Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the activation of T cells, the primary signal is antigen-specific and given through T cell receptor (TcR)/CD3 ligation. Furthermore, costimulatory molecules such as CD28 and CD27, provide an essential signal for activation through interaction with their ligands, present on the membrane of antigen-presenting cells. During asymptomatic human immunodeficiency virus (HIV)-1 infection, T cell function is progressively lost. Here, we investigated whether in the presence of impaired responses of T cells from HIV-infected individuals to signal one, costimulation through CD28 and CD27 after interaction with their natural ligands CD80 and CD70 is intact. T cell proliferative responses to signal one in combination with CD80 or CD70 were decreased in a large fraction of asymptomatically HIV-infected individuals. This was due to impaired responses of signal one but not to impaired responses to costimulation, since CD80 or CD70 did enhance signal one-mediated proliferative responses to a normal extent. Moreover, in individuals with proliferative responses to signal one that were decreased to 50% of normal T cell responses, costimulation even was increased compared to controls. Our results demonstrate that in HIV-infected individuals the response to costimulation is relatively preserved compared to responses to the first signal and point to the defect in T cells in HIV infection being primarily in the CD3/TcR-mediated pathway.
 ...
PMID:Evidence for intact costimulation via CD28 and CD27 molecules in hyporesponsive T cells from human immunodeficiency virus-infected individuals. 753 Nov 46

Apoptosis (programmed cell death) of T lymphocytes has been proposed as a mechanism which plays an important role in the pathogenesis of human immunodeficiency virus (HIV) disease. Activation of Fas (CD95) can either result in costimulation of proliferation and cytokine production or in the induction of apoptosis of T lymphocytes. This raises the possibility that Fas is involved in the observed T cell apoptosis during HIV disease. In this report we show that peripheral blood CD4+ and CD8+ T lymphocytes from HIV-infected individuals undergo apoptosis in vitro in response to antibody stimulation (cross-linking) of Fas at a much higher frequency than from uninfected controls. This anti-Fas-induced T cell apoptosis is markedly higher than spontaneous T cell apoptosis in HIV-infected individuals. Antibodies against other members of the tumor necrosis factor (TNF)/nerve growth factor receptor family such as CD27, CD30, CD40, 4-1BB, p55 TNF receptor, p75 TNF receptor, and TNF receptor-related protein did not result in any increase of T cell apoptosis above that spontaneously observed in HIV+ individuals. Anti-Fas-induced apoptosis was much higher in symptomatic HIV-infected individuals; and the magnitude of anti-Fas-induced CD4+ T cell apoptosis correlated inversely with peripheral blood CD4+ T cell absolute counts. Surface expression of Fas on T cells was also found to be higher in HIV-infected individuals. Resting and activated CD4+ and CD8+ T cells both underwent apoptosis in response to anti-Fas antibody. L-Selectin positive memory CD4+ T cells were especially susceptible to anti-Fas-induced apoptosis. These findings show that CD4+ and CD8+ T lymphocytes in HIV-infected individuals are primed in vivo to undergo apoptosis in response to Fas stimulation, suggesting that Fas signaling may be responsible for the T lymphocyte functional defects and depletion observed in HIV disease.
 ...
PMID:Fas antigen stimulation induces marked apoptosis of T lymphocytes in human immunodeficiency virus-infected individuals. 753 37

T cells express CD28 and CD27 which transduce co-stimulatory signals after interaction with their ligands on antigen-presenting cells (APC). These ligands, CD80, CD86 and CD70, are also expressed to some extent on activated T cells. Here, we show that in human immunodeficiency virus (HIV)-infected individuals, CD28 and CD27 expression is decreased on CD8+ T cells. On the other hand, T cell stimulation in vitro induced high CD80, CD86 and CD70 expression on T cells from HIV-infected individuals. It appeared that an inverted CD4:CD8 T cell ratio could explain this enhanced expression of co-stimulatory ligands. Indeed, high expression levels of CD80, CD86 and CD70 were found on activated CD8+ T cells from HIV- individuals cultured in the absence of CD4+ T cells. Addition of CD4+ T cells prevented this up-regulation. However, in HIV-infected individuals, addition of excess autologous or healthy control CD4+ T cells did not completely counteract up-regulation of co-stimulatory ligand expression on CD8+ T cells. Thus, to some extent, CD8+ T cells in HIV-infected individuals appeared to be refractory to CD4+ T cell-mediated regulation of ligand expression in vitro. Activated T cells from HIV-infected individuals and activated CD8+ T cells from healthy controls were able to act as accessory cells in CD3-induced T cell proliferation, which was dependent on cell-cell contact. Thus, we showed that T cells from HIV-infected individuals express enhanced levels of co-stimulatory ligands upon activation, which provides them with accessory cell properties. Enhanced stimulatory potential of these nonprofessional APC may contribute to persistently high levels of immune activation in HIV infection related to disease progression.
 ...
PMID:Increased expression of CD80, CD86 and CD70 on T cells from HIV-infected individuals upon activation in vitro: regulation by CD4+ T cells. 876 9

Infection by human immunodeficiency virus (HIV)-1 is associated with quantitative and qualitative T cell alterations that severely impair the host's immune defense system. The molecular basis for this immunosuppression remains unclear. Peripheral blood mononuclear cells (PBMC) isolated from patients show markedly decreased interleukin (IL)-2 secretion but unaffected or even increased T helper (Th)2 cytokine production. T cell functional defects were recently reported to correlate more with T cell receptor (TcR) signaling, whereas signals provided by ligation of co-receptors CD27 and CD28 appeared to be preserved. Among the various mechanisms proposed to be involved in HIV-1-induced T cell dysfunction, we and others have reported that the nef gene product exhibited significant immunosuppressive activity. By using an inducible stably integrated nef gene, we demonstrated that Nef specifically down-regulated IL-2 and interferon (IFN)-gama produced upon TcR triggering. Here, using the same experimental system, we extended our initial observations to additional mitogenic signals, and investigated the co-stimulatory function of CD28. Nef down-regulated IL-2, but not IL-4 produced upon induction by combinations of mitogens that mimicked TcR signals together with CD28 mAb or CD28's natural ligand (CD80 and CD86). However, the co-signals provided by CD28 to up-regulate IL-2 induction were unaffected by Nef, since IL-2 produced by nef-transfected cells was proportionally enhanced to the same extent as that of control cells, either upon stimulation by the CD28 mAb or CD80 and CD86. In addition, phosphatidylinositol-3 kinase recruitment induced upon CD28 triggering was also found to be unaltered by nef expression. Together with the observation that similar levels of the Nef protein were detected in nef-transfected cells and upon infection of PBMC, these data suggest a selective immunosuppression induced by nef in human T cells by altering TcR signaling without detectable impact on CD28 co-receptor function. These data agree with the T cell defects observed in PBMC isolated from HIV-infected individuals.
 ...
PMID:Evidence for intact CD28 signaling in T cell hyporesponsiveness induced by the HIV-1 nef gene. 876 22

Few studies have examined longitudinal changes in human immunodeficiency virus type 1 (HIV)-specific cytotoxic T lymphocytes (CTL). To more closely define the natural history of HIV-specific CTL, we used HLA-peptide tetrameric complexes to study the longitudinal CD8(+) T-cell response evolution in 16 A*0201-positive untreated individuals followed clinically for up to 14 years. As early as 1 to 2 years after seroconversion, we found a significant association between high frequencies of A*0201-restricted p17(Gag/Pol) tetramer-binding cells and slower disease progression (P < 0.01). We observed that responses could remain stable over many months, but any longitudinal changes that occurred were typically accompanied by reciprocal changes in RNA viral load. Phenotypic analysis with markers CD45RO, CD45RA, and CD27 identified distinct subsets of antigen-specific cells and the preferential loss of CD27(+) CD45RO(+) cells during periods of rapid decline in the frequency of tetramer-binding cells. In addition we were unable to confirm previous studies showing a consistent selective loss of HIV-specific cells in the context of sustained Epstein-Barr virus-specific cell frequencies. Overall, these data support a role of HIV-specific CTL in the control of disease progression and suggest that the ultimate loss of such CTL may be preferentially from the CD27(+) CD45RO(+) subset.
 ...
PMID:Longitudinal phenotypic analysis of human immunodeficiency virus type 1-specific cytotoxic T lymphocytes: correlation with disease progression. 1051 22

In human immunodeficiency virus (HIV)-1 infection, highly increased T-cell turnover was proposed to cause exhaustion of lymphocyte production and consequently development of AIDS. Here, we investigated cell proliferation, as measured by expression of the Ki-67 nuclear antigen, in peripheral blood CD4(+) and CD8(+) lymphocyte subpopulations before and during highly active antiretroviral therapy (HAART). In untreated HIV-1 infection, both the percentage and number of Ki-67(+) CD4(+) and CD8(+) lymphocytes were significantly increased, compared with values obtained from healthy individuals. A more than 10-fold increase in the percentage of dividing naive CD4(+) T cells in the blood was found when the number of these cells were below 100 per microL. HAART induced an immediate decline in Ki-67 antigen expression, despite often very low CD4(+) T-cell numbers, arguing against increased proliferation being a homeostatic response. After approximately 24 weeks of HAART treatment, a transient increase in the number of proliferating cells was seen, but only in the CD4(+) CD27(+) memory pool. In the CD8(+) T-cell compartment, the number of dividing cells was elevated 20- to 25-fold. This increase was most notable in the CD27(+) CD 45RO(+) and CD27(-) CD45RO(+) memory CD8(+) T-cell pool, corresponding with the degree of expansion of these subsets. Reduction of plasma HIV-RNA load by HAART was accompanied by a decrease in numbers and percentages of dividing cells in all CD8(+) T-cell subsets. Taken together, our results indicate that peripheral T-cell proliferation is a consequence of generalized immune activation. (Blood. 2000;95:249-255)
 ...
PMID:T-cell division in human immunodeficiency virus (HIV)-1 infection is mainly due to immune activation: a longitudinal analysis in patients before and during highly active antiretroviral therapy (HAART). 1060 9

In response to viral infection, unprimed naive CD8(+), major histocompatibility complex class I-restricted, virus-specific T cells clonally expand and differentiate into memory- and effector-type cells. Changes in CD8(+) subset distribution were studied in 17 subjects with acute human immunodeficiency virus type 1 infection and in 14 subjects with acute Epstein-Barr virus (EBV) infection, with combined CD45RO, CD27, and CD28 monoclonal antibodies. A vast expansion of memory-type CD45RO(+)CD27(+)CD8(+) T cells, with high expression of the cell-cycle marker Ki-67, was observed in both infections. Strikingly, CD45RO(+)CD27(+)CD28(-) cells increased >10-fold in acute viral infection and had high Ki-67 expression. In acute EBV infection, a substantial portion of the expanded T cells were EBV-peptide specific. These cells resided mainly in the CD45RO(+)CD27(+) subpopulation, with most in the CD27(+)CD28(-) subpopulation. Content of perforin expression, as a measure of cytotoxic capacity, was relatively low in the CD27(+)CD28(+) T cells and highest in the CD27(-)CD28(-) subpopulation.
 ...
PMID:Changes in the composition of circulating CD8+ T cell subsets during acute epstein-barr and human immunodeficiency virus infections in humans. 1091 75

We evaluated the B cell memory pool among blood B cells from 20 patients with common variable immunodeficiency (CVID). CD27+ B cell number was normal or increased in 6 patients (with 95% CD27+ B cells in 1 patient) and decreased in 14 patients. In 13 or 15 patients studied, the CD27 molecule was detectable on less than 50% IgG or IgA B cells, indicating a defect in the maturation of these memory cells. Within the group of patients with a low number of CD27+ B cells, no up-regulation of this molecule was observed after in vitro stimulation of purified B cells from 3 of 5 patients studied, suggesting an intrinsic B cell defect. In addition, ligation of the CD27 molecule was unable to trigger terminal differentiation of purified B cells in 1 of 2 cases with a large number of CD27+ B cells. Finally, the CD27 ligand was normally expressed on activated T cells in only 5 of 14 patients studied. These data confirm the heterogeneity of immunological defects in patients with CVID. Abnormal expression and/or function of the CD27-CD70 members of the TNF/TNF receptor family contribute to the immunological defect.
 ...
PMID:Study of the B cell memory compartment in common variable immunodeficiency. 1100 84

CD27 and CD134 ligand (CD134L) are two B cell co-receptors for T(h) cell activation-induced ligands (i.e. CD70 and CD134) that promote differentiation of B cells into plasma cells and high-rate antibody production respectively. We explored the CD27 pathway and T cell CD134 expression in common variable immunodeficiency (CVID), a disease characterized by a lack of plasma cells and low Ig serum levels. Twelve patients were compared to seven healthy controls. We found a low percentage of circulating CD27(+) B cells in seven patients and B cell CD27 expression was not up-regulated by in vitro activation in two of them. Importantly, the number of circulating CD27(+) B cells was correlated with the severity of the disease--the patients with the lowest CD27(+) B cell counts having the lowest serum Ig concentrations and the lowest total peripheral blood B cell counts. In contrast, CD70 and CD134 were normally expressed on in vitro activated T cells. CD134L was not detected on patient and control B cells in our activation conditions. Functional studies of in vitro Ig production demonstrated an absence of B cell response to CD27 cross-linking, in particular in a patient with normal CD27 expression. Our results indicate that a defect in CD27 expression or function contributes to the pathogenesis of certain severe forms of CVID.
 ...
PMID:B cell co-receptors regulating T cell-dependent antibody production in common variable immunodeficiency: CD27 pathway defects identify subsets of severely immuno-compromised patients. 1143 17

Human immunodeficiency virus (HIV) type 2 infection is associated with a better clinical outcome, slower rates of CD4 T cell decline, and lower viremia than is HIV-1. This study compares HIV-1 and HIV-2 in regard to the percentages of interleukin (IL)-2-, interferon (IFN)-gamma-, and IL-4-producing cells at the single-cell level, as determined by flow cytometry. At a given degree of CD4 T cell depletion, the frequency of T cells able to produce IL-2 is better preserved in HIV-2 than in HIV-1 infection, particularly within the CD4 T cell subset. As described for HIV-1 immunodeficiency, HIV-2-positive patients exhibit a marked expansion of terminally differentiated effector CD8 T cells (CD28(-)CD27(-)IFN-gamma(+)). However, the proportion of CD8 T cells able to simultaneously produce IL-2 and IFN-gamma is higher in HIV-2 disease. Considering the central role of IL-2 as a lymphocyte proliferative and survival factor, these findings provide a possible immunologic basis for the distinct course of HIV-2 immunodeficiency.
 ...
PMID:Comparison of the frequency of interleukin (IL)-2-, interferon-gamma-, and IL-4-producing T cells in 2 diseases, human immunodeficiency virus types 1 and 2, with distinct clinical outcomes. 1149 61


1 2 3 4 5 6 7 8 9 10 Next >>