Prognostic value of indeterminate IFN-γ release assay results in HIV-1 infection

In this prospective, longitudinal study on 948 HIV-1-infected patients, subjects with an indeterminate IFN-γ (gamma interferon) release assay (IGRA) result at baseline were at significantly higher risk of developing AIDS-defining manifestations other than tuberculosis (TB) irrespective of CD4(+) T cell count. Thus, in HIV-1-infected patients with advanced quantitative CD4(+) T cell depletion, an indeterminate IGRA might indicate an additional loss of global T cell function, warranting detailed clinical evaluation and careful follow-up.     

Strain-dependent requirement for IFN-γ for respiratory control and immunotherapy in murine gammaherpesvirus infection

Interferon-γ (IFN-γ) and perforin (pfp) are important effector mechanisms used by CD8 T cells to clear virus-infected cells. In this study, we used IFN-γ/pfp double knockout mice to address if these two effector molecules play redundant roles in the control of acute infection with murine gammaherpesvirus-68 (MHV-68) in BALB/C mice. Perforin knockout (KO) mice and wild-type mice cleared infectious virus from the lungs, even following high-dose infection. However, the IFN-γ KO and IFN-γ/pfp double knockout (DKO) groups had higher virus titers in the lungs at day 10 post-infection, and both groups had higher mortality rates. In IFN-γ/pfp DKO mice, the virus titer and mortality rate were significant higher than in IFN-γ KO mice, indicating a role for perforin in protection from disease. WT mice given IFN-γ blocking antibody also showed significantly higher viral titers. In contrast, IFN-γ KO mice on a C57BL/6 background controlled respiratory infection comparably to wild-type mice. These data show that perforin plays a redundant role in the control of virus replication, but IFN-γ plays an essential role in BALB/C mice infected with MHV-68. We conclude that there is a marked strain-dependent difference in the effector mechanisms needed to control acute MHV-68 infection between C57BL/6 and BALB/C mice. In addition we show that immune therapy that re-establishes viral control after spontaneous reactivation in CD4-deficient mice depends upon perforin in C57BL/6 mice but IFN-γ in BALB/C mice.     

Down-regulation of Z39Ig on macrophages by IFN-γ in patients with chronic HBV infection

Co-inhibitory signals from the B7 superfamily have been demonstrated to induce T cell dysfunction in chronic HBV infection (CHB). However, the expression and function of Z39Ig, a new inhibitor of the B7 superfamily, is still unclear in CHB. Here immunohistochemical staining showed that Z39Ig was restricted to macrophages and that its level was decreased significantly in CHB patients compared to healthy controls. Moreover, reduced Z39Ig expression was positively correlated with plasma HBV load but was inversely related to serum alanine aminotransaminase levels. Further, Z39Ig mRNA had a negative relation to IFN-γ in vivo, and IFN-γ also down-regulated Z39Ig expression on monocyte-derived macrophages (MDMs) in a time- and dose-dependent manner in vitro. Interestingly, Z39Ig expression on MDMs was restored when IFN-γ neutralizing antibodies were added to the T cell/MDM co-culture system, indicating that the IFN-γ derived from activated-T cells may contribute to the reduction of Z39Ig in the CHB environment. Our results suggest that T cells can opposite T cell hyporesponsiveness through dampening Z39Ig inhibitory signals from macrophages and thus maintain their anti-viral function in CHB. Therefore, decreasing Z39Ig signals from macrophages could contribute to CHB clinical therapy.     

Dendritic cells and HIV infection; immunity with viral transmission versus compromised cellular immunity?

In this commentary we propose that changes in immune activity in HIV1 infection are secondary to two aspects of the function of dendritic antigen presenting cells (DC). Firstly DC initiate primary proliferative and cytotoxic T cell responses to HIV but disseminate virus to T cells. Secondly, balanced against the development of protective immunity is progressive inhibition of the capacity of DC to initiate primary T cell responses. With regard to viral transmission via DC, recent studies provide direct evidence that virus has evolved in vivo by passage between DC and T cells and that DC can act as a reservoir for virus. Thus, phylogenetic trees of the sequences of V3 loops of HIV viruses in individual blood samples show evolution via DC and T cells, and plasma virus can be related preferentially to that derived from DC. In functional studies, DC from asymptomatic individuals (lacking lymphadenopathy and without treatment) cause low levels of stimulation of allogeneic lymphocytes in the mixed leukocyte reaction (MLR). By contrast, lymphocytes from these patients respond to normal allogeneic DC. Our recent evidence shows that DC stimulate an MLR by transfer of alloantigens to DC of the responder type with subsequent syngeneic stimulation of T cells. The failure of T cell stimulation by DC in HIV infection therefore shows an incapacity of these DC to transfer antigenic signals to other DC but DC that acquire and present antigen directly to stimulate T cells are still functional. The latter situation provides encouragement that immunotherapy via DC may be feasible. However, DC from HIV infected individuals promote antibody production in B cells suggesting that the initial interaction of HIV with DC produces autocrine effects on DC populations that promote interaction with B cells rather than with Tcells. Treatment that pushes the DC back towards stimulating Tcells, despite increased viral dissemination, may promote protective immunity.     

Outcome of primary lethal and nonlethal Plasmodium yoelii malaria infection in BALB/c and IFN-γ receptor-deficient mice following chloroquine treatment

IFN-γ receptor-deficient (IFN-γR^?/?) mice and control wild-type (WT) mice, with or without chloroquine (CQ) treatment, were infected intraperitoneally with Plasmodium yoelii 17XL (lethal) and P. yoelii 17XNL (nonlethal), and then mouse survival, parasitemia, and antibody production were investigated during the course of infection. Without CQ treatment, both IFN-γR^?/? and WT mice were susceptible to infection showing 100 % mortality after infection with 1?×?10⁵ P. yoelii 17XL-parasitized erythrocytes. The P. yoelii 17XL-infected WT mice could survive by CQ treatment at a dose of 20 mg/kg for 3 days from day 3 postinfection (pi). Malaria parasites in their bloodstream could not be detected in the surviving mice after day 13 pi. CQ treatment, however, could not rescue IFN-γR^?/? mice infected with P. yoelii 17XL. Next, we examined the production of the parasite-specific antibodies in P. yoelii 17XL-infected, CQ-treated mice. Although the production of malaria-specific IgG1, IgG2a, IgG2b, and IgG3 antibodies was observed on days 14 and 28 pi in WT mouse sera, only IgG1 was detected on day 28 pi in IFN-γR^?/? mouse sera. On the other hand, in the nonlethal P. yoelii 17XNL infection, WT mice could control a primary infection with 1?×?10⁵ parasitized erythrocytes. Although IFN-γR^?/? mice could not control and died with increasing parasitemia, the mice could survive by CQ treatment. Both WT and IFN-γR^?/? mice with and without medication, which survived from P. yoelii 17XNL infection, showed the variable levels of malaria-specific IgG1, IgG2a, IgG2b, and IgG3 antibodies during the course of infection. The present data indicate that the IFN-γ receptors are needed to control the infection and parasite-specific IgG2a antibody plays an essential role in recovery from the infection of erythrocytic stages of P. yoelii 17XL or P. yoelii 17XNL parasite.     

Reduced IFN-γ production in elderly people following in vitro stimulation with influenza vaccine and endotoxin

Cytokine interferon gamma (IFN-γ) is pivotal in the defence against viruses and intracellular pathogens and an age-related decreased IFN-γ production may explain the increased infectious disease morbidity and mortality in the elderly. Therefore, we performed a series of clinical experiments evaluating the influence of age and health status on IFN-γ production following in vitro stimulation with influenza vaccine or endotoxin. Both healthy and frail elderly people produced significantly lower amounts of IFN-γ following ex vivo stimulation with influenza vaccine or endotoxin. We conclude that ageing is accompanied by a decreased capacity to produce IFN-γ. This may explain the increased incidence and case-fatality caused by viruses and intracellular pathogens in the elderly.     

The course of a primary infection of Plasmodium yoelii 17XL in both 129S1 and IFN-γ receptor-deficient mice

In the present study, we found that 129S1 mice are resistant to the infection with Plasmodium yoelii 17XL, which is highly virulent and causes lethal infection in various strains of mice. In contrast, IFN-γ receptor-deficient (IFN-γR(-/-)) mice on the 129S1 background were much more susceptible than 129S1 mice with intraperitoneal infection with 1?×?10(5) parasitized erythrocytes. The mortality in 129S1 and IFN-γR(-/-) mice was 11.6 and 79.4 %, respectively. Following inoculation of the parasites, both 129S1 and IFN-γR(-/-) mice showed a progressive increase in parasitemia. Growth rate of malaria parasites at the early stages of infection in the IFN-γR(-/-) mice was faster than that in 129S1 mice, and this difference in growth rate might cause the earlier death of IFN-γR(-/-) host from day 8 of infection than that of 129S1. In surviving mice of both strains, however, malaria parasites in their bloodstream began to decrease in number right after a peak of parasitemia and were not detectable by a microscopic examination during the observation period. Next, we investigated the cytokine and antibody production in 129S1 and IFN-γR(-/-) mice during infection. An analysis of cytokines showed that serum IFN-γ and IL-4 levels elevated significantly from day 1 and day 4 of infection, respectively, in both 129S1 and IFN-γR(-/-) mice when compared with the levels from the uninfected controls. Following the infection, significantly higher levels of malaria-specific IgG1 and IgG2a antibodies in the infected 129S1 mice were detected from day 15, and these elevations were coincident with the decrease of parasitemia. On the other hand, the levels of malaria-specific antibodies in IFN-γR(-/-) mice had a tendency to elevate on day 21 but did not reach statistical significance. The present data indicate that IFN-γR plays an essential role in mediating the early immune mechanisms induced by the infection of erythrocytic stages of P. yoelii 17XL parasite, leading to host survival.     

Age-dependent rise in IFN-γ competence undermines effective type 2 responses to nematode infection

The efficient induction of type 2 immune responses is central to the control of helminth infections. Previous studies demonstrated that strong Th1 responses driven by intracellular pathogens as well as a bias for type 1 activity in senescent mice impedes the generation of Th2 responses and the control of intestinal nematode infections. Here, we show that the spontaneous differentiation of Th1 cells and their expansion with age restrains type 2 immunity to infection with the small intestinal nematode H. polygyrus much earlier in life than previously anticipated. This includes the more extensive induction of IFN-γ competent, nematode-specific Th2/1 hybrid cells in BALB/c mice older than three months compared to younger animals. In C57BL/6 mice, Th1 cells accumulate more rapidly at steady state, translating to elevated Th2/1 differentiation and poor control of parasite fitness in primary infections experienced at a young age. Blocking of early IFN-γ and IL-12 signals during the first week of nematode infection leads to sharply decreased Th2/1 differentiation and promotes resistance in both mouse lines. Together, these data suggest that IFN-γ competent, type 1 like effector cells spontaneously accumulating in the vertebrate host progressively curtail the effectiveness of anti-nematode type 2 responses with rising host age.     

Elevated Serum Levels of IL-10 and IFN-γ in Patients with Acute Plasmodium falciparum Malaria

Serum levels of interleukin-10 (IL-10) and interferon-γ (IFN-γ) were determined in 37 patients with acute Plasmodium falciparum malaria in Bangkok, Thailand. Serum levels of IL-10 and IFN-γ were markedly elevated in patients with malaria prior to treatment (717 ± 260 pg/ml versus 2.2 ± 1.3 pg/ml in healthy controls; 123 ± 71 pg/ml versus 29 ± 9 pg/ml, respectively; mean ± SD). Serum levels of IFN-γ and IL-10 dropped significantly during treatment and were normal 14 and 21 days, respectively, after treatment was started. Prior to therapy a correlation between serum levels of IFN-γ and IL-10 existed (r = 0.563). These results suggest that stimulatory and inhibitory cytokines for macrophage activation and/or antibody production (i.e., TH1- and TH2-type immunoreaction, respectively) are coexpressed during acute P. falciparum infection and stress the multifactorial network between host and parasite in malaria immunology.     

Evolutionary genetics evidence of an essential, nonredundant role of the IFN-γ pathway in protective immunity

Identifying how natural selection has affected immunity-related genes can provide insights into the mechanisms that have been crucial for our survival against infection. Rare disorders of either chain of the IFN-γ receptor, but not of IFN-γ itself, have been shown to confer predisposition to mycobacterial disease in patients otherwise normally resistant to most viruses. Here, we defined the levels of naturally occurring variation in the three specific genes controlling the IFN-γ pathway (IFNG, IFNGR1, IFNGR2) and assessed whether and how natural selection has acted on them. To this end, we resequenced the three genes in 186 individuals from sub-Saharan Africa, Europe, and East-Asia. Our results show that IFNG is subject to strong purifying selection against nonsynonymous variants. Conversely, IFNGR1 and IFNGR2 evolve under more relaxed selective constraints, although they are not completely free to accumulate amino acid variation having a major impact on protein function. In addition, we have identified signatures of population-specific positive selection, including at one intronic variant known to be associated with higher production of IFN-γ. The integration of our population genetic data into a clinical framework demonstrates that the IFN-γ pathway is essential and nonredundant in host defense, probably because of its role in protective immunity against mycobacteria.     

PROP1 and CTNNB1 expression in adamantinomatous craniopharyngiomas with or without β-catenin mutations

INTRODUCTION:

Activating mutations in exon 3 of the β-catenin gene are involved in the pathogenesis of adamantinomatous craniopharyngiomas. Recently, the interaction between β-catenin and PROP1 has been shown to be responsible for pituitary cell lineage determination. We hypothesized that dysregulated PROP1 expression could also be involved in the pathogenesis of craniopharyngiomas.

OBJECTIVES:

To determine whether dysregulated gene expression was responsible for tumor pathogenesis in adamantinomatous craniopharyngiomas, the β-catenin gene was screened for mutations, and the expression of the β-catenin gene and PROP1 was evaluated.

METHODS:

The β-catenin gene was amplified and sequenced from 14 samples of adamantinomatous craniopharyngiomas. PROP1 and β-catenin gene expression was assessed by real-time RT-PCR from 12 samples, and β-catenin immunohistochemistry was performed on 11 samples.

RESULTS:

Mutations in the β-catenin gene were identified in 64% of the adamantinomatous craniopharyngiomas samples. Evidence of β-catenin gene overexpression was found in 71% of the tumors with β-catenin mutations and in 40% of the tumors without mutations, and β-catenin immunohistochemistry revealed a nuclear staining pattern for each of the analyzed samples. PROP1 expression was undetectable in all of the tumor samples.

CONCLUSION:

We found evidence of β-catenin gene overexpression in the majority of adamantinomatous craniopharyngiomas, and we also detected a nuclear β-catenin staining pattern regardless of the presence of a β-catenin gene mutation. These results suggest that WNT signaling activation plays an important role in the pathogenesis of adamantinomatous craniopharyngiomas. Additionally, this study was the first to evaluate PROP1 expression in adamantinomatous craniopharyngiomas, and the absence of PROP1 expression indicates that this gene is not involved in the pathogenesis of this tumor, at least in this cohort.