IFN-γ ameliorates autoimmune encephalomyelitis by limiting myelin lipid peroxidation

Evidence has suggested both a pathogenic and a protective role for the proinflammatory cytokine IFN-γ in experimental autoimmune encephalomyelitis (EAE). However, the mechanisms underlying the protective role of IFN-γ in EAE have not been fully resolved, particularly in the context of CNS antigen-presenting cells (APCs). In this study we examined the role of IFN-γ in myelin antigen uptake by CNS APCs during EAE. We found that myelin antigen colocalization with APCs was decreased substantially and that EAE was significantly more severe and showed a chronic-progressive course in IFN-γ knockout (IFN-γ^−/−) or IFN-γ receptor knockout (IFN-γR^−/−) mice as compared with WT animals. IFN-γ was a critical regulator of phagocytic/activating receptors on CNS APCs. Importantly, “free” myelin debris and lipid peroxidation activity at CNS lesions was increased in mice lacking IFN-γ signaling. Treatment with N-acetyl-l-cysteine, a potent antioxidant, abolished lipid peroxidation activity and ameliorated EAE in IFN-γ–signaling-deficient mice. Taken together the data suggest a protective role for IFN-γ in EAE by regulating the removal of myelin debris by CNS APCs and thereby limiting the substrate available for the generation of neurotoxic lipid peroxidation products.IFN-γ has been implicated in the pathogenesis of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE) (1). The role of the Th1-derived cytokine IFN-γ in disease pathology was supported further by clinical evidence showing that MS patients treated with recombinant IFN-γ in clinical trials developed more severe inflammation (2). Paradoxically, EAE studies using IFN-γ knockout (IFN-γ^−/−) mice or neutralizing mAb (anti–IFN-γ mAb) showed that EAE was exacerbated under these conditions (3, 4). These results suggested that IFN-γ may be protective in EAE, for example by inducing T-cell apoptosis (5).More recent studies suggest a central role for other cytokines and T-cell subsets, such as Th17 cells, in several autoimmune diseases, including EAE (6–8). Among the T-cell subsets with the highest pathogenic potential in both EAE and MS are Th17 cells coexpressing IFN-γ, known as “Th1-like” Th17 cells (9–12), or coexpressing GM-CSF (7, 8). The protective versus disease-promoting role of IFN-γ in EAE and MS, and in particular the potential protective role of this cytokine in the context of CNS antigen-presenting cells (APCs) in EAE, has not been fully resolved.The effects of IFN-γ on APCs are pleiotropic and encompass up-regulation of MHC molecules, induction of reactive oxygen species (ROS) production, phagocytic activity, and increased production of other proinflammatory cytokines including TNF (13). CNS APCs, such as resident microglia and infiltrating peripheral macrophages and dendritic cells (DCs), have been shown to express MHC class II molecules as well as costimulatory molecules, including CD80 and CD86, that are important for the pathogenesis of EAE (14, 15). However, the roles of CNS APCs, including the mechanisms guiding the uptake and clearance of free myelin debris by CNS APCs during EAE, and the mechanisms that limit the extent of CNS damage during neuroinflammation are not well established.It has been suggested that intervention in ROS generation potentially could represent a novel therapeutic strategy to reduce inflammation in the CNS during MS (16). Along these lines, it has been reported that cytokines such as IFN-γ can stimulate microglia and macrophages to break down oxidized lipids as a self-limiting mechanism to prevent host tissue from inadvertent oxidative damage (17).Thus, in this study we investigated the mechanisms guiding myelin antigen (Ag) uptake and clearance by CNS APCs and found that the uptake of myelin Ag was related directly to the presence of IFN-γ. In C57BL/6 WT mice with EAE, most CNS APCs contained myelin Ag, whereas the number of myelin Ag⁺ APCs was dramatically decreased in IFN-γ^−/− and IFN-γ receptor (IFN-γR)^−/− mice, despite substantially increased disease severity. Importantly, free myelin debris at CNS lesions was increased and lipid peroxidation activity was enhanced in mice lacking IFN-γ signaling. Treatment with N-acetyl-l-cysteine (NAC), a potent antioxidant, abolished lipid peroxidation activity and ameliorated EAE in IFN-γ–signaling-deficient mice.Taken together, the data suggest IFN-γ has a protective role in EAE by regulating myelin debris removal by CNS APCs and limiting the substrate available for the generation of neurotoxic lipid peroxidation products.     

Interferon β transduction of peripheral blood lymphocytes from HIV-infected donors increases Th1-type cytokine production and improves the proliferative response to recall antigens

We are developing a gene therapy method of HIV infection based on the constitutive low production of interferon (IFN) β. Peripheral blood lymphocytes (PBL) from HIV-infected patients at different clinical stages of infection were efficiently transduced with the HMB-H^bHuIFNβ retroviral vector. The constitutive low production of IFN-β in cultured PBL from HIV-infected patients resulted in a decreased viral production and an enhanced survival of CD4⁺ cells, and this protective effect was observed only in the PBL derived from donors having a CD4⁺ cell count above 200 per mm³. In IFN-β-transduced PBL from healthy and from HIV-infected donors, the production of the Th1-type cytokines IFN-γ and interleukin (IL)-12 was enhanced. In IFN-β-transduced PBL from HIV-infected donors, the production of IL-4, IL-6, IL-10, and tumor necrosis factor α was maintained at normal levels, contrary to the increased levels produced by the untransduced PBL. The proliferative response to recall antigens was partially restored in IFN-β-transduced PBL from donors with an impaired antigen response. Thus, in addition to inhibiting HIV replication, IFN-β transduction of PBL from HIV-infected donors improves several parameters of immune function.     

Low-dose interferon-alpha accelerates atherosclerosis in an LDL receptor-deficient mouse model

Background: Solid evidence suggests that atheroscleosis is associated with immune reactions. Most of the activated T cells in the plaque are T helper 1 subtype (Th1), which secrete interferon-γ (IFN-γ), now generally accepted as a proatherogenic cytokine. Interferon-α (IFN-α) has been found to inhibit the secretion of IL-12 and IFN-γ and to increase IL-10 production. It may, therefore, be atheroprotective. The aim of the present study was to clarify the effect of IFN-α on atherogenesis in a transgenic mouse model of atherosclerosis. Methods: 8-week-old low-density lipoprotein (LDL) receptor-deficient mice were allocated randomly into treatment and control groups (n=13 each). The treatment group received 1000 units of IFN-α i.p. every other day for 5 weeks and the control mice received 0.9% NaCl. The mice were fed a Western diet. Results: The IFN-α-treated and the control mice showed a similar weight gain (mean 3.9±1.0 g vs. 3.4±1.8 g, respectively). Treatment with IFN-α significantly increased the plasma cholesterol levels in both treated and untreated mice (mean 31.03±5.53 mmol/l vs. 24.91±6.03 mmol/l, respectively; p<0.022) as well as the plasma triglyceride levels (mean 4.79±1.57 mmol/l vs. 3.10±1.85 mmol/l, respectively; p<0.033). The IFN-α treated mice had a significantly increased atherosclerotic plaque area (mean 61,590±22,368 μm² vs. 37,272±15,469 μm², respectively; p<0.008). Conclusion: The putative atheroprotective effect of IFN-α by the decrease in IL-10 and IFN-γ is abolished by hyperlipidemia. Therefore, the net effect of IFN-α in this murine model is the exacerbation of atherosclerosis.     

Cellular and Cytokine Responses to Salmonella enterica Serotype Typhi Proteins in Patients with Typhoid Fever in Bangladesh

We assessed interferon-gamma (IFN-γ) responses via enzyme-linked immunosorbent spot (ELISPOT) to a number of S. Typhi antigens in samples from humans with S. Typhi bacteremia and typhoid fever in Bangladesh. Compared with responses in healthy endemic zone controls, there were significantly increased IFN-γ responses at the time of clinical presentation (acute phase) and at convalescence 14–28 days later. The majority (80–90%) of IFN-γ expressing T cells were CD4+. We observed a significant increase in interleukin-17 (IL-17) positive CD4 + T cells at convalescent versus acute stage of infection using an intracellular cytokine staining assay. We also found that stimulated peripheral blood mononuclear cells (PBMCs) produced significantly increased levels of a number of cytokines at the convalescent versus acute phase of infection, including IFN-γ, MIP-1β, sCD40L, TNF-β, IL-13, and IL-9. These results suggest that S. Typhi antigens induce a predominantly Th1 response, but that elevations in other cytokines may be modulatory.     

Insights Into Circulating Cytokine Dynamics during Pregnancy in HIV-Infected Beninese Exposed to Plasmodium falciparum Malaria

We investigated the circulating plasma levels of Th1- (Interleukin-2 [IL-2], tumor necrosis factor-α [TNF-α], interferon-gamma [IFN-γ]) and Th2-type (IL-4, IL-5, IL-10) cytokines in human immunodeficiency virus (HIV)-infected pregnant women living in a malaria-endemic area. We analyzed samples from 200 pregnant women included in the prevention of pregnancy-associated malaria in HIV-infected women: cotrimoxazole prophylaxis versus mefloquine (PACOME) clinical trial who were followed until delivery. Cytokine concentrations were measured by flow cytometry-based multiplex bead array. Significantly elevated levels of IL-10 and lower levels of TNF-α were observed at delivery compared with inclusion (P = 0.005). At inclusion, the presence of circulating IFN-γ, a higher CD4⁺ T cell count and having initiated intermittent preventive treatment of malaria with sulfadoxine pyrimethamine (SP-IPTp) were all associated with a lower likelihood of Plasmodium falciparum infection. At delivery, the inverse relationship between the presence of infection and circulating IFN-γ persisted, although there was a positive association between the likelihood of infection and the presence of circulating TNF-α. Initiation of antiretroviral therapy was associated with elevated IL-5 production. Consistent with our own and others'' observations in HIV seronegative subjects, this study shows circulating IL-10 to be a marker of infection with P. falciparum during pregnancy even in HIV-infected women, although plasma IFN-γ may be a marker of anti-malarial protection in such women.     

Interferon-β gene therapy inhibits tumor formation and causes regression of established tumors in immune-deficient mice

Despite the potential of type 1 interferons (IFNs) for the treatment of cancer, clinical experience with IFN protein therapy of solid tumors has been disappointing. IFN-β has potent antiproliferative activity against most human tumor cells in vitro in addition to its known immunomodulatory activities. The antiproliferative effect, however, relies on IFN-β concentrations that cannot be achieved by parenteral protein administration because of rapid protein clearance and systemic toxicities. We demonstrate here that ex vivo IFN-β gene transduction by a replication-defective adenovirus in as few as 1% of implanted cells blocked tumor formation. Direct in vivo IFN-β gene delivery into established tumors generated high local concentrations of IFN-β, inhibited tumor growth, and in many cases caused complete tumor regression. Because the mice were immune-deficient, it is likely that the anti-tumor effect was primarily through direct inhibition of tumor cell proliferation and survival. Based on these studies, we argue that local IFN-β gene therapy with replication-defective adenoviral vectors might be an effective treatment for some solid tumors.     

Differential effects of interferon alpha-2b and beta on the signaling pathways in human liver cancer cells

Background Interferon (IFN) has been reported to reduce the incidence of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C and the recurrence of HCC after effective treatment. We examined the effect of IFNs on the proliferation and the signaling pathways of human HCC cells.Methods Cellular proliferation was examined by a modified 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay. Activities of signaling molecules were evaluated by Western blot analysis.Results Cellular growth was not significantly modulated by IFNα-2b or by IFN-β, even though the HCC cells expressed the IFN receptors. However, extracellular signal-regulated kinase (ERK)1/2 was activated by treatment with IFNα-2b, and both ERK1/2 and AKT were activated by treatment with IFN-β, implying a possible role in resistance to IFNs. Contrary to our expectations, inhibition of mitogen-activated ERK-regulating kinase (MEK) or phosphatidylinositol-3-OH kinase (PI3K) did not modulate the proliferation of HCC cells. Also, abrogation of the ERK1/2 and AKT signaling pathways did not affect cell-cycle arrest at the G1/S phase caused by IFNα-2b.Conclusions IFNα-2b and IFN-β activated ERK1/2 and/or AKT independently of modulating the proliferation of HCC cells and the cell-cycle machinery. A signal transduction-based approach for HCC treatment needs to focus on other possible signaling molecules besides ERK1/2 and AKT when challenged with IFNs.     

Cytokine Responses to Novel Antigens in a Peri-Urban Population in Brazil Exposed to Leishmania infantum chagasi

Visceral leishmaniasis (VL) is fatal if untreated, and there are no vaccines for this disease. High levels of CD4-derived interferon-γ (IFN-γ) in the presence of low levels of interleukin-10 (IL-10) predicts vaccine success. Tumor necrosis factor-α (TNF-α) is also important in this process. We characterized human immune responses in three groups exposed to Leishmania infantum chagasi in Brazil: 1) drug-cured VL patients (recovered VL); 2) asymptomatic persons with positive Leishmania-specific delayed-type hypersensitivity skin reactions (DTH+); and 3) DTH-negative household contacts. Magnitude of DTH correlated with crude Leishmania antigen–driven IFN-γ, TNF-α, and IL-5, but not IL-10. DTH+ persons showed equivalent levels of IFN-γ, but higher levels of IL-10, to tryparedoxin peroxidase and Leishmania homolog of receptor for activated C kinase compared with recovered VL patients. The IFN-γ:IL-10 and TNF-α:IL-10 ratios were higher in recovered VL patients than in DTH+ persons. Seven of 11 novel candidates (R71, L37, N52, L302.06, M18, J41, and M22) elicited cytokine responses (36–71% of responders) in recovered VL patients and DTH+ persons. This result confirmed their putative status as cross-species vaccine/immunotherapeutic candidates.     

Thyroid Dysfunction in Chinese Patients with Chronic Hepatitis C Treated with Interferon Alpha: Incidence,Long-Term Outcome and Predictive Factors

Background

Thyroid dysfunction (TD) represents an extra-hepatic manifestation of chronic hepatitis C (CHC) and it may also be a side effect of interferon-alpha (IFN-α) based treatment. However, previous studies have shown a wide variation in the incidence of TD in patients with CHC. Furthermore, the long-term outcomes and the predictive factors of TD in patients who receive IFN-α based treatment have still not been fully studied.

Objectives

The purpose of this study was to describe the incidence and long-term outcomes of TD in Chinese patients with CHC receiving IFN-αbased treatment. We also aimed to identify the predictive factors of TD associated with this type of therapy.

Patients and Methods

A retrospective case-series study of 592 consecutive CHC patients with normal baseline thyroid functions, who received IFN-αbased therapy, was performed. Thyroid function was assessed at baseline and every three months during treatment, as well as in the follow-up after cessation of therapy. The incidence and long-term outcomes of TD were observed. The prevalence of pretreatment thyroid peroxidase antibodies (TPOAb) were assayed in a sex- and age-matched nested case-control study. Multivariable stepwise regression analysis was used to explore the independent effects of the baseline factors, on the incidence of TD.

Results

At the end of the IFN-αbased therapy, 68 patients (11.5%) in the study had developed TD, 58 patients (85.3%) presented with subclinical TD, and only 10 patients (14.7%) developed overt thyroiditis. The thyroid function of 46 patients (67.8%) spontaneously returned to normal in the six months of follow-up and only three patients (4.4%) had persistent overt TD symptoms after the 24 month follow-up period. Multivariate stepwise analysis suggested that gender and pretreatment TPOAb were the independent factors related to the incidence of TD. Both female patients (OR, 4.31; 95%CI, 2.06–7.31; P = 1.26×10-4) and participants with a positive pretreatment TPOAb (OR = 3.9, 95%CI, 1.72–8.54, P = 0.008) had an increased risk for the development of TD.

Conclusions

The incidence of TD in Chinese patients with CHC during IFN-αbased therapy was 11.5%, the majority of which was subclinical, while only a very small group had long-term overt TD requiring ongoing medical therapy. Female gender and pretreatment TPOAb positivity are risk factors for the development of TD during IFN-αbased therapy.     

Short- and long-term outcome of interferon therapy for chronic hepatitis B infection

Hepatitis B virus (HBV) infection is a serious clinical problem worldwide. Conventional interferon (IFN)-α has been approved for the treatment of chronic hepatitis B (CHB). Short-term studies have demonstrated that IFN-based therapy is moderately effective in inducing the loss of hepatitis e antigen (HBeAg) or seroconversion (30%-40%) in HBeAg-positive patients and also produces sustained HBV DNA suppression (20%-30%) in HBeAg-negative patients. Many studies have reported a correlation between the HBV genotype and response to IFN treatment. The highest response rate to IFN treatment was found in patients infected with HBV genotype A, followed by HBV genotypes B, C, and D. The long-term effect of IFN-α on CHB has not yet been elucidated. The ability of IFN-α treatment to prevent new cirrhosis, complications associated with cirrhosis, and development of hepatocellular carcinoma (HCC) is controversial. The beneficial effect of IFN-α treatment in reducing the development of HCC has mainly been observed in treatment responders who already have cirrhosis. These inconsistent findings may be attributed to the inevitable limitations of comparisons across studies, including differences in the baseline characteristics of the study and the moderate suppression of HBV replication by IFN-α relative to nucleoside/nucleos(t)ide analogs.     

Detection of HCV-Specific IFN-γ Responses in HCV Antibody and HCV RNA Negative Injecting Drug Users

Background:

Detectable HCV-specific cellular immune responses in HCV antibody and RNA negative people who inject drugs (PWID) raise the question of whether some are resistant to HCV infection. Immune responses from people who have been exposed to hepatitis C virus (HCV) and remain anti-HCV negative are of interest for HCV vaccine development; however, limited research addresses this area.

Objectives:

In a cohort of HCV antibody and RNA negative PWID, we assessed whether the presence of HCV-specific IFN-γ responses or genetic associations provide any evidence of protection from HCV infection.

Patients and Methods:

One hundred and ninety-eight participants were examined longitudinally for clinical, behavioral, social, environmental and genetic characteristics (IFNL3 genotype [formally IL-28B] and HLA type). Sixty-one of the 198 participants were HCV antibody and RNA negative, with 53 able to be examined longitudinally for HCV-specific IFN-γ ELISpot T cell responses.

Results:

Ten of the 53 HCV antibody and RNA negative participants had detectable HCV-specific IFN-γ responses at baseline (18%). The magnitude of IFN-γ responses averaged 131 +/- 96 SFC/106 PBMC and the breadth was mean 1 +/- 1 pool positive. The specificity of responses were mainly directed to E2, NS4b and NS5b. Participants with (10) and without (43) HCV-specific IFN-γ responses did not differ in behavioral, clinical or genetic characteristics (P > 0.05). There was a larger proportion sharing needles (with 70%, without 49%, P = 0.320) and a higher incidence of HCV (with 35.1 per 100 py, 95% CI 14.6, 84.4, without 16.0 per 100 py, 95% CI 7.2, 35.6, P = 0.212) in those with IFN-γ responses, although not statistically significant. Half the participants with baseline IFN-γ responses became HCV RNA positive (5/10), with one of these participants spontaneously clearing HCV. The spontaneous clearer had high magnitude and broad Th1 responses, favorable IFNL3 genotype and favorable HLA types.

Conclusions:

This study demonstrated the detection of HCV-specific IFN-γ responses in HCV antibody and RNA negative individuals, with a tendency for HCV-specific IFN-γ responses to be associated with HCV exposure. The potential role of HCV-specific IFN-γ responses in those who remained HCV RNA negative is of value for the development of novel HCV therapeutics.     

IFN-γ receptor signaling mediates spinal microglia activation driving neuropathic pain

Neuropathic pain, a highly debilitating pain condition that commonly occurs after nerve damage, is a reflection of the aberrant excitability of dorsal horn neurons. This pathologically altered neurotransmission requires a communication with spinal microglia activated by nerve injury. However, how normal resting microglia become activated remains unknown. Here we show that in naive animals spinal microglia express a receptor for the cytokine IFN-γ (IFN-γR) in a cell-type-specific manner and that stimulating this receptor converts microglia into activated cells and produces a long-lasting pain hypersensitivity evoked by innocuous stimuli (tactile allodynia, a hallmark symptom of neuropathic pain). Conversely, ablating IFN-γR severely impairs nerve injury-evoked microglia activation and tactile allodynia without affecting microglia in the contralateral dorsal horn or basal pain sensitivity. We also find that IFN-γ-stimulated spinal microglia show up-regulation of Lyn tyrosine kinase and purinergic P2X₄ receptor, crucial events for neuropathic pain, and genetic approaches provide evidence linking these events to IFN-γR-dependent microglial and behavioral alterations. These results suggest that IFN-γR is a key element in the molecular machinery through which resting spinal microglia transform into an activated state that drives neuropathic pain.     

Demonstration of an interferon γ-dependent tumor surveillance system in immunocompetent mice

This study demonstrates that endogenously produced interferon γ (IFN-γ) forms the basis of a tumor surveillance system that controls development of both chemically induced and spontaneously arising tumors in mice. Compared with wild-type mice, mice lacking sensitivity to either IFN-γ (i.e., IFN-γ receptor-deficient mice) or all IFN family members (i.e., Stat1-deficient mice) developed tumors more rapidly and with greater frequency when challenged with different doses of the chemical carcinogen methylcholanthrene. In addition, IFN-γ-insensitive mice developed tumors more rapidly than wild-type mice when bred onto a background deficient in the p53 tumor-suppressor gene. IFN-γ-insensitive p53^−/− mice also developed a broader spectrum of tumors compared with mice lacking p53 alone. Using tumor cells derived from methylcholanthrene-treated IFN-γ-insensitive mice, we found IFN-γ’s actions to be mediated at least partly through its direct effects on the tumor cell leading to enhanced tumor cell immunogenicity. The importance and generality of this system is evidenced by the finding that certain types of human tumors become selectively unresponsive to IFN-γ. Thus, IFN-γ forms the basis of an extrinsic tumor-suppressor mechanism in immunocompetent hosts.     

Immunohistochemical analysis of hepatic interferon alpha-beta receptor level: relationship between receptor expression and response to interferon therapy in patients with chronic hepatitis C

Background/Aims: This study aimed to determine the expression level of interferon alpha/beta (IFN-α/β) receptor in the liver immunohistochemically and evaluate its usefulness in predicting the outcome to IFN therapy in patients with chronic hepatitis C.Methods: The level of IFN-α/β receptor expression was determined in immunoperoxidase-stained pretreatment sections of 55 chronic hepatitis C patients later treated with IFN. We used liver biopsy specimens and mouse monoclonal anti-human IFN-α/β receptor antibody. Quantitative analysis of immunostaining was performed by image analysis software. The level of IFN-α/β receptor was expressed as Unit (U). Sustained responders were patients who showed persistent disappearance of serum HCV-RNA during the 6-month period after treatment, while non-responders showed persistence of viremia after therapy.Results: Positive immunostaining was observed in the cytoplasm of hepatocytes. The mean expression level of hepatic IFN-α/β receptor in sustained responders (2.65±1.11 U, n=15) was significantly (p<0.001) higher than in non-responders (1.61±1.05 U, n=40). A significant decrease in IFN-α/β receptor expression level was observed in patients with advanced liver fibrosis. In patients with low level viremia (pretreatment serum HCV-RNA <1 Meq/ml, n=18), the level of IFN-α/β receptor in sustained responders (2.89±1.12 U, n=11) was significantly (p<0.01) higher than in non-responders (0.93±0.33 U, n=7).Conclusions: Our results suggest that measurement of the level of hepatic IFN-α/β receptor in patients with chronic hepatitis C might be useful for predicting the response to IFN therapy. Resistance to IFN therapy in patients with chronic hepatitis C might be due to low levels of hepatic IFN-α/β receptor.     

TLR-independent neutrophil-derived IFN-γ is important for host resistance to intracellular pathogens

IFN-γ is a major cytokine that is critical for host resistance to a broad range of intracellular pathogens. Production of IFN-γ by natural killer and T cells is initiated by the recognition of pathogens by Toll-like receptors (TLRs). In an experimental model of toxoplasmosis, we have identified the presence of a nonlymphoid source of IFN-γ that was particularly evident in the absence of TLR-mediated recognition of Toxoplasma gondii. Genetically altered mice lacking all lymphoid cells due to deficiencies in Recombination Activating Gene 2 and IL-2Rγ_c genes also produced IFN-γ in response to the protozoan parasite. Flow-cytometry and morphological examinations of non-NK/non-T IFN-γ⁺ cells identified neutrophils as the cell type capable of producing IFN-γ. Selective elimination of neutrophils in TLR11^−/− mice infected with the parasite resulted in acute susceptibility similar to that observed in IFN-γ–deficient mice. Similarly, Salmonella typhimurium infection of TLR-deficient mice induces the appearance of IFN-γ⁺ neutrophils. Thus, neutrophils are a crucial source for IFN-γ that is required for TLR-independent host protection against intracellular pathogens.     

Lymphadenitis caused by infection with an isoniazid- and rifampin-resistant strain of Mycobacterium bovis BCG in an infant with IFN-γ/IL-12 pathway defect

We report a rare case in a female infant (age, 3.5 months) with primary immunodeficiency (IFN-γ/IL-12 pathway defect) who presented with suppurative lymphadenitis after Mycobacterium bovis BCG vaccination. The strain of M. bovis BCG identified was found to be resistant to isoniazid and rifampin. The patient was treated with a special pharmacological regimen involving isoniazid (in a limited, strategic manner), ethambutol, streptomycin, and IFN-γ, after which there was complete resolution of the lesions.