scholarly journals Human peripheral blood leucocyte non-obese diabetic-severe combined immunodeficiency interleukin-2 receptor gamma chain gene mouse model of xenogeneic graft-versus-host-like disease and the role of host major histocompatibility complex

2009 ◽  
Vol 157 (1) ◽  
pp. 104-118 ◽  
Author(s):  
M. A. King ◽  
L. Covassin ◽  
M. A. Brehm ◽  
W. Racki ◽  
T. Pearson ◽  
...  
Keyword(s):  
Human Peripheral Blood ◽  
Severe Combined Immunodeficiency ◽  
Interleukin 2 ◽  
Chain Gene ◽  
Combined Immunodeficiency ◽  
Gamma Chain ◽  
Peripheral Blood Leucocyte ◽  
Graft Versus Host ◽  
Histocompatibility Complex

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.

Functional Role of Interleukin-4 (IL-4) and IL-7 in the Development of X-Linked Severe Combined Immunodeficiency

Blood ◽  
1999 ◽  
Vol 93 (2) ◽  
pp. 607-612 ◽  
Author(s):  
Satoru Kumaki ◽  
Naoto Ishii ◽  
Masayoshi Minegishi ◽  
Shigeru Tsuchiya ◽  
David Cosman ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Severe Combined Immunodeficiency ◽  
T Cell Development ◽  
Interleukin 2 ◽  
Cell Development ◽  
Interleukin 4 ◽  
Combined Immunodeficiency ◽  
Survival Signal

X-linked severe combined immunodeficiency (X-SCID) is characterized by an absent or diminished number of T cells and natural-killer (NK) cells with a normal or elevated number of B cells, and results from mutations of the γc chain. The γc chain is shared by interleukin-2 (IL-2), IL-4, IL-7, IL-9, and IL-15 receptors. Recently, a survival signal through the IL-7 receptor  (IL-7R) chain was shown to be important for T-cell development in mice and was suggested to contribute to the X-SCID phenotype. In the present study, we examined function of a mutant γc chain (A156V) isolated from an X-SCID patient and found that T cells expressing the mutant γc chain were selectively impaired in their responses to IL-4 or IL-7 compared with the wild-type γc chain expressing cells although responses to IL-2 or IL-15 were relatively maintained. The result shows that IL-4– and/or IL-7–induced signaling through the γc chain is critical for T-cell development and plays an important role in the development of the X-SCID phenotype.

Three novel mutations in the interleukin-2 receptor ? chain gene in four Japanese patients with X-linked severe combined immunodeficiency

1995 ◽  
Vol 96 (6) ◽  
pp. 681-683 ◽  
Author(s):  
Yoshiyuki Minegishi ◽  
Naoto Ishii ◽  
Hirotoshi Maeda ◽  
Shuji Takagi ◽  
Masahiro Tsuchida ◽  
...  
Keyword(s):  
Severe Combined Immunodeficiency ◽  
Interleukin 2 ◽  
Japanese Patients ◽  
Chain Gene ◽  
Combined Immunodeficiency ◽  
Novel Mutations ◽  
Interleukin 2 Receptor ◽  
Receptor Chain

scholarly journals Severe combined immunodeficiency, interleukin-2 (IL-2), and the IL-2 receptor: experiments of nature continue to point the way [see comments]

Blood ◽  
1994 ◽  
Vol 83 (3) ◽  
pp. 626-635 ◽  
Author(s):  
SD Voss ◽  
R Hong ◽  
PM Sondel
Keyword(s):  
Gene Therapy ◽  
Severe Combined Immunodeficiency ◽  
Interleukin 2 ◽  
Hematopoietic Progenitor ◽  
Gamma Chain ◽  
Molecular Defects ◽  
Lymphoid Malignancies ◽  
Precise Knowledge ◽  
Molecular Nature

The recent discovery of molecular defects in three forms of X-linked immunodeficiency has quickly transformed the study of immunodeficiency into one of the most exciting in basic and clinical immunology. The identification of defects in the IL-2R gamma chain in the etiology of X- linked SCID has suggested a heretofore unanticipated functional role of the gamma chain in immunologic development. While new and novel cytokines and cytokine receptors continue to be identified, it has become clear that our knowledge of IL-2, one of the best understood cytokine/receptor systems, is far from complete. Clarifying the molecular interactions between IL-2 and its receptor complex will improve the sophistication with which these interactions are manipulated in the clinic for the treatment of autoimmune disorders and allograft rejection, treatment of lymphoid malignancies, and cytokine- based therapies for immunotherapeutic treatment of nonlymphoid cancers. Recent gene therapy approaches to the treatment of children with the ADA-deficient form of SCID offers yet another exciting path for investigation. The use of retrovirally infected cord blood hematopoietic progenitor cells in attempts to reconstitute the immune system of ADA-deficient SCID children with ADA-producing cells raises the possibility of similarly “correcting” the defect in X-linked SCID. Such approaches almost certainly loom on the near horizon for other diseases. However, in view of the complexity and potentially pleiomorphic nature of defects in the IL-2R gamma chain, both in terms of their identification and correction, gene therapy for treatment of X- linked SCID will require a thorough understanding of the molecular nature of the respective defects. Effective therapy will require precise knowledge of the defects, in terms of their influence on the ligand, receptor, and signaling apparatus, as well as their potential effects on cells of multiple lineages. However, these caveats aside, the potential for understanding and correcting a disease that robs infants at so early an age of the potential for a normal life will continue to make these exciting and extraordinarily rewarding pursuits.

Functional Role of Interleukin-4 (IL-4) and IL-7 in the Development of X-Linked Severe Combined Immunodeficiency

Blood ◽  
1999 ◽  
Vol 93 (2) ◽  
pp. 607-612 ◽  
Author(s):  
Satoru Kumaki ◽  
Naoto Ishii ◽  
Masayoshi Minegishi ◽  
Shigeru Tsuchiya ◽  
David Cosman ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Severe Combined Immunodeficiency ◽  
T Cell Development ◽  
Interleukin 2 ◽  
Cell Development ◽  
Interleukin 4 ◽  
Combined Immunodeficiency ◽  
Survival Signal

Abstract X-linked severe combined immunodeficiency (X-SCID) is characterized by an absent or diminished number of T cells and natural-killer (NK) cells with a normal or elevated number of B cells, and results from mutations of the γc chain. The γc chain is shared by interleukin-2 (IL-2), IL-4, IL-7, IL-9, and IL-15 receptors. Recently, a survival signal through the IL-7 receptor  (IL-7R) chain was shown to be important for T-cell development in mice and was suggested to contribute to the X-SCID phenotype. In the present study, we examined function of a mutant γc chain (A156V) isolated from an X-SCID patient and found that T cells expressing the mutant γc chain were selectively impaired in their responses to IL-4 or IL-7 compared with the wild-type γc chain expressing cells although responses to IL-2 or IL-15 were relatively maintained. The result shows that IL-4– and/or IL-7–induced signaling through the γc chain is critical for T-cell development and plays an important role in the development of the X-SCID phenotype.

scholarly journals Function of the interleukin-2 (IL-2) receptor gamma-chain in biologic responses of X-linked severe combined immunodeficient B cells to IL-2, IL-4, IL-13, and IL-15

Blood ◽  
1995 ◽  
Vol 85 (1) ◽  
pp. 38-42 ◽  
Author(s):  
DJ Matthews ◽  
PA Clark ◽  
J Herbert ◽  
G Morgan ◽  
RJ Armitage ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Severe Combined Immunodeficiency ◽  
Interleukin 2 ◽  
Gene Mutations ◽  
Chain Gene ◽  
B Cell Activation ◽  
Gamma Chain ◽  
Common Component

The interleukin-2 (IL-2) receptor gamma-chain is a common component of several members of the cytokine receptor superfamily including those for IL-2, IL-4, IL-7, IL-9, IL-15, and possibly IL-13, and has recently been renamed the common gamma-chain (gamma c-chain). Transfection experiments have shown that the gamma c-chain participates in signal transduction by IL-2, IL-4 and IL-7, but a functional role for the gamma c-chain in biological responses by normal T cells and B cells to these cytokines has not been established. In this study, we have used X- linked severe combined immunodeficiency (X-SCID) as a naturally occurring gamma c-chain gene disruption model to examine the role of the gamma c-chain in human B-cell responses to IL-2, IL-4, IL-13, and IL-15. Our experiments show that B cells from two X-SCID patients with characterized gamma c-chain gene mutations do not respond to IL-2 or IL- 15, but respond as well or better than normal B cells to both IL-4 and IL-13 in assays for B-cell activation, proliferation, and IgE secretion. This finding raises important questions about the function of the gamma c-chain in receptors for IL-4 and IL-13, and the nature of the immune defect in X-SCID.

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.

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).

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