversion of the mutation in a common T-cell precursor. This genetic correction in T cells resulted in a diverse T-cell repertoire and significant immunity despite failure to produce specific antibodies linked to an intrinsic defect of mutant B cells. These observations confirm the potential of revertant T-cell precursors to reconstitute immune function, but questions remain on the longevity of revertant cells implicating the need for careful follow up and early consideration of hematopoietic stem cell transplantation (HSCT).

Interleukin-2 receptor common gamma chain (IL2RG) defects present a diagnostic challenge

2018 ◽  
Vol 5 (4) ◽  
pp. 130-134
Author(s):  
Caroline Weisser ◽  
Dennis E. Bulman ◽  
Kayla Flamenbaum ◽  
Maian Roifman
Keyword(s):  
Genetic Analysis ◽  
Severe Combined Immunodeficiency ◽  
Genetic Defect ◽  
Interleukin 2 ◽  
Combined Immunodeficiency ◽  
Gamma Chain ◽  
Gene Encoding ◽  
Common Gamma Chain ◽  
Interleukin 2 Receptor ◽  
The Common

Background: The protein encoded by interleukin-2 receptor common gamma chain (IL2RG) is an important signaling component of many interleukin receptors, including those of interleukin-2, -4, -7, and -21, known as the common gamma chain. Mutations in the gene encoding the common gamma chain of the interleukin-2 receptor cause X-linked severe combined immunodeficiency (SCID). In this report, we present an unknown genetic defect of a patient diagnosed with SCID whose genetic analysis was performed 2 decades later. Methods: Whole genome sequencing and Sanger confirmation were used to identify a novel frameshift mutation in IL2RG. Massively parallel sequencing of genes associated with SCID were performed on the patient’s mother and sister. Results: Next generation sequencing techniques identified a heterozygous frame-shift deletion in the gene encoding the common gamma chain of IL2RG in our patient. The patient’s mother had a low level mosaicism for the same deletion. The sister had no detectable deletion. Conclusion: We have identified a novel mutation in IL2RG resulting in an X-linked SCID phenotype. The genetic analysis of the patient’s mother revealed a mosaicism which was not passed on to his sister. The importance of genetic analysis in family members and SCID patients with an unknown genetic defect should be emphasized for family planning and subsequent genetic counseling. Statement of novelty: Genetic testing is an extremely important component in evaluating severe combined immunodeficiency as it impacts treatment course and prognosis, and allows for genetic analysis and counselling of family members.

scholarly journals Retroviral-mediated gene correction for X-linked severe combined immunodeficiency

Blood ◽  
1996 ◽  
Vol 87 (8) ◽  
pp. 3097-3102 ◽  
Author(s):  
F Candotti ◽  
JA Johnston ◽  
JM Puck ◽  
K Sugamura ◽  
JJ O'Shea ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lines ◽  
Cellular Proliferation ◽  
Severe Combined Immunodeficiency ◽  
Allogeneic Bone Marrow Transplantation ◽  
Interleukin 2 ◽  
Current Therapy ◽  
Allogeneic Bone ◽  
Combined Immunodeficiency ◽  
Gene Correction

X-linked severe combined immunodeficiency (XSCID) is a lethal disease caused by a defect in the gene encoding the common gamma chain (gamma- c) of the receptor for interleukin-2 (IL-2), IL-4, IL-7, IL-9, and IL- 15. Allogeneic bone marrow transplantation, the current therapy of choice for this defect, is often complicated by graft-versus-host disease and/or incomplete reconstitution of B-lymphocyte functions. Correction of the gene defect at the level of the autologous lymphohematopoietic progenitors could therefore represent an improvement in the medical management of these patients. To study the feasibility of a gene therapy approach for XSCID, a retroviral vector expressing gamma-c was used to transduce Epstein-Barr virus-transformed B-cell lines derived from patients with XSCID. After transduction, XSCID cells newly expressed gamma-c on the cell surface at levels comparable to those observed on B-cell lines obtained from normal donors. Moreover, the reconstituted gamma-c restored function to the IL- 2 and IL-4 receptors as shown by signal transduction mediated by phosphorylation of the JAK1 and JAK3 members of the Janus family of tyrosine kinases and by restoration of cellular proliferation in response to IL-2.

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