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The pathogenesis of end-stage, chronic lung disease is thought to be characterized by an initial inflammatory response followed by fibroproliferation and deposition of extracellular matrix. Many of these chronic lung disorders share a variety of common properties, including an unknown etiology, undefined mechanisms of initiation and maintenance, and progressive fibrosis. Unfortunately, efficacious therapeutic options are not readily available for the treatment of many chronic lung diseases, which may reflect the limited scientific and mechanistic understanding of these disorders. However, recent studies have shown that cytokine networks are likely operative in dictating the progression of these diseases, as these mediators can influence fibroblast activation, proliferation, and collagen deposition during the maintenance of chronic fibrotic lung disease. Accumulating data support the concept that the specific cytokine phenotype may provide a fundamental mechanism for the regulation or continuation of the fibrotic process. For example, interferon-γ appears to suppresses fibroblast activities, such as proliferation and collagen production, while interleukin (IL)-4 and IL-13 can augment fibroblast growth and collagen production. Interestingly, these mediators are prototypic cytokines that functionally define either a type-1 or a type-2 immune response. Thus, experimental models of cell-mediated lung inflammation, which are characterized by either a type-1 or a type-2 response, will be useful in delineating the mechanisms that either maintain or resolve chronic lung inflammation and accompanying fibrosis.

Skeletal muscle regeneration is a highly orchestrated process that depends on multiple immune-system cell types, notably macrophages (MFs) and Foxp3⁺CD4⁺ regulatory T (Treg) cells. This study addressed how Treg cells rein in MFs during regeneration of murine muscle after acute injury with cardiotoxin. We first delineated and characterized two subsets of MFs according to their expression of major histocompatibility complex class II (MHCII) molecules, i.e., their ability to present antigens. Then, we assessed the impact of Treg cells on these MF subsets by punctually depleting Foxp3⁺ cells during the regenerative process. Treg cells controlled both the accumulation and phenotype of the two types of MFs. Their absence after injury promoted IFN-γ production, primarily by NK and effector T cells, which ultimately resulted in MF dysregulation and increased inflammation and fibrosis, pointing to compromised muscle repair. Thus, we uncovered an IFN-γ–centered regulatory layer by which Treg cells keep MFs in check and dampen inflammation during regeneration of skeletal muscle.

Background The interferon‐γ (IFN‐γ) signaling pathway is activated in systemic lupus erythematosus (SLE). This study aimed to assess the causal association between IFN‐γ, IFN‐γ receptor 1 (IFN‐γR1), and IFN‐γR2 and SLE using a bidirectional Mendelian randomization (MR) design. Methods Genetic instruments for exposure to IFN‐γ, IFN‐γR1, and IFN‐γR2 were derived from a large genome‐wide association study (GWAS) that included a sample size of 3301 participants. Instrumental variables for SLE were selected from another independent GWAS analysis comprising 5201 cases and 6099 controls with European ancestry. Bidirectional two‐sample MR was performed using inverse variance weighting, MR‐Egger regression, and weighted median methods. A series of sensitivity analyses were conducted to assess the robustness of the results. Results The inverse variance weighting showed that IFN‐γ had a positive causal association with the risk of SLE (odd ratio [OR] = 1.24, 95% confidence interval [CI]: 1.03–1.47, p = 0.018). IFN‐γR2 levels were not associated with SLE risk after adjustment for multiple comparisons (OR = 0.85, 95% CI: 0.73–0.99, p = 0.034). No genetic association was also detected between IFN‐γR1 and SLE (OR = 0.97, 95% CI: 0.79–1.19, p = 0.768). Evidence from bidirectional MR did not support reverse causality. The weighted median regression also showed directionally similar estimates. Conclusion Higher levels of IFN‐γ are significantly associated with an increased risk of SLE, providing insights into the pathogenesis of SLE. This study aims to assess the causal association between Interferon‐γ (IFN‐γ), IFN‐γ receiver α (IFN‐γR1), IFN‐γ receiver β (IFN‐γR2) and Systemic lupus erythematosus (SLE) within a bidirectional Mendelian‐randomization design. Bidirectional two‐sample MR was performed using inverse variance weighting (IVW), MR‐Egger regression, and weighted median methods. A series of sensitivity analyses were conducted to assess the robustness of the results. Our study provides new insights into the role of IFN‐γ, IFN‐γR1, and IFN‐γR2 in the treatment of SLE. Key points Higher levels of interferon (IFN)‐γ are associated with an increased risk of SLE. In contrast, IFN‐γ receptor 1 (IFN‐γR1) and IFN‐γ receptor 2 (IFN‐γR2) levels were not causally related to SLE risk. This shows that IFN‐γ plays an important role in SLE, and inhibition of IFN‐γ levels plays a potential role in the treatment of SLE. IFN‐γR, mainly IFNγR2, plays a role in SLE and IFN‐γR2 is a potential therapeutic target for the treatment of SLE.

Background Evading immune surveillance is necessary for tumor metastasis. Thus, there is an urgent need to better understand the interaction between metastasis and mechanisms of tumor immune evasion. In this study, we aimed to clarify a novel mechanism that link tumor metastasis and immunosuppression in the development of esophageal squamous cell carcinoma (ESCC). Methods The expression of melanoma‐associated antigen C3 (MAGE‐C3) was detected using immunohistochemistry. Transwell assays were used to evaluate the migration and invasion ability of esophageal squamous cell carcinoma (ESCC) cells. Metastasis assays in mice were used to evaluate metastatic ability in vivo. Lymphocyte‐mediated cytotoxicity assays were performed to visualize the immune suppression function on tumor cells. RNA sequencing was performed to identify differentially expressed genes between MAGE‐C3 overexpressing ESCC cells and control cells. Gene ontology (GO) enrichment analyses was performed to identify the most altered pathways influenced by MAGE‐C3. The activation of the interferon‐γ (IFN‐γ) pathway was analyzed using Western blotting, GAS luciferase reporter assays, immunofluorescence, and flow cytometry. The role of MAGE‐C3 in the IFN‐γ pathway was determined by Western blotting and immunoprecipitation. Furthermore, immunohistochemistry and flow cytometry analysis monitored the changes of infiltrated T cell populations in murine lung metastases. Results MAGE‐C3 was overexpressed in ESCC tissues. High expression of MAGE‐C3 had a significant association with the risk of lymphatic metastasis and poor survival in patients with ESCC. Functional experiments revealed that MAGE‐C3 promoted tumor metastasis by activating the epithelial‐mesenchymal transition (EMT). MAGE‐C3 repressed antitumor immunity and regulated cytokine secretion of T cells, implying an immunosuppressive function. Mechanistically, MAGE‐C3 facilitated IFN‐γ signaling and upregulated programmed cell death ligand 1 (PD­L1) by binding with IFN‐γ receptor 1 (IFNGR1) and strengthening the interaction between IFNGR1 and signal transducer and activator of transcription 1 (STAT1). Interestingly, MAGE‐C3 displayed higher tumorigenesis in immune‐competent mice than in immune‐deficient nude mice, confirming the immunosuppressive role of MAGE‐C3. Furthermore, mice bearing MAGE‐C3‐overexpressing tumors showed worse survival and more lung metastases with decreased CD8+ infiltrated T cells and increased programmed cell death 1 (PD‐1)+CD8+ infiltrated T cells. Conclusion MAGE‐C3 enhances tumor metastasis through promoting EMT and protecting tumors from immune surveillance, and could be a potential prognostic marker and therapeutic target. Our results identified that MAGE‐C3 promotes tumor metastasis not only through the EMT but also by protecting tumors from immunosurveillance

Type I and type II interferons (IFN) are central to both combating virus infection and modulating the antiviral immune response. Indeed, an absence of either the receptor for type I IFNs or IFN-y have resulted in increased susceptibility to virus infection, including increased virus replication and reduced survival. However, an emerging area of research has shown that there is a dual nature to these cytokines. Recent evidence has demonstrated that both type I and type II IFNs have immunoregulatory functions during infection and type II immune responses. In this review, we address the dual nature of type I and type II interferons and present evidence that both antiviral and immunomodulatory functions are critical during virus infection to not only limit virus replication and initiate an appropriate antiviral immune response, but to also negatively regulate this response to minimize tissue damage. Both the activating and negatively regulatory properties of type I and II IFNs work in concert with each other to create a balanced immune response that combats the infection while minimizing collateral damage.

Abstract Rationale In the absence of active tuberculosis, a positive tuberculin skin test (TST) or interferon-γ release assay (IGRA) result defines latent infection with Mycobacterium tuberculosis, although test results may vary depending on immunodeficiency. Objectives This study compared the performance of TST and IGRAs in five different groups of immunocompromised patients, and evaluated their ability to identify those at risk for development of tuberculosis. Methods Immunocompromised patients with HIV infection, chronic renal failure, rheumatoid arthritis, solid-organ or stem-cell transplantation, and healthy control subjects were evaluated head-to-head by the TST, QuantiFERON-TB-Gold in-tube test (ELISA), and T-SPOT.TB test (enzyme-linked immunospot) at 17 centers in 11 European countries. Development of tuberculosis was assessed during follow-up. Measurements and Main Results Frequencies of positive test results varied from 8.7 to 15.9% in HIV infection (n = 768), 25.3 to 30.6% in chronic renal failure (n = 270), 25.0% to 37.2% in rheumatoid arthritis (n = 199), 9.0 to 20.0% in solid-organ transplant recipients (n = 197), 0% to 5.8% in stem-cell transplant recipients (n = 103), and 11.2 to 15.2% in immunocompetent control subjects (n = 211). Eleven patients (10 with HIV infection and one solid-organ transplant recipient) developed tuberculosis during a median follow-up of 1.8 (interquartile range, 0.2–3.0) years. Six of the 11 patients had a negative or indeterminate test result in all three tests at the time of screening. Tuberculosis incidence was generally low, but higher in HIV-infected individuals with a positive TST (3.25 cases per 100 person-years) than with a positive ELISA (1.31 cases per 100 person-years) or enzyme-linked immunospot result (1.78 cases per 100 person-years). No cases of tuberculosis occurred in patients who received preventive chemotherapy. Conclusions Among immunocompromised patients evaluated in this study, progression toward tuberculosis was highest in HIV-infected individuals and was poorly predicted by TST or IGRAs. Clinical trial registered with www.clinicaltrials.gov (NCT 00707317).

Anti‐interferon‐gamma autoantibody (AIGA) is a rare adult‐onset immunodeficiency disease that increases the risk of occult infection. Nontuberculous mycobacteria (NTM) infections represent a diverse group of species and subspecies, and mixed infections with two or more NTM species have been reported. However, there is no consensus on the optimal antibiotics or immune modulator treatments for mixed NTM infections in AIGA patients. Here, we present the case of a 40‐year‐old female who initially presented with suspected lung cancer with obstructive pneumonitis. Tissue samples obtained through bronchoscopy, endoscopy, and bone marrow biopsy revealed disseminated mycobacterium infection. PCR‐based testing confirmed a mixed pulmonary infection with Mycobacterium kansasii and Mycobacterium smegmatis, as well as M. kansasii bacteremia. The patient received 12 months of anti‐NTM medications for M. kansasii, and the symptoms improved. Additionally, the images showed resolution after 6 months, even without the need for immune modulator treatment. In this case report, we present a newly diagnosed AIGA patient who initially presented with disseminated mycobacterial infection. PCR‐based testing revealed a mixed pulmonary infection with Mycobacterium kansasii and Mycobacterium smegmatis, as well as disseminated M. kansasii infection. After completing 12 months of antibiotics treatment, the infection resolved, and there was no evidence of reactivation, even in the absence of AIGA‐specific treatment.

Interferon-γ neutralizing autoantibodies (nIFNγ-autoAbs) are reported in patients with disseminated nontuberculous mycobacteria (NTM) infection and may function by increasing the infection risk. Notwithstanding, the prevalence of nIFNγ-autoAbs as well as the clinical presentation, diagnosis, and natural history of disseminated NTM infection in these patients is poorly understood. In this retrospective observational study, data and sera for 331 Japanese subjects with mycobacterial infection were collected and analyzed. IFNγ-autoAb titers in sera were quantified using an enzyme-linked immunosorbent assay; neutralizing capacity was evaluated via flow cytometry. Disseminated NTM was identified in 50 human immunodeficiency virus-uninfected patients. Of these, 30 of 37 (81%) immunocompetent patients had an increased nIFNγ-autoAb titer whereas only 1 of 13 (7.7%) immunodeficient patients had an increased nIFNγ-autoAb titer (P < .0001, χ2 test). Presenting symptoms were nonspecific and NTM infection was not included in the differential diagnosis in most cases. All patients with disseminated NTM and an increased serum nIFNγ-autoAb level received prolonged antimicrobial therapy. In 6 cases when antibiotic treatment was discontinued, NTM infection recurred and required resumption of antibiotic therapy for infection control. The mortality rate was 3.2% in disseminated NTM patients with nIFNγ-autoAbs and 21% in those without. nIFNγ-autoAbs were present in most patients with disseminated NTM infection without a diagnosis of clinical immunodeficiency. Diagnosis of disseminated NTM requires a high degree of suspicion and can be improved by measuring serum nIFNγ-autoAb titer. Long-term antibiotic therapy helps prevent recrudescent NTM infection.

Background Immune checkpoint inhibitors are a standard treatment for advanced lung cancer, although it remains important to identify biomarkers that can accurately predict treatment response. Immune checkpoint inhibitors enhance the antitumor T‐cell response, and interferon‐γ plays an important role in this process. Therefore, this study evaluated whether the number of interferon‐γ‐releasing peripheral T cells after phytohemagglutinin stimulation in the interferon‐γ release assay might act as a biomarker for the response of non‐small cell lung cancer to immune checkpoint inhibitor treatment. Methods Data were retrospectively collected regarding 74 patients with non‐small cell lung cancer who had received immune checkpoint inhibitors. Pretreatment screening tests had been performed using the T‐SPOT.TB assay, which quantifies the number of interferon‐γ‐releasing T cells (as immunospots) in response to phytohemagglutinin and tuberculosis‐specific antigen stimulation. Clinical factors and the number of spots in the T‐SPOT fields were evaluated for associations with patient outcomes. The median number of spots was used to categorize patients as having high or low values, and the two groups were compared. Results Relative to patients with a low ratio, patients with a high ratio of phytohemagglutinin/tuberculosis‐specific antigen spots (i.e. more responsive T cells) had significantly better progression‐free survival after immune checkpoint inhibitor treatment. When we only considered patients with negative T‐SPOT results, a high number of phytohemagglutinin‐stimulated spots corresponded to significantly longer progression‐free survival. Conclusion The T‐SPOT.TB assay can be used to quantify the number of immunospots in response to antigen stimulation, which may predict the response to immune checkpoint inhibitors in patients with non‐small cell lung cancer. This study evaluated whether the T‐SPOT test could be used to predict the response to immune checkpoint inhibitor treatment in patients with non‐small cell lung cancer. Among patients with negative T‐SPOT results, a high number of phytohemagglutinin‐stimulated spots was associated with longer progression‐free survival.

Recent evidence has shown that several chemokines—including those involved in angiogenesis—have been implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF) and sarcoidosis. We speculated that these differences could be attributed to distinct angiogenic and angiostatic profiles. This hypothesis was investigated by estimating the levels of three angiogenic chemokines (growth-related gene [GRO]-α, epithelial neutrophil-activating protein [ENA]-78, and interleukin [IL]-8), and three angiostatic chemokines (monokine induced by interferon (IFN)-γ [MIG], IFN-γ–inducible protein [IP]-10, and IFN-γ–inducible T-cell α chemoattractant) in serum and BAL fluid (BALF). We studied prospectively 20 patients with sarcoidosis (median age, 46 years; range, 25 to 65 years), 20 patients with IPF (median age, 68 years; range, 40 to 75 years), and 10 normal subjects (median age, 39 years; range, 26 to 60 years). The GRO-a serum and BALF levels of IPF patients were found significantly increased in comparison with healthy subjects (799 pg/mL vs 294 pg/mL [p = 0.022] and 1,827 pg/mL vs 94 pg/mL [p < 0.001], respectively) and sarcoidosis patients (799 pg/mL vs 44 pg/mL [p < 0.001] and 1,827 pg/mL vs 214 pg/mL [p < 0.001], respectively). Moreover, ENA-78 and IL-8 BALF levels in IPF patients were significantly higher compared with sarcoidosis patients (191 pg/mL vs 30 pg/mL [p < 0.001] and 640 pg/mL vs 94 pg/mL [p = 0.03], respectively). MIG serum levels in IPF patients were found significantly upregulated in comparison with sarcoidosis patients and healthy control subjects. However, MIG and IP-10 BALF levels (1,136 pg/mL vs 66 pg/mL [p < 0.001] and 112 pg/mL vs 56 pg/mL [p = 0.037], respectively) were significantly higher in sarcoidosis patients compared with IPF patients. Our data suggest distinct angiogenic profiles between IPF and sarcoidosis, indicating a potential different role of CXC chemokines in the local immunologic response in IPF and pulmonary sarcoidosis.