A novel X-linked combined immunodeficiency disease.

Brooks, Edward G.; Schmalstieg, Frank C.; Wirt, Daniel P.; Rosenblatt, Howard M.; Adkins, Linda; Lookingbill, Donald P.; Rudloff, Helen E.; Rakusan, Tamara A.; Goldman, Armond S.

doi:10.1172/jci114884

Cited by 82 publications

(63 citation statements)

References 42 publications

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“…Several different primary immunodeficiencies (PIDs) within both the innate and adaptive immune system have previously been recognized to predispose to infection with VZV as well as a range of other pathogens. These include disseminated VZV infection in children with SCID or NK cell defect (6)(7)(8). More recently, additional conditions conferring increased susceptibility to VZV infection have been described, including lossof-function mutations in GATA2, DOCK2, DOCK8, IFNGR1 and TYK2 (9-13).…”

Section: Identification Of Heterozygous Mutations In Polr3a and Polr3mentioning

confidence: 99%

Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections

Ogunjimi¹,

Zhang²,

Sørensen³

et al. 2017

Journal of Clinical Investigation

129

121

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Section: Identification Of Heterozygous Mutations In Polr3a and Polr3mentioning

confidence: 99%

Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections

Ogunjimi¹,

Zhang²,

Sørensen³

et al. 2017

Journal of Clinical Investigation

129

121

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“…It is interesting to note that human SCID patients have a different phenotype than the Jak3 or ␥c KO mice in that they lack both T and natural killer (NK) cells, but have peripheral B cells that are nonfunctional [34,35]. However, the phenotype of patients with a moderate combined immunodeficiency disease (XCID) does resemble the murine ␥c-and Jak3 -/-phenotype [36]. XCID is the result of a point mutation in the cytoplasmic tail of ␥c that diminishes, but does not abolish, Jak3 binding [37].…”

Section: Peripheral T Cells Require Jak3 To Maintain Proper Functionmentioning

confidence: 99%

“…XCID is the result of a point mutation in the cytoplasmic tail of ␥c that diminishes, but does not abolish, Jak3 binding [37]. XCID patients have about half the normal number of T cells in the periphery, and just like the Jak3-and ␥c-deficient mice, these T cells have an activated phenotype and do not proliferate in response to stimulation [36]. The most likely explanation for the difference in the T cell phenotype observed between patients with SCID and XCID is that in XCID there is sufficient function of the Jak3-␥c signaling pathway to allow for normal development of T cells in the thymus.…”

Section: Peripheral T Cells Require Jak3 To Maintain Proper Functionmentioning

confidence: 99%

T cell development and activation in Jak3-deficient mice

Baird

Thomis

Berg

1998

Journal of Leukocyte Biology

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Jak3, a member of the Janus family of tyrosine kinases, participates in signaling through cytokine receptors that contain the common ␥-chain, including the receptors for interleukin (IL)-2, IL-4, IL-7, IL-9, and IL-15. Jak3-and ␥c-deficient mice have pleiotropic defects that can be attributed to their inability to respond to multiple specific cytokines. A great deal of recent work has focused on the T cell defects in these mutant mice. Specifically, Jak3-and ␥c-deficient mice have small thymuses revealing a defect in T cell development, and in addition, have functionally unresponsive peripheral T cells with an activated/memory cell phenotype. The thymic defect in these mutant mice strongly resembles that seen in IL-7 and IL-7 receptor knockout mice, suggesting that the lack of IL-7 receptor signaling accounts for this defect in Jak3 -/-and ␥c ؊ mice. To characterize this defect further, we have examined the earliest stages of T cell development in adult and fetal Jak3 -/-thymuses. These studies identify two discrete developmental defects at the CD4 ؊ CD8 ؊ stage of T cell maturation. Analyses of peripheral T cells in Jak3 -/-and ␥c ؊ mice have also revealed a number of abnormalities. All of the T cells in these mutant mice have an activated phenotype and a large fraction of them are proliferating in vivo. In addition, Jak3 -/-and ␥c ؊ T cells are more prone to undergo apoptosis than wild-type T cells. Together, these features account for the decreased IL-2 secretion by in vitro-stimulated Jak3 -/-T cells. Overall, many of the lymphoid defects of Jak3-and ␥c-deficient mice can be accounted for by the lack of IL-7R and IL-2R signaling; however, other cytokine systems must also be involved in maintaining peripheral T cell homeostasis.

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“…X-SCID is diagnosed early in life, but some exceptional cases and families have been reported in which CD132 mutations resulted in an immunological phenotype distinct from classical X-SCID. [29][30][31][32][33][34] These so-called X-CID (combined immune deficiency) patients may have impaired rather than absent function of CD132. Mosaicism due to somatic gene reversion has been observed in the immune system as well as in various other disease entities.…”

Section: Introductionmentioning

confidence: 99%

A reversion of an IL2RG mutation in combined immunodeficiency providing competitive advantage to the majority of CD8+ T cells

Kuijpers

Leeuwen²,

Barendregt

et al. 2013

Haematologica

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Mutations in the common gamma chain (γ c , CD132, encoded by the IL2RG gene) can lead to B + T − NK − X-linked severe combined immunodeficiency, as a consequence of unresponsiveness to γc-cytokines such as interleukins-2, -7 and -15. Hypomorphic mutations in CD132 may cause combined immunodeficiencies with a variety of clinical presentations. We analyzed peripheral blood mononuclear cells of a 6-year-old boy with normal lymphocyte counts, who suffered from recurrent pneumonia and disseminated mollusca contagiosa. Since proliferative responses of T cells and NK cells to γc -cytokines were severely impaired, we performed IL2RG gene analysis, showing a heterozygous mutation in the presence of a single X-chromosome. Interestingly, an IL2RG reversion to normal predominated in both naïve and antigen-primed CD8 + T cells and increased over time. Only the revertant CD8 + T cells showed normal expression of CD132 and the various CD8 + T cell populations had a different T-cell receptor repertoire. Finally, a fraction of γδ + T cells and differentiated CD4 + CD27 − effector-memory T cells carried the reversion, whereas NK or B cells were repeatedly negative. In conclusion, in a patient with a novel IL2RG mutation, gene-reverted CD8 + T cells accumulated over time. Our data indicate that selective outgrowth of particular T-cell subsets may occur following reversion at the level of committed T progenitor cells. A reversion of an IL2RG mutation in combined immunodeficiency

show abstract

A novel X-linked combined immunodeficiency disease.

Cited by 82 publications

References 42 publications

Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections

Inborn errors in RNA polymerase III underlie severe varicella zoster virus infections

T cell development and activation in Jak3-deficient mice

A reversion of an IL2RG mutation in combined immunodeficiency providing competitive advantage to the majority of CD8+ T cells

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