Stroke is classified as ischemic or hemorrhagic, and there are few effective treatments for either type. Immunologic mechanisms play a critical role in secondary brain injury following a stroke, which manifests as cytokine release, blood-brain barrier disruption, neuronal cell death, and ultimately behavioral impairment. Suppressing the inflammatory response has been shown to mitigate this cascade of events in experimental stroke models. However, in clinical trials of anti-inflammatory agents, long-term immunosuppression has not demonstrated significant clinical benefits for patients. This may be attributable to the dichotomous roles of inflammation in both tissue injury and repair, as well as the complex pathophysiologic inflammatory processes in stroke. Inhibiting acute harmful inflammatory responses or inducing a phenotypic shift from a pro-inflammatory to an anti-inflammatory state at specific time points after a stroke are alternative and promising therapeutic strategies. Identifying agents that can modulate inflammation requires a detailed understanding of the inflammatory processes of stroke. Furthermore, epigenetic reprogramming plays a crucial role in modulating post-stroke inflammation and can potentially be exploited for stroke management. In this review, we summarize current findings on the epigenetic regulation of the inflammatory response in stroke, focusing on key signaling pathways including nuclear factor-kappa B, Janus kinase/signal transducer and activator of transcription, and mitogen-activated protein kinase as well as inflammasome activation. We also discuss promising molecular targets for stroke treatment. The evidence to date indicates that therapeutic targeting of the epigenetic regulation of inflammation can shift the balance from inflammation-induced tissue injury to repair following stroke, leading to improved post-stroke outcomes.

Lipid nanoparticles (LNPs) have demonstrated significant therapeutic value for non-viral delivery of mRNA and siRNA. While there is considerable interest in utilizing LNPs for delivering DNA (DNA-LNPs) to address a broad range of genetic disorders, acute inflammatory responses pose significant safety concerns and limit transgene expression below therapeutically relevant levels. However, the mechanisms and immune signaling pathways underlying DNA-LNP-triggered inflammatory responses are not well characterized. Through the use of gene-targeted mouse models, we have identified cGAS-STING and interferon-α/β receptor (IFNAR) pathways as major mediators of acute inflammation triggered by systemic delivery of DNA-LNPs. cGAS-STING activation induces expression of numerous JAK-STAT-activating cytokines, and we show that treatment of mice with the JAK inhibitors ruxolitinib or baricitinib significantly improves tolerability to systemically delivered DNA-LNPs. Furthermore, specific inhibition of IFNAR signaling enhances both DNA-LNP tolerability and transgene expression. Utilization of JAK inhibitors or IFNAR blockade represent promising strategies for enhancing the safety and efficacy of non-viral DNA delivery for gene therapy.

Brucellosis is a zoonotic disease, with an important economic impact on the livestock industry and public health worldwide. Both Brucella abortus and Brucella melitensis can infect Mediterranean Buffalo (Bubalus bubalis), leading to infertility and abortion. In ruminants, the standard diagnostic approach involves two serological tests, the Rose Bengal Test and the Complement Fixation Test, applied in parallel, though their specificity requires improvement. Cytokines play a crucial role in coordinating immune responses through complex networks and can serve as biomarkers for various diseases. This study explored the potential use of cytokines as immunological biomarkers for Brucella infection in Mediterranean Buffalo. For this purpose, we included 18 healthy and 20 Brucella-infected buffaloes in our analysis. Heparinized blood samples were stimulated with the Brucella antigen, with PBS as nil control and PWM as lymphocyte viability control. After 16-24 h, plasma levels of IL-1α, IL-1β, IL-4, IL-6, IL-10, IL-17, IL-36Ra, MIP-1α, MIP-1β, MCP-1, CXCL8, IP-10, IFN-γ, TNF, and VEGF-A were measured using multiplex ELISA. Our results showed that infected animals released significantly higher levels of IFN-γ, IP-10, MCP-1 in response to Brucella antigen compared to healthy controls. Conversely, healthy animals released instead higher levels of IL-1α, IL-1β, IL-6 and IL-10 following antigen stimulation compared to infected animals. Finally, sequential canonical discriminant analyses were performed to generate predictive cytokine profiles for each group. The findings indicated that a combination of five cytokines (IFN-γ, IP-10, IL-1α, IL-1β, IL-6) can effectively distinguished infected from healthy buffaloes. Overall, this study suggests that incorporating these key immune cytokines could improve the diagnostic accuracy of brucellosis in Mediterranean Buffalo.

By performing a biological network analysis, we identified some hub genes, which were up- or down-regulated in the breast cancer (BC) cell line after treatment with IFN-γ. Moreover, several pathways including cytokine-cytokine receptor interaction, TNF signaling pathway, NOD-like receptor signaling pathway, and NF-κB signaling pathway were detected that their activation leads to the antiproliferation, proapoptosis, and antiviral activities. To validate in silico results, the bioactivity of recombinant human IFN-γ (hIFN-γ) produced in different hosts was analyzed by antiviral and anticancer assays. The antiviral role of the hIFN-γ preparations was evaluated by inhibition of Vesicular Stomatitis Virus (VSV)-mediated cytopathic effects on Vero cells. A dose-dependent increase in cell viability was observed at different concentrations of recombinant proteins. The maximum amount of the cell viability detected for the hIFN-γ preparations was determined at a concentration of 32.00 pg/mL. To analyze the cytotoxic efficacy of the hIFN-γ preparations on the growth and development of tumor cells, a BC cell line (MCF-7) was treated with both recombinant protein forms in a time- and dose-dependent way. The highest level of inhibiting cell proliferation was detected at a concentration of 32.00 pg/mL hIFN-γ after 72 h incubation. Anticancer and antiviral functions of IFN-γ were confirmed via the expression analysis of hub genes cd74, cxcl10, il6, and stat1 using RT-PCR. Furthermore, the hIFN-γ preparations were significantly able to up-regulate the expression of proapoptotic Bax and p53 and to down-regulate Bcl-2 as an antiapoptotic gene, showing the cytotoxic effect of hIFN-γ toward MCF-7 cells via apoptosis induction.

Q fever is a highly contagious zoonosis capable of causing large outbreaks of important health and economic consequences. Host genetic factors are believed to influence the development of severe chronic Q fever following the infection by the etiological agent, Coxiella burnetii. Targetted next generation sequencing (NGS) was performed in a case-control genetic association study on 53 confirmed Q fever cases, including 38 compatible with acute and 15 with chronic disease, and 29 samples from the general Portuguese population. Four SNPs in the IFNGR2 locus, rs78407108 G > A, rs17879956 C > T, rs7277167 C > T, and rs9974603 C > A, showed a statistically significant association to chronic Q fever, resisting the Bonferroni correction. These belonged to haplotypes significantly associated with chronic Q fever. The individual SNPs are referenced in the GTEx database as possible eQTLs. Given the direct bearing of IFNGR2 on IFN-γ signaling, the possible involvement of the associated variants with higher IFNGR2 expression could be in line with observations suggesting that IFN-γ production in chronic Q fever patients is significantly higher than in healthy controls. Further investigations are required to clarify the role of IFNGR2 signaling in association with chronic Q fever.

New treatment strategies are urgently needed for patients with advanced cervical cancer (CC). Here, a synergistic anti-CC effect of a novel combinatorial immunotherapy with adoptively transferred autologous Vγ9Vδ2 T cells and αβ T cells is shown. The pivotal role of both circulating and tumor-infiltrating Vγ9Vδ2 T cells in anti-CC immunity is uncovered. Importantly, autologous Vγ9Vδ2 T cells show a synergistic anti-CC effect with αβ T cells not only through killing tumor directly, but also by promoting the activation and tumoricidal activity of syngeneic αβ T cells through antigen presentation, which can be further boosted by conventional chemotherapy. Moreover, Vγ9Vδ2 T cells can restore the tumoricidal function of αβ T cell through competitively binding to BTN3A1, a TCR-Vγ9Vδ2 ligand on CC cells upregulated by IFN-γ derived from activated αβ T cell. These findings uncover a critical synergistic effect of autologous Vγ9Vδ2 T cells and αβ T cells in immunotherapy of CC and reveal the underlying mechanisms.

Tuberculosis (TB), especially pulmonary tuberculosis (PTB), is a prevalent infectious disease affecting the respiratory system and is characterized by high morbidity, disability, and mortality rates that significantly impact the quality of life of patients and their families. Host genetic susceptibility plays a crucial role in the infection process of Mycobacterium tuberculosis (M. tuberculosis) with single nucleotide polymorphisms (SNPs) identified as key factors in the genetic loci associated with tuberculosis occurrence and progression. Research indicates that polymorphisms in cytokine genes-including interferons, interleukins, tumor necrosis factors, and chemokines-are closely linked to the onset, progression, and treatment outcomes of pulmonary tuberculosis. Investigating cytokine gene polymorphisms in PTB patients is essential for understanding disease mechanisms and prognosis. This review summarizes the role of cytokine polymorphisms in tuberculosis morbidity, elucidates the biological genetic mechanisms involved at the molecular level, and provides insights into clinical treatment strategies for TB.

High-altitude environments, characterized by hypobaric and hypoxic conditions, induce acute hypoxia, resulting in decreased blood oxygen saturation. This hypoxic stress perturbs gut microecological homeostasis, significantly contributing to the pathogenesis of acute mountain sickness. Consequently, elucidating the mechanisms by which high altitude affects gut homeostasis is crucial for developing effective interventions.

Type 1 immunity mediates host defense through pathogen elimination, but whether this pathway also impacts tissue function is unknown. Here, we demonstrate that rapid induction of interferon γ (IFNγ) signaling coordinates a multicellular response that is critical to limit tissue damage and maintain gut motility following infection of mice with a tissue-invasive helminth. IFNγ production is initiated by antigen-independent activation of lamina propria CD8+ T cells following MyD88-dependent recognition of the microbiota during helminth-induced barrier invasion. IFNγ acted directly on intestinal stromal cells to recruit neutrophils that limited parasite-induced tissue injury. IFNγ sensing also limited the expansion of smooth muscle actin-expressing cells to prevent pathological gut dysmotility. Importantly, this tissue-protective response did not impact parasite burden, indicating that IFNγ supports a disease tolerance defense strategy. Our results have important implications for managing the pathophysiological sequelae of post-infectious gut dysfunction and chronic inflammatory diseases associated with stromal remodeling.

Colorectal cancer (CRC) development is influenced by both iron and gut microbiota composition. While iron supplementation is routinely used to manage anemia in CRC patients, it may also impact gut microbiota and promote tumorigenesis. In this study, we investigated the impact of initial gut microbiota composition on iron-promoted tumorigenesis. We performed fecal microbiota transplantation (FMT) in ApcMin/+ mice using samples from healthy controls, CRC patients, and mice, followed by exposure to iron sufficient or iron excess diets.

We found that iron supplementation promoted CRC and resulted in distinct gut microbiota changes in ApcMin/+ mice receiving FMT from CRC patients (FMT-CRC), but not from healthy controls or mice. Oral treatment with identified bacterial strains, namely Faecalibaculum rodentium, Holdemanella biformis, Bifidobacterium pseudolongum, and Alistipes inops, protected FMT-CRC mice against iron-promoted tumorigenesis.

Our findings suggest that microbiota-targeted interventions may mitigate tumorigenic effects of iron supplementation in anemic patients with CRC.

This prospective cohort study explored the association between two upstream IFN-γ variants (rs2069709: G > T and rs2069705: A > G) and hazard factors for malaria outcomes in a longitudinal cohort of children (n = 941, 3-36 mos.), followed for three years. The impact of age, sex, previous malaria exposure, HIV1 infection, and sickle-cell genotypes (HbAA, HbAS, and HbSS) was also investigated. Reduced malaria episodes were associated with older age at enrollment [HR = 0.957 (95% CI = 0.953-0.961) per month, P < 2.2e-16], HIV1 infection [0.687 (0.545-0.866), P = 0.001], being female [0.910 (0.859-0.964), P = 0.040], and HbAS [0.823 (0.754-0.898), P = 0.005]. The GA/TA diplotype [0.376 (0.230-0.614), P = 0.002] also reduced the hazard of malaria, while TA haplotype increased susceptibility [1.749 (1.159-2.640), P = 0.029]. Factors protecting against the development of SMA [Hemoglobin (Hb < 6.0 g/dL)] included older age [0.927 (0.913-0.942) per month, P < 2.2e-16], previous malaria episodes [0.576 (0.542-0.614, P = 9.5e-32)], HbAS [0.553 (0.400-0.766), P = 0.015]. The rs2069705AG genotype increased the hazard of SMA [1.697 (1.002-2.875), P = 0.042]. Reduced hazard of mortality was observed for older children [0.898 (0.857-0.941), P < 2.2e-16], while a higher hazard was present in HIV-infected children [12.475 (6.380-24.392), P < 2.2e-16], and in those with HbSS [6.341 (1.944-20.686), P = 0.007]. The GG haplotype increased the mortality hazard [1.817 (0.936-3.527), P = 0.078]. The results here highlight critical factors influencing the hazard of malaria, SMA, and mortality.

Natural killer (NK) cells have proven to be safe and effective immunotherapies, associated with favorable treatment responses in chronic myeloid leukemia (CML). Augmenting NK-cell function with oncological drugs could improve NK-cell-based immunotherapies. Here, we used a high-throughput drug screen consisting of >500 small-molecule compounds, to systematically evaluate the effects of oncological drugs on primary NK cells against CML cells. We identified second mitochondrially derived activator of caspases (SMAC) mimetics as potent enhancers of NK-cell cytotoxicity in both cell lines and primary patient samples. In contrast, several drug classes, including glucocorticoids and tyrosine kinase inhibitors such as dasatinib, inhibited NK-cell cytotoxicity. Single-cell RNA sequencing revealed drug-induced transcriptomic changes in both NK and target CML cells. SMAC mimetics upregulated NF-κB target genes in NK cells, potentially contributing to their enhanced cytotoxicity. Inhibitory drugs dexamethasone, dasatinib, and sotrastaurin prevented NK-cell transition to an activated state and suppressed the expression of interferon gamma (IFN-γ) by NK cells, thus preventing IFN-γ-mediated target cell transcriptomic response. In conclusion, we discovered that SMAC mimetics sensitize cancer cells to NK-cell-mediated killing, with potential clinical applications especially in patients with advanced phase CML.

The three major autoimmune liver diseases are autoimmune hepatitis (AIH), primary biliary cholangitis (PBC), and primary sclerosing cholangitis (PSC).These conditions are assumed to result from a breakdown in immunological tolerance, which leads to an inflammatory process that causes liver damage.The self-attack is started by T-helper cell-mediated identification of liver autoantigens and B-cell production of autoantibodies,and it is maintained by a reduction in the number and activity of regulatory T-cells.Infections and environmental factors have been explored as triggering factors for these conditions, in addition to a genetic predisposition.Allelic mutations in the HLA locus have been linked to vulnerability, as have relationships with single nucleotide polymorphisms in non-HLA genes.Despite the advances in the management of these diseases, there is no curative treatment for these disorders, and a significant number of patients eventually progress to an end-stage liver disease requiring liver transplantation.In this line, tailored immune-therapeutics have emerged as possible treatments to control the disease.In addition, early diagnosis and treatment are pivotal for reducing the long-lasting effects of these conditions and their burden on quality of life.Herein we present a review of the etiology, clinical presentation, diagnosis, and challenges on ALDs and the feasible solutions for these complex diseases.

Both global ischemia caused by circulatory arrest and extracorporeal circulation circuits have been shown to trigger cytokine release. We hypothesized that inserting a hemoadsorption device during thoraco-abdominal normothermic regional perfusion (TA-NRP) in the donation after circulatory death setting would mitigate the inflammatory response, potentially resulting in improved cardiac allograft function.

In 15 pigs, circulatory arrest was induced by hypoxia. After a 15-min no-touch-period, TA-NRP was performed for 60 min. Eight pigs had a hemoadsorption device incorporated in the ECC, while seven did not. Plasma concentrations of IFN-α, IFN-γ, TNF-α, IL-1β, IL-4, IL-6, IL-8, IL-10, and IL-12p40 were assessed by ELISA at baseline, immediately at start of TA-NRP, 60 min after start of TA-NRP (just before weaning from ECC), and at 30 and 60 min after weaning from ECC. Cardiac function was assessed with pressure-volume loop analysis.

Hemoadsorption had no relevant effects on systemic cytokine levels post TA-NRP. IL-6 plasma levels gradually rose throughout the procedure for both groups. Hemoadsorption did not affect systolic or diastolic left ventricular function, nor were global hemodynamics improved by hemoadsorption.

The insertion of a hemoadsorption device did not significantly affect plasma cytokine levels or cardiac function. Further research is necessary to assess the role of the inflammatory response in DCD heart transplantation and its modulation by TA-NRP.

This study aimed to explore the relationship between corneal nerve degeneration and elevated dendritic cells (DCs) in diabetic keratopathy.

Corneas from diabetic and healthy mice were analyzed using single-cell RNA sequencing. Corneal nerve density and DC and T-cell infiltration were quantified through whole-mount corneal staining. Freshly isolated mouse trigeminal ganglion (TG) neurons were co-cultured with immature DCs, mature DCs, activated CD8+ T cells, and CD4+CD25- T cells. TG neurite outgrowth was assessed to identify potential effector cells driving corneal nerve degeneration. In addition, interferon-gamma (IFN-γ) and blocking antibodies were used to evaluate their effects on TG neurite outgrowth and corneal nerve degeneration in mice.

Compared with age-matched healthy mice, diabetic mice exhibited a significant reduction in corneal nerve density and sensitivity, along with increased infiltration of DCs, CD4+ T cells, and CD8+ T cells. In vitro co-culture experiments revealed that CD4+CD25- T cells, rather than DCs and CD8+ T cells, significantly inhibited TG neurite outgrowth. Among cytokines, elevated IFN-γ in diabetic corneas impaired TG neurite outgrowth and induced corneal nerve degeneration, whereas IL-4 and IL-17 had no such effect. Blocking IFN-γ alleviated CD4+CD25- T-cell-induced inhibition of TG neurite outgrowth and corneal nerve degeneration in diabetic mice.

CD4+CD25- T cells, but not DCs or CD8+ T cells, contribute to corneal nerve degeneration in diabetic mice, a process partially mediated by IFN-γ.

JOURNAL/nrgr/04.03/01300535-202504000-00033/figure1/v/2024-07-06T104127Z/r/image-tiff Behavioral recovery using (viable) peripheral nerve allografts to repair ablation-type (segmental-loss) peripheral nerve injuries is delayed or poor due to slow and inaccurate axonal regeneration. Furthermore, such peripheral nerve allografts undergo immunological rejection by the host immune system. In contrast, peripheral nerve injuries repaired by polyethylene glycol fusion of peripheral nerve allografts exhibit excellent behavioral recovery within weeks, reduced immune responses, and many axons do not undergo Wallerian degeneration. The relative contribution of neurorrhaphy and polyethylene glycol-fusion of axons versus the effects of polyethylene glycol per se was unknown prior to this study. We hypothesized that polyethylene glycol might have some immune-protective effects, but polyethylene glycol-fusion was necessary to prevent Wallerian degeneration and functional/behavioral recovery. We examined how polyethylene glycol solutions per se affect functional and behavioral recovery and peripheral nerve allograft morphological and immunological responses in the absence of polyethylene glycol-induced axonal fusion. Ablation-type sciatic nerve injuries in outbred Sprague-Dawley rats were repaired according to a modified protocol using the same solutions as polyethylene glycol-fused peripheral nerve allografts, but peripheral nerve allografts were loose-sutured (loose-sutured polyethylene glycol) with an intentional gap of 1-2 mm to prevent fusion by polyethylene glycol of peripheral nerve allograft axons with host axons. Similar to negative control peripheral nerve allografts not treated by polyethylene glycol and in contrast to polyethylene glycol-fused peripheral nerve allografts, animals with loose-sutured polyethylene glycol peripheral nerve allografts exhibited Wallerian degeneration for all axons and myelin degeneration by 7 days postoperatively and did not recover sciatic-mediated behavioral functions by 42 days postoperatively. Other morphological signs of rejection, such as collapsed Schwann cell basal lamina tubes, were absent in polyethylene glycol-fused peripheral nerve allografts but commonly observed in negative control and loose-sutured polyethylene glycol peripheral nerve allografts at 21 days postoperatively. Loose-sutured polyethylene glycol peripheral nerve allografts had more pro-inflammatory and less anti-inflammatory macrophages than negative control peripheral nerve allografts. While T cell counts were similarly high in loose-sutured-polyethylene glycol and negative control peripheral nerve allografts, loose-sutured polyethylene glycol peripheral nerve allografts expressed some cytokines/chemokines important for T cell activation at much lower levels at 14 days postoperatively. MHCI expression was elevated in loose-sutured polyethylene glycol peripheral nerve allografts, but MHCII expression was modestly lower compared to negative control at 21 days postoperatively. We conclude that, while polyethylene glycol per se reduces some immune responses of peripheral nerve allografts, successful polyethylene glycol-fusion repair of some axons is necessary to prevent Wallerian degeneration of those axons and immune rejection of peripheral nerve allografts, and produce recovery of sensory/motor functions and voluntary behaviors. Translation of polyethylene glycol-fusion technologies would produce a paradigm shift from the current clinical practice of waiting days to months to repair ablation peripheral nerve injuries.

Cancer cachexia (CC) is a multifactorial disease marked by a severe and progressive loss of lean muscle mass and characterized further by inflammation and a negative energy/protein balance, ultimately leading to muscle atrophy and loss of muscle tissue. As a result, patients experiencing cachexia have reduced muscle function and thus less independence and a lower quality of life. CC progresses through stages of increasing severity: pre-cachexia, cachexia and refractory cachexia. Two proposed underlying mechanisms that drive cancer-induced muscle wasting are the autophagy-lysosome and ubiquitin-proteasome systems. An increase in autophagic flux and proteolytic activity leads to atrophy of both cardiac and skeletal muscle, ultimately mediated by tumour or immune-secreted inflammatory cytokines. These pathways occur at a basal level to maintain cellular homeostasis; therefore, it is the overactivation of the pathways that leads to muscle atrophy. Recent evidence demonstrates the ability of aerobic and resistance training to restore these pathways to their basal levels. The mechanism is not yet understood, and more research is needed to determine exactly how exercise influences each pathway. However, exercise has great promise as a therapeutic strategy for CC because of the evidence for it preserving muscle mass and function, and attenuating protein degradative pathways. The extent to which exercise affects the ubiquitin-proteasome and autophagy-lysosome systems is determined by the frequency, intensity and duration of the exercise protocol. As such, an ideal exercise prescription is lacking for individuals with CC.

Biologics targeting the TNF and IL-17/23 axis are highly effective treatments for psoriasis but can result in cutaneous adverse events. The pathogenesis of paradoxical eczema, the occurrence of an atopic dermatitis phenotype after biologic initiation in people with psoriasis, is unknown. Using single-cell RNA sequencing and mass cytometry, we found increased expression of TNF, IFN-γ, and IFN-α and their signaling pathways in paradoxical eczema case cell clusters compared with that in matched psoriasis controls. Genetic variants influencing the expression of chemokine signaling and TNF pathway genes were associated with paradoxical eczema in a separate genotyped cohort, and this association was independent of known atopic risk loci. This suggests that paradoxical eczema has a predominantly type 1 systemic inflammatory signature and that genetic susceptibility to aberrant chemokine and TNF pathway signaling could contribute to development of this phenotype during biologic treatment.

Most trauma patients require intensive care treatment and are susceptible to developing persistent inflammation and immunosuppression, potentially leading to multi organ dysfunction syndrome (MODS) and dependence on long term care facilities. T cells undergo changes in numbers and function post trauma. T cell dysfunction in polytraumatized patients was characterized using functional immunomonitoring to predict individual clinical outcome. Moreover, the potential to reverse T cell dysfunction using Interleukin (IL)-7 was examined.

Blood samples were drawn from healthy individuals and prospectively enrolled polytrauma patients (Injury Severity Score ≥ 18) on admission, 8, 24 and 48 hours, 5 and 10 days after. CD3/28-stimulated cytokine production of T cells in whole blood was assessed via Enzyme Linked Immuno Spot (ELISpot). T cell subsets were quantified via counting and flow cytometry. Unfavorable physical performative outcome was defined as death or new functional disability necessitating long term care. Secondary outcomes were the development of MODS and in-hospital mortality. IL-7 was added ex vivo to test reversibility of cytokine disturbances.

34 patients were enrolled. The different outcome groups showed no difference in injury severity. Patients with favorable physical performative outcome revealed higher functional T cell specific Interferon γ (IFN-γ) and IL-17 (8 hours) and lower IL-10 production (day 5) and higher CD8 T cell concentrations. Patients without MODS development showed a higher IFN-γ (day 10), higher IL-2 (8 hours) and higher IL-17 production (admission, day 5). There were no differences regarding in-hospital mortality. Systemic blood IFN-γ, IL-2 and IL-10 concentrations only correlated with MODS (24 hours). Systemic CD8 T cell numbers correlated with functional IFN-γ production. Whole blood stimulation with IL-7 increased functional T cell IFN-γ release.

Our study reveals an early characteristic overall T cell dysfunction of pro-inflammatory (IFN-γ, IL-2, IL-17) and immunosuppressive (IL-10) subtypes in polytraumatized patients. Our data indicates that rather the functional capacity of T cells to release cytokines, but not systemic cytokine concentrations can be used to predict outcome post trauma. We assume that the early stimulation of pro- and anti-inflammatory T cells benefits polytraumatized patients. Potentiation of functional IFN-γ release might be achieved by IL-7 administration.

Avian Pathogenic Escherichia coli (APEC) poses a significant threat to the U.S. poultry industry, causing respiratory infections and systemic colibacillosis. Understanding APEC's impact on the immune response is crucial for developing effective prevention and treatment strategies. This study investigates the dynamic immune responses to APEC infection in broiler chickens, with a focus on survival rates, airsac lesion scores, and cytokine gene expression patterns in lung tissue. Seven-day-old broiler chicks were divided into control and APEC-inoculated groups, with the control group receiving tryptic soy broth and the APEC group receiving 7 × 10^7 CFU of APEC via intratracheal inoculation. Survival data included both male and female birds, while airsac lesion score and lung tissue samples for gene expression analyses were collected only from male birds at nine time points post-infection (days 1, 3, 5, 7, 9, 11, 13, 15, and 21). High airsac lesion incidence and mortality were observed during early infection stages, decreasing in mid to later stages as anti-inflammatory cytokines were upregulated. The lung gene expression study analyzed the expression of pro-inflammatory cytokines (IFN-γ, IL-1β, IL-8, and IL-6), regulator (SOCS3), and anti-inflammatory cytokines (IL-10, TGFβ-2, TGFβ-3, and IL-1RN) via RT-qPCR assays, using 18S rRNA for normalization. A two-way ANOVA followed by Tukey's Kramer test evaluated the effects of APEC treatment and days post-infection on gene expression, with the Mann-Whitney U test comparing fold changes between groups. Results indicated an early upregulation of pro-inflammatory cytokines like IFN-γ and IL-1β, followed by the modulatory roles of SOCS3, TGF-β, and IL-1RN, balancing the immune response and possibly preventing excessive tissue damage. This study elucidates the dynamic regulation of key cytokines during APEC infection in chickens, providing insights into immune mechanisms. Understanding these mechanisms is crucial for developing targeted therapies and improving disease management in poultry, potentially reducing antibiotic dependence and enhancing overall poultry health and productivity.

Currently, no approved antiviral drugs target dengue virus (DENV) infection, leaving treatment reliant on supportive care. DENV vaccine efficacy varies depending on the vaccine type, the circulating serotype, and vaccine coverage. We investigated defective interfering particles (DIPs) and lipid nanoparticles (LNPs) to deliver DI290, an anti-DENV DI RNA. Both DIPs and DI290-loaded LNPs (LNP-290) effectively suppressed DENV infection in human primary monocyte-derived macrophages (MDMs), THP-1 macrophages, and fibroblasts-natural DENV targets. Inhibiting interferon (IFN) signaling with a Janus kinase 1/2 inhibitor or an IFN-α/β receptor 1 (IFNAR1)-binding antibody blocked DIP and LNP-290 antiviral activity. LNP-290 demonstrated a greater than log10 inhibition of DENV viral loads in IFNAR-deficient (Ifnar -/- ) and IFN regulatory factor (IRF) 3 and 7 double knockout (Irf3/7 -/- ) mice. Pathway analysis of RNA sequencing data from LNP-treated C57BL/6J mice, Ifnar -/- mice, and human MDMs treated with LNPs or DENV DIPs indicated DI290 treatment enhanced IFN responses, suggesting IFN-λ and IFN-γ provided antiviral activity when IFN-α/β responses were diminished. While viral interference by DI290 is possible, results did not support RNA replication competition as an inhibition mechanism. These findings suggest that DI290 may be a promising DENV therapeutic by activating the innate immune system.

Buprenorphine and methadone are widely used as medication for addiction treatment (MAT) in patients with opioid use disorders. However, there is no compelling evidence of their impact on the immune-endocrine response. Therefore, the aim of this study was to examine the effects of the aforementioned medications on craving and on biomarkers of inflammation and cortisol, approaching the dose issue concurrently. Sixty-six patients (thirty-four under methadone and thirty-two under buprenorphine) who had just entered a MAT program and were stabilized with the suitable administered doses after a two-week process were divided into four groups based on medication dose (i.e., methadone high dose, buprenorphine high dose, methadone medium dose, and buprenorphine medium dose). The heroin craving questionnaire for craving assessment was completed, and the blood biomarkers were measured on Days 1 and 180. According to the results, high doses of both medications were accompanied by low levels of craving, cortisol, and inflammation on Day 1, and no alterations were observed on Day 180. On the contrary, medium doses reduced the tested psychosocial and biochemical parameters in terms of time, indicating a positive action for the patients. Concludingly, modifications in MAT doses are needed soon after the stabilization process to prevent inflammation and avoid relapse, thus helping opioid-addicted patients toward rehabilitation.

The efficacy of neoantigen-reactive T cells (NRT) therapy in solid tumors, encompassing aspects such as infiltration, recognition, cytotoxicity, and enduring persistence, is notably influenced by the immunological microenvironment. This study endeavors to investigate whether the co-administration of pemetrexed and cisplatin augments the therapeutic efficacy of NRT therapy in lung cancer. Neoantigens were predicted using a comprehensive analysis of mutation data from Lewis lung carcinoma cells and mouse tail tissues. The immunogenicity of NRT cells was assessed through flow cytometry and IFN-γ ELISpot assays. A mouse model of NSCLC was used to investigate the anti-tumor effects of NRT combined with chemotherapy. The combination of NRT cells and chemotherapy significantly inhibited tumor growth in a mouse model, increased CD3+/CD137+ T cells to promote IFN-γ secretion from NRT cells, and up-regulated the levels of inflammatory cytokine proteins including IFN-γ, TNF, IL-6 and IL-10. Immunofluorescence analysis confirmed increased T-cell infiltration in tumor tissues without adverse effects on vital organs. In addition, transcriptome analyses indicated that the tumor microenvironment was altered to favor M1-like macrophages with an increased M1/M2 ratio, creating a pro-inflammatory environment. The integration of NRT with frontline chemotherapy for lung cancer could yield profoundly ideal therapeutic outcomes.

The bone marrow (BM) is a multifactorial, highly dynamic, still not fully "mapped," reservoir. The BM labyrinthine landscape is subject to a relentless debate on the specialized and stem/progenitor cells' scattering within designated microareas. Certainly, BM tissue plays a watchdog role in bone modeling and remodeling, hematopoiesis, immune surveillance, and endocrine response integration. Parameters like tissue topographical distinctiveness, stiffness and porosity grade, and cells' behavioral idiosyncrasies in terms of stem/progenitor cell housing, activation, and motility represent a knotty problem not easily solved. Given that the disruption of BM microdomains has been associated with a number of severe pathological disorders, the comprehension and preservation of the BM workspace at multiple levels have become mandatory. Solid evidence has showed the existence of an intricate and tightly regulated cross-talk between the BM cellular occupants. Direct physical cell-cell connections and soluble mediators, including cytokines, chemokines, growth factors, exosomes and microvesicles, orchestrate composite intracellular signaling routes. The spatiotemporal action of definite biofactors ensures a functional blood-producing organ with a physiological bone turnover and prompts the action of multipotent stromal/hematopoietic cells. Recently, significant research efforts have been addressed to build bioengineered niche-mimic models based on biofunctionalized scaffolds and organoid-like constructs. These artificial BM niches combine and transduce various aspects of bioinformatics and tissue engineering to unravel the complexities of BM organization. This chapter aims to unfold the recent breakthroughs in the understanding of a BM intramural cell-cell dialogue in a physiological and, in some cases, within an inflammatory background. BM maze is gradually being discovered, but there is still a long way to go.

Electro-hyperthermia therapy (EHT) has been known to cause temperature-dependent cell death and enhance the effects of conventional antitumor treatments, such as chemotherapy and radiotherapy. Furthermore, EHT modulates the innate and adaptive immune systems. Mistletoe is one of the most broadly studied complementary and alternative therapeutic agents for cancer treatment due to its ability to stimulate the immune systems. This study aimed to investigate the effects of EHT and mistletoe therapy combination on immune responses. Tumors induced by B16-BL6 melanoma cells were treated twice with modulated EHT (mEHT) (43°C for 10 or 20 min) and with intravenous injection of a Korean mistletoe extract (KME). We examined the level of interferon (IFN)-γ, granzyme, interleukin (IL)-2, IL-10, and tumor-specific antibodies using enzyme-linked immunosorbent assay methods to further study the immunological responses in the combination of mEHT and KME. Additionally, cytotoxic T lymphocyte (CTL) activity is investigated. In this study, we revealed a significant anti-tumor immunological activity elevation in tumor-bearing mice by combined mEHT and KME therapy. Specifically, the combination of mEHT and KME treatment was effective in inhibiting tumor growth in mice. The combination treatment elicited CTL immune response and increased IFN-γ and granzyme secretion. Particularly, the co-treatment appeared to efficiently suppress the immune signal related to tumor-associated macrophage differentiation. Importantly, tumor cell-specific antibodies could be induced in mice after mEHT-treated tumor cell immunization, which represent a promising cancer vaccine strategy. Thus, our results indicate the therapeutic actions of KME as a feasible partner of mEHT, suggesting its potential candidate for cancer immunotherapy. Abbreviations: APC, Antigen-presenting cell; CTL, Cytotoxic T lymphocyte; EHT, Electro-hyperthermia therapy; ELISA, Enzyme-linked immunosorbent assay; HSP, Heat shock protein; KME, Korean mistletoe extract; NK, Natural killer; PBS, Phosphate-buffered saline; QOL, Quality of life; RF, Radio-frequency; TAM, Tumor-associated macrophage.

Foot-and-mouth disease virus (FMDV) is a highly contagious picornavirus that poses a serious threat to the global livestock industry. This study aimed to investigate the impact of FMDV infection on the memory immune response in pigs and to analyze the role of type II interferon (IFN-γ) in this process. By comparing pigs artificially infected with FMDV and those vaccinated with inactivated FMDV vaccine, we found that FMDV infection significantly suppressed the development of memory T helper (Th) and B cell populations, affecting the memory immune response. Further experiments showed that pretreatment with IFN-γ could counteract the immunosuppression caused by FMDV, and this counteraction was achieved by promoting the expression of three transcription factors: T-bet, Eomes, and Bcl-6. Our findings emphasize the key role of IFN-γ in regulating the host's immune response to FMDV infection and provide new scientific evidence for the development of effective FMDV vaccines.

Human T-lymphotropic virus-1 (HTLV-1) induces neoplastic adult T-cell leukemia/lymphoma (ATLL) and neurological HTLV-1 associated myelopathy (HAM) in approximately 3 %-5 % of infected individuals. The precise factors that facilitate disease manifestation are still unknown; interaction between the virus and the host's immune response is key. Cytokines regulates physiological activities and their dysregulation may initiate the pathogenesis of various malignant and infectious diseases. Genetic variations, particularly polymorphisms in gene regulatory regions, lead to varying cytokine production patterns. Interferon-gamma (IFN-γ), a key cytokine in HTLV-1 infection, is a signature cytokine for T-helper 1 (Th1) cells that interferes with viral replication and enhances innate and adaptive immune responses during viral infections. The IFNG gene possesses several single nucleotide polymorphisms (SNPs), among which the + 874 A/T SNP has been widely studied for its functional role in HTLV-1 infection. The purpose of this review was to provide insight into the impact of IFNG SNPs on HTLV-1 Infection.

Modern management of chicks hinders the vertical transmission of intestinal microbiota, which is closely related to immunity. Inulin is a substrate that can be utilized by the microbiota. This study aimed to determine whether fecal microbiota transplantation (FMT) combined with inulin played a "1 + 1 > 2" role in enhancing the development and function of immune organs. Chicks were treated with 1 % inulin and/or fecal microbiota suspension on days 1-6. The growth performance, immune organ development, and immune indicators were evaluated on days 7, 14, and 21. Results showed that the combination of FMT and inulin significantly increased the immune organ index on day 7 and promoted the morphological structure and the expression of proliferating cell nuclear antigen (PCNA) in immune organs on days 7, 14, and 21. Each treatment increased the gene expression of interferon-gamma (IFN-γ), interleukin-4 (IL-4), interleukin-2 (IL-2), B cell-activating factor receptor (BAFFR), B cell linker (BLNK), C-X-C Motif Chemokine Ligand 12 (CXCL12), C-X-C Motif Chemokine Receptor 4 (CXCR4), and Biotin (Bu-1) to varying degrees. FMT combined with inulin significantly increased the expression of IgA-positive cells on days 7 and 14. In conclusion, the synergistic effect of FMT and inulin had beneficial impacts on the development and function of immune organs.

Erythema nodosum leprosum (ENL), an inflammatory reaction in leprosy, causes painful nodules, fever, and malaise due to immune system activation. Thalidomide is an effective treatment, although associated with important adverse effects. We aimed to evaluate the association of genetic variants in genes encoding tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β) and interleukin-6 (IL-6) with the response to treatment of ENL with thalidomide. 148 patients from the South and Northeast regions of Brazil were included. Genomic DNA was isolated from blood and/or saliva samples using commercial kits, and genetic variants in TNF, IL6, IL1β, and IFNγ genes were genotyped by TaqMan system. We identified an association between polymorphisms in TNF (rs1799964C, rs1800630A, rs1799724T and rs1800629A) IL1β (rs4848306G, rs1143623G, rs16944A, and rs1143627A), IL6 (rs2069840C and rs2069845G) and IFNγ (rs2430561T) with thalidomide dose variation in a time-dependent manner. Associations of IL6 and TNF haplotypes with thalidomide dosage variation over the time of treatment were also observed. Polymorphisms in TNF, IL6, IL1β, and IFNγ genes may modulate their expression levels, potentially impacting the required dosage of thalidomide in the treatment of ENL. Our findings should be confirmed in further studies to estimate the size effect of these polymorphisms on ENL treatment with thalidomide.

Eosinophils are immune cells that are crucial for the pathogenesis of allergic diseases, such as asthma. These cells play multifunctional roles in various situations, including infection. They are activated during viral infections and exert antiviral activity. Pattern recognition receptors, toll-like receptor 7 and retinoic acid inducible gene-I, are important for the recognition and capture of RNA viruses. In addition, intracellular granule proteins (eosinophil cationic protein and eosinophil-derived neurotoxin) and intracellular nitric oxide production inactivate and/or degrade RNA viruses. Interestingly, eosinophil-synthesizing specialized pro-resolving mediators possess antiviral properties that inhibit viral replication. Thus, eosinophils may play a protective role during respiratory virus infections. Notably, antiviral activities are impaired in patients with asthma, and eosinophil activities are perturbed in proportion with the severity of asthma. The exact roles of eosinophils in RNA virus (rhinovirus, respiratory syncytial virus, and influenza virus)-induced type 2 inflammation-based asthma exacerbation remain unclear. Our research demonstrates that interferons (IFN-α and IFN-γ) stimulate human eosinophils to upregulate antiviral molecules, including guanylate-binding proteins and tripartite motifs. Furthermore, IFN-γ specifically increases the expression of IL5RA, ICAM-1, and FCGR1A, potentially enhancing cellular responsiveness to IL-5, ICAM-1-mediated adhesion to rhinoviruses, and IgG-induced inflammatory responses, respectively. In this review, we have summarized the relationship between viral infections and asthma and the mechanisms underlying the development of antiviral functions of human and mouse eosinophils in vivo and in vitro.

In the tumor microenvironment (TME), hypoxia stands as a significant factor that modulates immune responses, especially those driven by T cells. As T cell-based therapies often fail to work in solid tumors, this study aims to investigate the effects of hypoxia on T cell topo-distribution in the TME, gene expression association with T cell states, and clinical responses in melanoma.

To generate detailed information on tumor oxygenation and T cell accessibility, we used mathematical modeling of human melanoma tissue microarrays that incorporate oxygen supply from vessels, intratumoral diffusion, and cellular uptake. We created tumor maps and derived plots showing the fraction of CD4 and CD8 T cells against the distance to the nearest vessel and oxygen pressure. To assess their function and transcriptional changes caused by hypoxia, effector T cells were generated and cultured under hypoxia (0.5% oxygen) or normoxia (21% oxygen). The T cell hypoxia-transcriptional signature was compared against datasets from msigDB, iATLAS (clinical trials of melanoma patients treated with immune checkpoint inhibitors (ICIs)), ORIEN AVATAR (real-world melanoma patients treated with ICIs), and a single-cell atlas of tumor-infiltrating lymphocytes.

We made three specific observations: (1) in melanoma T cells preferentially accumulated in oxygenated areas close to blood vessels (50-100 µm from the vasculature in the regions of high oxygen availability) but not in hypoxic areas far from blood vessels. (2) Our analysis confirmed that under hypoxia, T cell functions were significantly reduced compared with normoxic conditions and accompanied by a unique gene signature. Furthermore, this hypoxic gene signature was prevalent in resting and non-activated T cells. Notably and clinically relevant, the hypoxic T cell gene set was found to correlate with reduced overall survival and reduced progression-free survival in melanoma patients, which was more pronounced in non-responder patients undergoing ICI therapy. (3) Finally, compared with a single-cell atlas of tumor-infiltrating T cells, our hypoxia signature aligned with a population of cells at a state termed stress response state (TSTR).

Our study highlights the critical role of hypoxia in shaping T cell distribution and its correlation with clinical outcomes in melanoma. We revealed a preferential accumulation of T cells in oxygenated areas. Moreover, hypoxic T cells develop a distinct hypoxic gene signature prevalent in resting, non-activated T cells and TSTR that was also associated with poorer outcomes, particularly pronounced among non-responders to ICIs.

This study aimed to investigate and elucidate the clinical characteristics, immune status, infection types and patterns, treatment responses, and disease progression in patients with positive anti-interferon-gamma (IFN-γ) autoantibodies in combination with Mycobacterium infections.

We conducted a retrospective analysis of clinical data from patients with positive anti-IFN-γ autoantibodies and concurrent Mycobacterial infections, including Mycobacterial infections (MTB) and non-tuberculous mycobacteria (NTM). The study included cases treated at the Fourth People's Hospital of Nanning, Guangxi, from 2018 to 2023. Data collected comprised symptoms, clinical signs, laboratory test results, imaging findings, and other relevant clinical information. Patients were also followed up to evaluate treatment responses and long-term therapeutic outcomes.

A total of 30 patients with MTB and NTM infections were analyzed. The majority presented with common symptoms, such as cough, sputum production, weight loss, extrapulmonary tuberculosis (TB), and a range of opportunistic infections. Laboratory and imaging studies revealed complex infection patterns and various pathological changes. Treatment primarily involved targeted anti-infective therapy combined with immunosupportive measures. However, frequent treatment relapses and side effects were observed, resulting in two deaths.

Immune deficiency associated with positive anti-IFN-γ autoantibodies resembles the immunosuppression seen in advanced stages of human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS), rendering patients highly susceptible to opportunistic infections. These infections were predominantly caused by NTM, followed by MTB and Talaromyces marneffei (TM). This represents a novel immune deficiency syndrome that predisposes patients to a spectrum of opportunistic infections.

Suicide is defined as the act of a person attempting to take their own life by causing death. Suicide is a complex phenomenon that is influenced by a multitude of factors, including psychosocial, cultural, and religious aspects, as well as genetic, biochemical, and environmental factors. From a biochemical perspective, it is crucial to consider the communication between the endocrine, immune, and nervous systems when studying the etiology of suicide. Several pathologies involve the bidirectional communication between the peripheral activity and the central nervous system by the action of molecules such as cytokines, hormones, and neurotransmitters. These humoral signals, when present in optimal quantities, are responsible for maintaining physiological homeostasis, including mood states. Stress elevates the cortisol and proinflammatory cytokines levels and alter neurotransmitters balance, thereby increasing the risk of developing a psychiatric disorder and subsequently the risk of suicidal behavior. This review provides an integrative perspective about the neurochemical, immunological, and endocrinological disturbances associated with suicidal behavior, with a particular focus on those alterations that may serve as potential risk markers and/or indicators of the state preceding such a tragic act.