BMC Immunol
· 2026 Mar · PMID 41826817
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BACKGROUND: Inflammatory bowel disease (IBD) is characterized by dysregulated T helper immune responses. Crohn’s disease is predominantly associated with excessive Th1 and Th17 responses, while ulcerative colitis display...BACKGROUND: Inflammatory bowel disease (IBD) is characterized by dysregulated T helper immune responses. Crohn’s disease is predominantly associated with excessive Th1 and Th17 responses, while ulcerative colitis displays a more heterogeneous immune profile. However, the molecular mechanisms underlying Th1 cell differentiation in intestinal inflammation remain incompletely understood. CD30, a member of the tumor necrosis factor receptor superfamily, has been implicated in various inflammatory conditions, yet its role in IBD pathogenesis has not been fully elucidated. OBJECTIVES: This study aimed to investigate the role of CD30 in experimental colitis and its regulation of Th1 cell differentiation through the NF-κB signaling pathway. METHODS: Acute colitis was induced in wild-type and CD30-deficient mice using 3% dextran sulfate sodium (DSS) for 7 days. CD30 expression in colonic tissues was assessed by immunohistochemistry, quantitative real-time PCR, and Western blot. Naive CD4 + T cells were isolated and stimulated under Th1-polarizing conditions with or without CD30 knockdown using small interfering RNA. Th1 differentiation was evaluated by flow cytometry with verification using T-bet and IL-17 A staining, and related transcription factors and cytokines were measured. The NF-κB signaling pathway was examined in lipopolysaccharide (LPS)-stimulated conditions. RESULTS: CD30 expression was significantly upregulated in DSS-induced colitis, correlating with increased Th1 markers including T-bet and IFN-γ. In vitro, CD30 knockdown markedly suppressed Th1 cell differentiation from naive CD4 + T cells, reducing IFN-γ + cell proportions among CD4 + T cells and downregulating T-bet, STAT4, and IL-12Rβ2 expression. Mechanistically, CD30 deficiency inhibited NF-κB pathway activation by reducing p65 phosphorylation and preventing IκBα degradation. In vivo, CD30-/- mice exhibited attenuated colitis severity with reduced disease activity index, improved colon length, decreased histological damage, and diminished Th1 cytokine production compared to wild-type littermates. CONCLUSIONS: CD30 promotes Th1 cell differentiation and exacerbates experimental colitis through NF-κB-dependent mechanisms. These findings identify CD30 as a potential therapeutic target for IBD treatment.
Baye N, Atnafu A, Girma S
… +8 more, Nigussie B, Belete Y, Girma T, Yimam S, Bobosha K, Chanyalew Z, Gize A, Chanyalew M
BMC Immunol
· 2026 Mar · PMID 41807953
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BACKGROUND: Tuberculosis (TB), caused by the Mycobacterium tuberculosis complex (MTBC), remains a major global health concern. It manifests as pulmonary TB and extrapulmonary TB (EPTB), with the latter including TB lymph...BACKGROUND: Tuberculosis (TB), caused by the Mycobacterium tuberculosis complex (MTBC), remains a major global health concern. It manifests as pulmonary TB and extrapulmonary TB (EPTB), with the latter including TB lymphadenitis (TBLN) and endometrial TB (ETB). While TBLN is the most common form, ETB is among the least studied despite its serious clinical consequences, such as infertility. Owing to its asymptomatic nature, ETB is often diagnosed at a late stage after irreversible tissue damage has occurred. The immune response in TB varies by infection site, yet very little is known about the local immune response at the infection site of the ETB. Cytokines such as TNF-α, IFN-γ, and TGF-β play critical roles in TB immunity, but their expression patterns differ across infection sites. Limited data exist on site-specific cytokine responses in the ETB and TBLN, making it essential to investigate immune markers in these forms of TB. This study examines cytokine expression and T-cell surface markers in formalin-fixed, paraffin-embedded (FFPE) biopsy samples to provide insights into immune dynamics and potential biomarkers for EPTB diagnosis. METHODS: A retrospective cross-sectional study was conducted using formalin-fixed, paraffin-embedded (FFPE) biopsy samples from ETB patients, TBLN patients, and controls. Immunohistochemistry (IHC) was performed to assess the expression of IFN-γ, TNF-α, and TGF-β, as well as CD4 + and CD8 + T-cell markers. Cytokine expression levels were quantified via QuPath softwares, and statistical comparisons were made via the Mann‒Whitney U test and the Kruskal‒Wallis test. RESULTS: Compared with controls, both ETB patients and TBLN patients presented significantly elevated IFN-γ and TNF-α expression (p < 0.05). However, TGF-β expression was notably greater in the ETB than in the TBLN (p < 0.05), suggesting a distinct immunoregulatory environment in the endometrium. CD4 + T-cell infiltration was significantly greater in the TBLN, whereas CD8 + T-cell presence was more pronounced in the ETB, indicating site-specific immune responses. CONCLUSIONS: This study highlights distinct cytokine expression patterns in patients with endometrial tuberculosis (ETB) and tuberculosis lymphadenitis (TBLN). The differential cytokine expression in the ETB may be influenced by the unique immune microenvironment of endometrial tissue. These site-specific immune responses could contribute to variations in disease presentation and progression. The differential expression of TGF-β in the ETB suggests a potential role in immune modulation and fibrosis, which may contribute to tissue remodeling and reproductive dysfunction. Additionally, the increased levels of IFN-γ and TNF-α in both EPTB forms reinforce the involvement of localized immune responses in disease pathogenesis. Identifying these cytokine patterns may help uncover potential biomarkers for early diagnosis, which, upon validation through further studies, could enhance the detection and management of ETB.
Atherosclerosis serves as the fundamental pathological process underlying numerous cardiovascular disorders, and the change of macrophage polarisation is the key to regulate the inflammatory response of AS. SIRT6 plays a...Atherosclerosis serves as the fundamental pathological process underlying numerous cardiovascular disorders, and the change of macrophage polarisation is the key to regulate the inflammatory response of AS. SIRT6 plays a protective effect in AS, but whether it regulates macrophage polarisation in AS remains uncertain. We aimed to characterise the mechanistic role of SIRT6 in atherosclerosis development mediated by macrophage polarisation. ApoE mice were fed a Western diet to construct the AS mouse model, and LPS treatment was performed on RAW264.7 cells to induce an inflammation cell model. Quantitative real-time PCR was performed to measure the expression of SIRT6 and M1/M2 macrophage polarisation markers. Plaque size was evaluated by Oil red O staining. M1/M2 macrophage polarisation was evaluated by immunofluorescence staining. The underlying mechanism was determined by Western blot, immunoprecipitation (IP), and co-IP. Results suggested that SIRT6 was downregulated in the AS mouse model and LPS-induced macrophages. SIRT6 overexpression decreased plaque size and blood lipid levels in the AS mouse model and inhibited macrophages polarisation to the M1-like phenotype both in vivo and in vitro. Mechanically, SIRT6 overexpression downregulated the protein level of TLR4 by decreasing acetylation on TLR4. Moreover, TLR4 overexpression restored M1 macrophage polarisation in LPS-induced macrophages inhibited by SIRT6 overexpression. In conclusion, we demonstrated that SIRT6 attenuated AS by suppressing M1 macrophage polarisation through downregulating TLR4 by deacetylation. These results may provide a potential therapeutic target for targeted macrophage polarisation therapy for AS.
Arthur JF, Ahor HS, Vivekanandan MM
… +18 more, Minadzi D, Yeboah A, Lamptey M, Ofori VA, Kegya AD, Arthur R, Amoakoa LA, Adankwah E, Owusu DO, Abass MK, Apraku FG, Ayisi-Boateng NK, Adane S, Zakaria S, Mayatepek E, Seyfarth J, Phillips RO, Jacobsen M
Pulmonary tuberculosis in humans is characterised by features of immunopathology, which influence both antimycobacterial therapy and the long-term prognosis. In the blood of tuberculosis patients, immunopathology manifes...Pulmonary tuberculosis in humans is characterised by features of immunopathology, which influence both antimycobacterial therapy and the long-term prognosis. In the blood of tuberculosis patients, immunopathology manifests itself in reduced immune responses to mitogenic substances. Previous studies have demonstrated the influence of tuberculosis serum on T-cell and monocyte function, but the exact mechanisms remain unclear. Here, we performed a case/control study to analyse the influence of tuberculosis serum milieu changes on (i) T-cell stimulation (using Staphylococcal Enterotoxin B), (ii) monocyte stimulation (using the Toll-like receptor agonist Pam3CSK4), (iii) T-cell/monocyte interaction characterised by the response against the lectin phytohemagglutinin, by using a novel peripheral blood mononuclear cell in vitro assay. Cell-specific activation marker and cytokine expression were determined by multicolor flow cytometry. Staphylococcal Enterotoxin B mainly induced cytokine expression by T cells, while Pam3CSK4 stimulated monocytes to secrete distinct cytokine signatures. Phytohemagglutinin induced activation and cytokine expression in both T cells and monocytes. Notably, tuberculosis patient serum samples affected exclusively phytohemagglutinin stimulated T-cell responses and particularly activation marker as well as CD40L/IL-2 positive CD4 T-cell subsets were decreased as compared to serum from healthy contacts. Neither Staphylococcal Enterotoxin B-mediated T-cell stimulation nor phytohemagglutinin or Pam3CSK4 induced monocyte cytokines (i.e., Interleukin-6, Interleukin-8, Tumour Necrosis Factor-α) were affected by the tuberculosis patients' serum samples. These results highlight the immunosuppressive influence of the tuberculosis serum milieu, which specifically reduced T-cell responses to phytohemagglutinin, probably through impaired function of the accessory monocytes required for stimulation.
The engineering of chimeric antigen receptor (CAR) T cells has evolved from first-generation constructs to sophisticated armoured CAR T cells of the fourth generation. These advanced cellular constructs are engineered to...The engineering of chimeric antigen receptor (CAR) T cells has evolved from first-generation constructs to sophisticated armoured CAR T cells of the fourth generation. These advanced cellular constructs are engineered to co-express cytokines, chemokines or other immunomodulatory factors alongside CARs, aiming to enhance the efficacy, safety and persistence of CAR T cells within the tumour microenvironment. In particular, the potential for reversion of immunosuppression may allow for the treatment of solid tumours, which are in need of new therapeutic options. Here, we explore clinical and preclinical findings with cytokine-enhanced CAR T cells and discuss strategies for conditional cytokine secretion to mitigate systemic toxicity.
Chang C, Man X, Hao Q
… +3 more, Yan W, Wang Z, Wang J
BMC Immunol
· 2026 Mar · PMID 41782081
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OBJECTIVE: This research explored the pan-immune-inflammation value (PIV) as prognostic significance factors in patients with diffuse large B-cell lymphoma (DLBCL). And we examined the PILE score, a composite parameter d...OBJECTIVE: This research explored the pan-immune-inflammation value (PIV) as prognostic significance factors in patients with diffuse large B-cell lymphoma (DLBCL). And we examined the PILE score, a composite parameter derived from lactate dehydrogenase (LDH), and Eastern Cooperative Oncology Group performance status (ECOG PS) and PIV as well. The findings were intended to contribute to more reliable prognostic assessment in clinical settings. METHODS: We retrospectively analyzed 90 patients diagnosed with DLBCL who accepted standard therapy consisting of a CD20 monoclonal antibody combined with the CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone),with appropriate dose or cycle adjustments made according to age, cardiac function, and performance status.Specifically, CD20 monoclonal antibody was administered at 375 mg/m2 on day 0 of each 21-day cycle. CHOP consisted of cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2 (reduced to 30–40 mg/m2 in patients ≥70 years or with cardiac dysfunction), vincristine 1.4 mg/m2 on day 1, and prednisone 100 mg/m2 on days 1–5. Most patients received 6 cycles, while those with high-risk features received 8 cycles.A total of 16 patients with bulky disease, high-risk extranodal involvement, or suboptimal response to first-line chemotherapy as assessed by PET-CT received chemotherapy combined with radiotherapy.The PIV was established by integrating quantitative data on platelets, lymphocytes, monocytes and neutrophils obtained from routine peripheral blood tests. The PILE score was subsequently determined by integrating PIV with ECOG PS and LDH levels. Associations of PIV and PILE scores with treatment outcomes and prognosis were examined, and their potential relationships with pathological tumor characteristics were also evaluated. RESULTS: Elevated PIV was independently correlated with poorer overall survival (OS) (hazard ratio (HR) = 3.79; 95% confidence interval (CI): 1.31–10.97; p = 0.0135), PIV was statistically significant in univariate analysis for PFS (P<0.001), making it the most robust prognostic marker among all assessed immune-inflammatory indices. Similarly, patients exhibiting higher PILE scores experienced significantly reduced progression-free survival (PFS) and OS (p < 0.01, respectively). We evaluated the association of PIV, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), systemic immune-inflammation index (SII), and PILE with treatment outcomes by conducting both univariable Cox regression and multivariable logistic regression analyses, defining treatment response as the measured endpoint. While all markers showed significant association with the outcome in univariable analyses (p < 0.01, respectively) at statistical level, none demonstrated independent predictive capacity in multivariable models. Among DLBCL patients, the PIV demonstrated an independent prognostic significance for OS outcomes. Furthermore, the PILE score, along with other systemic immune-inflammatory markers, demonstrated potential utility in forecasting treatment outcome or response.
This study reveals a novel gut microbiota-CD8 T cell axis driving immunosuppression in colorectal cancer. Analysis of 16S rRNA sequencing identified significant gut dysbiosis in CRC patients, with marked enrichment of Ph...This study reveals a novel gut microbiota-CD8 T cell axis driving immunosuppression in colorectal cancer. Analysis of 16S rRNA sequencing identified significant gut dysbiosis in CRC patients, with marked enrichment of Phocaeicola and Bacteroides. Single-cell transcriptomics uncovered substantial T cell depletion and elevated CTLA4PD1 immune cells within the tumour microenvironment. Critically, spatial transcriptomics demonstrated co-localization of CTLA4CD8 T cells with tumour cells, indicating direct immunosuppressive interactions. Functional validation confirmed CTLA4 overexpression impairs CD8 T cell effector capacity, accelerating CRC cell proliferation and invasion. In vivo models demonstrated that faecal microbiota transplantation (FMT) promoted CTL activation, reduced Bacteroides abundance, decreased the formation of CD8CTLA4 T cells and ameliorated CRC symptoms. Additionally, CTLA4 knockdown inhibited tumour growth and metastasis. These findings establish a mechanistic pathway: gut dysbiosis induces chronic inflammation, triggering CTLA4 upregulation on CD8 T cells to promote T cell exhaustion and tumour immune evasion. The study provides immunological evidence for targeting the microbiota-CTLA4 axis in CRC immunotherapy.
Psoriasis is a chronic, immune-mediated inflammatory disorder in which neutrophils are central to pathogenesis. While recent studies have implicated the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING)...Psoriasis is a chronic, immune-mediated inflammatory disorder in which neutrophils are central to pathogenesis. While recent studies have implicated the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway in psoriasis, its specific role in neutrophil-mediated inflammation remains unclear. To investigate neutrophil function in psoriasis, we integrated single-cell RNA-seq from human lesions with studies in IMQ-treated mouse models (wild-type, STING-/-, PADi4-/-) and HL-60 cells. We employed transcriptomic, cytometric and functional assays to assess neutrophil recruitment, cytokine secretion and neutrophil extracellular trap (NET) formation. Our study revealed significant upregulation of STING expression in both lesional and peripheral blood neutrophils of psoriasis patients. In the IMQ-induced mouse model, STING knockout markedly alleviated disease severity, reduced neutrophil infiltration and suppressed IL-1β release. Mechanistically, STING promoted neutrophil chemotactic migration via the IRF3/NF-κB axis while directly regulating the formation of NETs in neutrophils and the release of cytotoxic mediators. Besides, distinct mouse strains exhibited significant differences in STING pathway activation, indicating genetic heterogeneity in the immunoregulatory mechanisms underlying psoriasis. Collectively, the above findings indicated that STING signalling in neutrophil-mediated psoriatic inflammation not only regulates cell recruitment but also directly drives the terminal effector function of NETs production. Furthermore, strain-specific differences suggest that the regulation of this pathway in the disease context is complex and context-dependent, potentially influencing individualised therapeutic responses. Targeting the STING pathway could serve as a therapeutic strategy to simultaneously inhibit multiple pathogenic processes mediated by neutrophils.
BMC Immunol
· 2026 Mar · PMID 41772437
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OBJECTIVE: To investigate the role of lactate clearance rate (LCR) and Sequential Organ Failure Assessment (SOFA) score in prognostic assessment of patients with severe pneumonia (SP). METHODS: A retrospective study of 1...OBJECTIVE: To investigate the role of lactate clearance rate (LCR) and Sequential Organ Failure Assessment (SOFA) score in prognostic assessment of patients with severe pneumonia (SP). METHODS: A retrospective study of 185 SP patients was conducted. Baseline characteristics were compared between survivors (n = 128) and non-survivors (n = 57). Following univariate and correlation analyses, significant variables were used to build a combined prediction model via binary logistic regression. Model calibration and predictive performance for 28-day mortality were assessed using Hosmer-Lemeshow and ROC curve analyses, respectively. Dynamic changes in LCR and SOFA scores at admission (T0), 6 h (T6), and 24 h (T24) were compared. RESULTS: The 28-day mortality rate was 30.81% (57/185). Univariate analysis revealed statistically significant differences in age, chronic lung disease, procalcitonin (PCT), LCR, and SOFA score (P < 0.05). Spearman correlation analysis showed a moderate negative correlation between LCR and SOFA score (r = -0.401, P < 0.001). Multivariate analysis identified LCR [0.911 (0.861–0.965)] and SOFA score [1.508 (1.278–1.779)] as independent predictors (P < 0.05). The combined model demonstrated superior predictive accuracy (AUC: 0.882, 95% CI: 0.833–0.932) compared to LCR (AUC: 0.793) or SOFA score (AUC: 0.832) alone (Delong test, P < 0.05). Survivors exhibited significantly higher LCR and lower SOFA scores at T6 and T24, with improving trends over time, unlike non-survivors. CONCLUSION: The combined model integrating LCR and SOFA score outperforms either parameter alone in predicting 28-day mortality risk in SP, offering a potential tool for early risk stratification.
Interferon gamma (IFNγ) is a pivotal inflammatory mediator and immune regulator, but its in vivo spatiotemporal dynamics and functional roles in inflammation and carcinogenesis remain incompletely understood. Here, we de...Interferon gamma (IFNγ) is a pivotal inflammatory mediator and immune regulator, but its in vivo spatiotemporal dynamics and functional roles in inflammation and carcinogenesis remain incompletely understood. Here, we developed a C57BL/6J- Ifng-2A-luciferase knock-in mouse strain using CRISPR/Cas9-mediated homology-directed repair, enabling real-time bioluminescence imaging (BLI) of IFNγ-expressing cells by inserting a luciferase cassette under the endogenous Ifng promoter. The validation confirmed that this model is capable of directly detecting Poly(I:C) -induced transient IFNγ, enhancing intratumoral IFNγ signals upon anti-PD-1/CTLA-4 therapy, and dynamically tracking IFNγ expression during imiquimod-induced psoriasis. This transgenic mouse model provides a powerful tool for non-invasive, longitudinal tracking of IFNγ-expressing cells, offering novel insights into IFNγ-mediated immune regulation in inflammation and cancer. It holds promise for identifying IFNγ-related therapeutic targets and predicting responses to immunotherapies.
Bruton's Tyrosine Kinase (BTK) is a cytoplasmic kinase essential for B cell-mediated signalling, yet has also received recent recognition as a direct regulator of myeloid cell function. Beyond its established role in B c...Bruton's Tyrosine Kinase (BTK) is a cytoplasmic kinase essential for B cell-mediated signalling, yet has also received recent recognition as a direct regulator of myeloid cell function. Beyond its established role in B cell malignancies, BTK influences receptor-driven activation in monocytes, macrophages, microglia, granulocytes, and other organ-specific macrophages by influencing key molecular pathways involved in phagocytosis, inflammatory-mediated signalling, and cell metabolism (e.g., NFκB, STAT3, and NLRP3). BTK inhibitors (BTKis) were initially developed and approved to treat B cell-related cancers, however, they have also demonstrated significant therapeutic/clinical efficacy in autoimmune, allergic, and immune-driven neuroinflammatory disorders, including rheumatoid arthritis, IgA nephropathy, multiple sclerosis, and chronic spontaneous urticaria. This review specifically addresses, compares, and summarises how BTK inhibition within distinct myeloid-derived cell subsets alters inflammatory-related phenotypes and functions within these cells. Together, providing cell-specific insights into BTK as a central regulator of innate immunity and myeloid cell function may help generate significant translational potential for BTKis in multiple inflammatory-mediated diseases.
Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a deadly disorder with poor therapeutic opportunities, driven by dysregulated immunity. Here we position monocyte-derived alveolar macrophages (Mo-AMs...Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a deadly disorder with poor therapeutic opportunities, driven by dysregulated immunity. Here we position monocyte-derived alveolar macrophages (Mo-AMs) as central mediators of ALI/ARDS pathogenesis, contrasting with homeostatic tissue-resident alveolar macrophages (TR-AMs). This review first traces the origin pathway of Mo-AMs, which differentiate from haematopoietic stem cells (HSCs) in the bone marrow and are recruited to the inflamed lung via a CCR2/CCL2-dependent pathway, ultimately differentiating into pathogenic effector cells within the alveolar microenvironment. Subsequently, we elucidate their primary pathogenic mechanisms: Mo-AMs mediate critical pathological injury by generating cytokine storms, depleting TR-AMs, disrupting the alveolar-capillary barrier and promoting fibrotic remodelling. Given their well-defined pathogenic role, Mo-AMs have emerged as a promising therapeutic target. Therefore, we conclude by reviewing recent advances in strategies targeting Mo-AMs, primarily encompassing the inhibition of their recruitment, induction of their apoptosis and reprogramming of their proinflammatory functions. These approaches collectively provide valuable insights for developing novel therapies for ALI/ARDS.
BMC Immunol
· 2026 Feb · PMID 41724974
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Fowl cholera is caused by P. multocida. The currently available commercial kit is relatively expensive for Ethiopian laboratories. To address this issue indirect ELISA kit to detect antibodies against P. multocida in chi...Fowl cholera is caused by P. multocida. The currently available commercial kit is relatively expensive for Ethiopian laboratories. To address this issue indirect ELISA kit to detect antibodies against P. multocida in chicken was developed. In-house made indirect ELISA kit was developed and optimized. Re-constituted local avian P. multocida biotype A was used for the preparation of coating antigen. The purity of the P. multocida biotype A inoculum was checked by gram staining and centrifugation at 4500 rpm for 30 min. The assay was developed and evaluated using 128 samples of chicken serum. Optimizations of various components were carried out against both anti-P. multocida hyper immune and pre immune serum. To develop an indirect ELISA test, washing buffer concentration of 500 µl of T-20, blocking buffer concentration of 200 µl, antigen concentration of 0.1 µg/ml, serum samples with a final dilution of 1:500 and optimal dilution of Rabbit anti-sheep IgG HRP-conjugate of 1: 1000 µg/ml are determined by checker board titration (CBT) method. The cut-off value was determined to be 0.23. Sensitivity, specificity and accuracy of in-house made indirect ELISA were 96%, 90% and 93%, respectively. This test result indicated good correlation with that of the commercial kit with a Cohen's κ agreement of 0.86 with a 95% confidence interval of 0.77 to 0.95. We found that in-house made indirect ELISA was more sensitive and convenient to perform. Consequently, in-house made indirect ELISA was as good as the commercial indirect ELISA in screening chicken serum samples for detection of antibodies against P. multocida.