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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this review, we discuss the role of cytokines and their signaling pathways in immunodeficiency. We focus primarily on severe combined immunodeficiency (SCID) diseases as the most severe forms of primary immunodeficiencies, reviewing the different genetic causes of these diseases. We focus in particular on the range of forms of SCID that result from defects in cytokine-signaling pathways. The most common form of SCID, X-linked SCID, results from mutations in the common cytokine receptor gamma-chain, which is shared by the receptors for interleukin (IL)-2, IL-4, IL-7, IL-9, IL-15, and IL-21, underscoring that X-linked SCID is indeed a disease of defective cytokine signaling. We also review the signaling pathways used by these cytokines and the phenotypes in humans and mice with defects in the cytokines or signaling pathways. We also briefly discuss other cytokines, such as interferon-gamma and IL-12, where mutations in the ligand or receptor or signaling components also cause clinical disease in humans.
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PMID:Cytokines and immunodeficiency diseases: critical roles of the gamma(c)-dependent cytokines interleukins 2, 4, 7, 9, 15, and 21, and their signaling pathways. 1554 86

Five pediatric patients with no history of immunodeficiency had a life-threatening course of varicella. Strikingly, natural killer (NK) cells were absent from the circulation in all children, and, despite active viral infection, up to 98% of the CD8(+) cells were naive. Primary immunodeficiencies were excluded--NK cells and primed CD8(+) cells reappeared in the circulation, granzymes were detectable in plasma early during infection, and no abnormalities could be detected in interleukin-15 receptor function. Our data indicate that varicella-zoster virus (VZV) has a unique capability to seclude primed CD8(+) cells and NK cells from the circulating lymphocyte pool. This may be the consequence of an overwhelming immune response to VZV that is influenced by factors such as infectious dose, age, and the presence of maternal antibodies during infancy. Because both homozygous twin sisters in the study had a severe course of varicella, particular genetic factors may contribute to severe varicella.
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PMID:Absence of circulating natural killer and primed CD8+ cells in life-threatening varicella. 1560 29

Immunodeficiency due to inborn errors, infections, autoimmune diseases and the toxicity of certain therapies, has become an important clinical challenge. Strategies to enhance immune function could improve the outcome for a considerable number of patients. Although myeloid growth factors have found widespread use in clinical medicine, a 'lymphoid growth factor' has not yet been established in clinical use. Several recent studies have proposed two candidate immunostimulatory cytokines: interleukin-7 (IL-7) and IL-15. In this Review, we discuss recent findings regarding the effects of IL-7 and IL-15 on lymphopoiesis and their potential use for the treatment of immunodeficiency.
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PMID:IL-7 and IL-15: therapeutic cytokines for immunodeficiency. 1562 10

Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) cause clinically important persistent infections. The effects of virus persistence on innate immunity, including NK cell responses, and the underlying mechanisms are not fully understood. We examined the frequency, phenotype, and function of peripheral blood CD3- CD56+ NK subsets in HIV+ and HCV+ patients and identified significantly reduced numbers of total NK cells and a striking shift in NK subsets, with a marked decrease in the CD56(dim) cell fraction compared to CD56(bright) cells, in both infections. This shift influenced the phenotype and functional capacity (gamma interferon production, killing) of the total NK pool. In addition, abnormalities in the functional capacity of the CD56(dim) NK subset were observed in HIV+ patients. The shared NK alterations were found to be associated with a significant reduction in serum levels of the innate cytokine interleukin 15 (IL-15). In vitro stimulation with IL-15 rescued NK cells of HIV+ and HCV+ patients from apoptosis and enhanced proliferation and functional activity. We hypothesize that the reduced levels of IL-15 present in the serum during HIV and HCV infections might impact NK cell homeostasis, contributing to the common alterations of the NK pool observed in these unrelated infections.
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PMID:Shared alterations in NK cell frequency, phenotype, and function in chronic human immunodeficiency virus and hepatitis C virus infections. 1616 Jan 63

To evaluate clinical and immunological parameters, interleukin (IL)-15 production and outcome of patients with visceral leishmaniasis (VL), including HIV positive patients, we analyzed 48 cases of VL. Clinical manifestations and response to therapy were similar in VL/HIV- and VL/HIV+ patients. However, relapses were more frequent in patients with HIV infection. Low levels of IL-15 concentrations were found in HIV+ patients without VL. These levels were comparable to concentrations obtained in healthy donors. We found a relationship between response to therapy and IL-15 levels. We found increased levels of IL-15 in VL/HIV- and VL/HIV+ patients with clinical and parasitological response to therapy. Our data demonstrate that VL in HIV-infected patients occurs in subjects with severe immunodeficiency and presents high rate of relapses. Low levels of IL-15 in illness patients and restored production in cured persons suggest that this cytokine could play a central role in immune responses during Leishmania/HIV co-infection.
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PMID:Central role of interleukin-15 in human immunodeficiency virus (HIV)-infected patients with visceral leishmaniasis. 1696 79

Human APOBEC3G (A3G), a deoxycytidine deaminase, is a broadly acting antiretroviral factor expressed in a variety of cells. Mitogen activation of CD4 T cells enhances A3G expression and leads to recruitment of low molecular mass (LMM) A3G, which functions as a post-entry human immunodeficiency virus (HIV) restriction factor, into enzymatically inactive, high molecular mass (HMM) RNA-protein complexes that include Staufen RNA-transporting granules. We now report that interleukin-2 (IL-2), IL-15 and, to a lesser extent, IL-7 enhance the expression of A3G in peripheral blood lymphocytes and that this effect is blocked by inhibitors of the JAK and MAPK signaling pathways. In mixed cultures of CD4+ T cells containing either HMM or LMM A3G, HIV preferentially infected cells containing HMM A3G. A3G shifted into a HMM complex when IL-2, -7, or -15 was added to resting T cells, likely explaining how cytokine treatment renders resting CD4+ T cells permissive to HIV infection. Similarly, poly(I:C)/tumor necrosis factor-alpha-induced maturation of dendritic cells was associated with a sharp increase in A3G expression; however, this induction led to the accumulation of LMM A3G. Together, these results highlight the distinct inductive effects of select cytokines on A3G gene expression and A3G complex assembly that occur in natural cellular targets of HIV infection.
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PMID:Distinct patterns of cytokine regulation of APOBEC3G expression and activity in primary lymphocytes, macrophages, and dendritic cells. 1711 Mar 77

We previously reported the clinical phenotype of two siblings with a novel inherited developmental and immunodeficiency syndrome consisting of severe intrauterine growth retardation and the impaired development of specific lymphoid lineages, including transient CD8 alphabeta T lymphopenia and a persistent lack of blood NK cells. We describe here the elucidation of a plausible underlying pathogenic mechanism, with a cellular phenotype of impaired survival of both fresh and herpesvirus saimiri-transformed T cells, in the surviving child. Clearly, NK cells could not be studied. However, peripheral blood T lymphocytes displayed excessive apoptosis ex vivo. Moreover, the survival rates of CD4 and CD8 alphabeta T cell blasts generated in vitro, and herpesvirus saimiri-transformed T cells cultured in vitro, were low, but not nil, following treatment with IL-2 and IL-15. In contrast, Fas-mediated activation-induced cell death was not enhanced, indicating a selective excess of cytokine deprivation-mediated apoptosis. In keeping with the known roles of IL-2 and IL-15 in the development of NK and CD8 T cells in the mouse model, these data suggest that an impaired, but not abolished, survival response to IL-2 and IL-15 accounts for the persistent lack of NK cells and the transient CD8 alphabeta T lymphopenia documented in vivo. Impaired cytokine-mediated lymphocyte survival is likely to be the pathogenic mechanism underlying this novel form of inherited and selective NK deficiency in humans.
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PMID:Familial NK cell deficiency associated with impaired IL-2- and IL-15-dependent survival of lymphocytes. 1714 86

Changes in T-cell function are a hallmark of human immunodeficiency virus type 1 (HIV-1) infection, but the pathogenic mechanisms leading to these changes are unclear. We examined the gene expression profiles in ex vivo human CD4+ and CD8+ T cells from untreated HIV-1-infected individuals at different clinical stages and rates of disease progression. Profiles of pure CD4+ and CD8+ T-cell subsets from HIV-1-infected nonprogressors with controlled viremia were indistinguishable from those of individuals not infected with HIV-1. Similarly, no gene clusters could distinguish T cells from individuals with early infection from those seen in chronic progressive HIV-1 infection, whereas differences were observed between uninfected individuals or nonprogressors versus early or chronic progressors. In early and chronic HIV-1 infection, three characteristic gene expression signatures were observed. (i) CD4+ and CD8+ T cells showed increased expression of interferon-stimulated genes (ISGs). However, some ISGs, including CXCL9, CXCL10, and CXCL11, and the interleukin-15 alpha receptor were not upregulated. (ii) CD4+ and CD8+ T cells showed a cluster similar to that observed in thymocytes. (iii) More genes were differentially regulated in CD8+ T cells than in CD4+ T cells, including a cluster of genes downregulated exclusively in CD8+ T cells. In conclusion, HIV-1 infection induces a persistent T-cell transcriptional profile, early in infection, characterized by a dramatic but potentially aberrant interferon response and a profile suggesting an active thymic output. These findings highlight the complexity of the host-virus relationship in HIV-1 infection.
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PMID:Distinct transcriptional profiles in ex vivo CD4+ and CD8+ T cells are established early in human immunodeficiency virus type 1 infection and are characterized by a chronic interferon response as well as extensive transcriptional changes in CD8+ T cells. 1725

Chimpanzees are susceptible to human immunodeficiency virus type-1 (HIV-1) and develop persistent infection but generally do not progress to full-blown AIDS. Several host and immunological factors have been implicated in mediating resistance to disease progression. Chimpanzees have a higher prevalence of circulating natural killer (NK) cells than humans; however, their role in mediating resistance to disease progression is not well understood. Furthermore, NK cell survival and activity have been shown to be dependent on interleukin-15 (IL-15). Accordingly, the influence of IL-15 on NK cell activity and gamma interferon (IFN-gamma) production was evaluated in naive and HIV-1-infected chimpanzees. In vitro stimulation of whole-blood cultures with recombinant gp120 (rgp120) resulted in enhanced IFN-gamma production predominantly by the CD3(-) CD8(+) subset of NK cells, and addition of anti-IL-15 to the system decreased IFN-gamma production. Moreover, in vitro stimulation with recombinant IL-15 (rIL-15) augmented IFN-gamma production from this subset of NK cells and increased NK cell cytotoxic activity. Stimulation with rgp120 also resulted in a 2- to 7-fold increase in IL-15 production. These findings suggest that chimpanzee CD3(-) CD8(+) NK cells play a vital role in controlling HIV-1 infection by producing high levels of IFN-gamma, and that IL-15 elicits IFN-gamma production in this subpopulation of NK cells in HIV-1-infected chimpanzees.
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PMID:Influence of interleukin-15 on CD8+ natural killer cells in human immunodeficiency virus type 1-infected chimpanzees. 1725 83

The aim of this study was to characterize the proinflammatory and T helper (Th)1/Th2 cytokine responses during acute parvovirus B19 (B19) infection and determine whether an imbalance of the Th1/Th2 cytokine pattern is related to persistent B19 infection. Cytokines were quantified by multiplex beads immunoassay in serum from B19-infected patients and controls. The cytokine responses were correlated with B19 serology, quantitative B19 DNA levels and clinical symptoms. In addition to a proinflammatory response, elevated levels of the Th1 type of cytokines interleukin (IL)-2, IL-12 and IL-15 were evident at time of the initial peak of B19 viral load in a few patients during acute infection. This pattern was seen in the absence of an interferon (IFN)-gamma response. During follow-up (20-130 weeks post-acute infection) some of these patients had a sustained Th1 cytokine response. The Th1 cytokine response correlated with the previously identified sustained CD8+ T cell response and viraemia. A cross-sectional study on patients with persistent B19 infection showed no apparent imbalance of their cytokine pattern, except for an elevated level of IFN-gamma response. No general immunodeficiency was diagnosed as an explanation for the viral persistence in this later group. Neither the acutely infected nor the persistently infected patients demonstrated a Th2 cytokine response. In conclusion, the acutely infected patients demonstrated a sustained Th1 cytokine response whereas the persistently infected patients did not exhibit an apparent imbalance of their cytokine pattern except for an elevated IFN-gamma response.
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PMID:Cytokine responses in acute and persistent human parvovirus B19 infection. 1730 90


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