Immunology Letters[JOURNAL]
Sun
200 papers
Characteristics and specific differential gene analysis of the TCR immune repertoire in secondary adult HLH lymphocytes.
Chen Y, Xiao W, Yuan S … +5 more , Wang C, Shi M, Yu D, Zhang Y, Lou S
Immunol Lett · 2025 Oct · PMID 40228699 · Publisher ↗
BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a severe, life-threatening, and hyperinflammatory disorder characterized by excessive immune activation and systemic immune dysregulation. Despite advancements in d...
BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a severe, life-threatening, and hyperinflammatory disorder characterized by excessive immune activation and systemic immune dysregulation. Despite advancements in diagnosis, the underlying alterations in the immune repertoire in HLH remain poorly understood. This study aimed to characterize remodeling in the T cell receptor (TCR) immune repertoire in patients with HLH, focusing on V(D)J gene usage, complementarity-determining region 3 (CDR3) diversity, and clonotypic distribution, to better understand the immunological basis of the disease. METHODS: Thirty individuals were enrolled, including 16 untreated patients with HLH(U group), 4 patients with HLH undergoing post-induction therapy (T group), and 10 healthy controls (Hc group). Peripheral blood TCRβ sequencing was performed to analyze V(D)J gene usage, CDR3 length distribution, and repertoire diversity. The relative diversity index (RDI) and hierarchical clustering of V-J pairing frequencies were applied to evaluate immune repertoire alterations. Statistical analyses included one-way ANOVA and Wilcoxon rank-sum tests to assess group differences, with a significance threshold of P < 0.05. RESULTS: Compared to healthy individuals, patients with HLH exhibited significant alterations in TCR diversity, including increased CDR3 length variability and shifts in V(D)J gene usage (P < 0.05). In particular, TRBV5-1 and TRBJ2-7 expression was observed in patients with HLH. The V-J pairing analysis demonstrated that HLH samples clustered distinctly from healthy controls, suggesting immune dysregulation. RDI analysis revealed a significantly higher diversity in the M-HLH group than in the non-M-HLH group (P < 0.05), indicating higher clonal expansion in the malignant subgroup. Following induction therapy, TCR diversity showed partial recovery (P < 0.05);however, the immune repertoire remained distinct from that of healthy individuals (P < 0.05). CONCLUSIONS: HLH is associated with profound immune repertoire remodeling, particularly in V-J gene pairing and CDR3 diversity. The RDI values and significant differences in gene pairing suggest antigen-driven clonal expansion in patients with HLH. Immune repertoire profiling may act as an effective biomarker for HLH classification and disease monitoring. Further studies with larger cohorts and longitudinal data are required to validate these findings and explore their clinical application in HLH.
Impact of afatinib on intestinal and salivary IgA: Immune response alterations linked to gastrointestinal side effects.
Uemura I, Takahashi-Suzuki N, Satoh T
Immunol Lett · 2025 Oct · PMID 40228698 · Publisher ↗
BACKGROUND: Afatinib, an oral molecular-targeted anticancer agent, is effective but causes significant gastrointestinal side effects. These effects are associated with EGFR inhibition in intestinal cells and changes in t...
BACKGROUND: Afatinib, an oral molecular-targeted anticancer agent, is effective but causes significant gastrointestinal side effects. These effects are associated with EGFR inhibition in intestinal cells and changes in the microbiota. OBJECTIVE: To investigate the effects of afatinib on intestinal mucosal immunity in rats, focusing on IgA levels in the intestine and saliva, and to understand the innate and acquired immune responses to these side effects. METHODS: Male Wistar rats received afatinib (5.2 mg/kg) daily for 24 h (Day 1) and for 2 weeks (Day 14). Gene expression in the intestine was analyzed using quantitative polymerase chain reaction. IgA levels in the intestine and saliva were measured using enzyme-linked immunosorbent assay. RESULTS: Afatinib suppressed α-defensin 5 and pIgR in the jejunum and ileum, indicating reduced innate immunity. It increased IgA levels in the intestine and saliva, suggesting altered acquired immunity. Salivary IgA levels significantly correlated with intestinal IgA levels. CONCLUSIONS: Afatinib affects gastrointestinal mucosal immunity, suppresses innate defense, and alters IgA production. Salivary IgA could serve as a marker for monitoring these effects, aiding cancer therapy management.
Corrigendum to "The role of IgA in gastrointestinal helminthiasis: A systematic review" [Immunology Letters (2022) 12-22, Volume: 249].
Ramos ACS, Oliveira LM, Santos YLDCO … +6 more , Dantas MCS, Walker CIB, Faria AMC, Bueno LL, Dolabella SS, Fujiwara RT
Immunol Lett · 2025 Oct · PMID 40204537 · Publisher ↗
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Inhibitor of differentiation-2 protein ameliorates complete Freund's adjuvant-induced arthritis and inhibits STAT3 phosphorylation in the synovium.
Haowen Y, Yuhan Y, Yuanyuan L … +7 more , Xibin M, Yuxin W, Lingyun X, Dong Y, Min L, Genshen Z, Minna W
Immunol Lett · 2025 Oct · PMID 40194667 · Publisher ↗
Rheumatoid arthritis (RA) is a chronic autoimmune disease causing joint inflammation, dysfunction, and deformity, along with systemic inflammatory manifestations. Inhibitor of differentiation-2 (ID2) is a transcription f...
Rheumatoid arthritis (RA) is a chronic autoimmune disease causing joint inflammation, dysfunction, and deformity, along with systemic inflammatory manifestations. Inhibitor of differentiation-2 (ID2) is a transcription factor containing a helix-loop-helix (HLH) structure. Studies suggest that ID2 regulates innate and adaptive immunity and inhibits the differentiation of osteoclasts. However, the effects and underlying molecular mechanisms of ID2 on rheumatoid arthritis (RA) remain unclear. In the present study, we found that exogenous supplementation of human recombinant ID2 (hID2) protein significantly reduced paw swelling and arthritis index scores in adjuvant-induced arthritis (AIA) rats, and improved ankle joint pathology. Analysis of pro-inflammatory factor levels in peripheral blood mononuclear cells and synovial tissues indicated that hID2 attenuated inflammatory responses in AIA rats. Furthermore, RNA sequencing demonstrated that hID2 down-regulated the JAK-STAT pathway, and the phosphorylation of its key molecule, Signal Transducer and Activator of Transcription 3 (STAT3), was inhibited in synovial tissues. Additionally, the expression of chemokine-related genes was noticeably down-regulated in synovial tissues, though further investigation is needed to understand the underlying mechanisms. Overall, these findings suggest that hID2 effectively attenuated the inflammatory response and joint destruction in AIA rats, highlighting the potential of hID2 as a therapeutic agent for the treatment of RA.
Double positive IL-17AIFN-γCCR6 ILCs contribute towards the immunopathology of lepromatous leprosy.
Saini C, Sapra L, Ramesh V … +2 more , Puri P, Srivastava RK
Immunol Lett · 2025 Oct · PMID 40189156 · Publisher ↗
Leprosy is a skin disease caused by Mycobacterium leprae, characterized by both localized and generalized immune responses. Th1/17 lymphocytes play a crucial role in the immune response against M. leprae. However, adapti...
Leprosy is a skin disease caused by Mycobacterium leprae, characterized by both localized and generalized immune responses. Th1/17 lymphocytes play a crucial role in the immune response against M. leprae. However, adaptive immunity alone is not sufficient to completely eradicate the pathogen, suggesting the involvement of other innate immune cells in pathogen removal. Therefore, we investigated innate lymphoid cells (ILCs), which are the innate counterparts of helper T cells in adaptive immunity and are known to produce IFN-γ and IL-17. In the present study, we evaluated the expression of ILC1 and ILC3 in borderline tuberculoid (BT) and lepromatous leprosy (LL) lesional skin by flow cytometry and real time PCR. Further, the expression of various in-situ genes, including cytokines, chemokines, cytokine receptors chemokine receptors, and transcription factors by qPCR in skin lesions of leprosy patients were analyzed. The phenotypes of ILC1 and ILC3 cells were determined as CD3CCR6CD19IFN-γ and CD3CCR6CD19IL-17A, respectively, by flow-cytometry analysis. BT skin lesions represents high CCR6expression on total ILCs as compared to LL patients. Our results clearly indicate that ILC1 and ILC3 were highly expressed in skin lesions of BT as compared to LL leprosy patients. Moreover, we observed that double positive (DP) CD3CCR6CD19IFN-γIL-17A ILCs were up-regulated in LL and showed a pathogenic role. The gene expression of IL-17A and IFN-γ were found to be significantly positively correlated with the percentage of CCR6 ILCs. On the other hand, CCR6 ILCs were negatively correlated with ILC1 and ILC3 associated markers. Summarily our results clearly suggest that both ILC1 and ILC3 are important and immune-protective, on the contrary DP (IFN-γIL-17A) ILCs may promote progression and immunopathology of leprosy.
Remdesivir alleviates joint damage in collagen-induced arthritis and inhibits inflammatory cell death of RA synovial fibroblasts.
Lee AR, Min HK, Lee SY … +5 more , Jeon SB, Lee CR, Kim TH, Park JH, La Cho M
Immunol Lett · 2025 Oct · PMID 40189155 · Publisher ↗
BACKGROUND: The antiviral agent, remdesivir, is adenosine analogue which is currently also used as anti-coronavirus disease 2019. Remdesivir also had anti-inflammatory effect which reduced pro-inflammatory cytokine produ...
BACKGROUND: The antiviral agent, remdesivir, is adenosine analogue which is currently also used as anti-coronavirus disease 2019. Remdesivir also had anti-inflammatory effect which reduced pro-inflammatory cytokine production, and inhibition of the cyclic GMP-AMP synthase-STING pathway. METHODS: We evaluated the antiarthritic effects of remdesivir in a mouse model of High-fat diet (HFD) collagen-induced arthritis (CIA) and in fibroblast-like synoviocytes from patients with RA. Type II collagen was administered to DBA/1J mice to induce CIA. Vehicle or remdesivir was injected subcutaneously three times a week. During 7 weeks of treatment, the arthritis score and incidence were evaluated twice a week. Flow cytometry and confocal imaging were used to evaluate CD4 + T cells in the spleen. FLSs from patients with RA were stimulated in vitro with remdesivir and tumor necrosis factor (TNF)-α, and western blotting was used to measure the expression of STING and necroptosis-related markers. RESULTS: Remdesivir administration suppressed the incidence and progression of arthritis in mice with CIA. Histological analysis revealed lower inflammation and cartilage damage scores in remdesivir-treated than in vehicle groups. Interleukin (IL)-17 + CD4 + T-cell differentiation was inhibited in the remdesivir-treated group. Furthermore, IL-17/-6/-1β, monocyte chemoattractant protein -1, and TNF-α expression was reduced in the remdesivir group. In vitro, remdesivir suppressed the expression of STING, nuclear factor-κB, RIPK3, and phosphorylated MLKL in RA-FLSs under TNF-α stimulation. CONCLUSIONS: The antiviral agent remdesivir suppressed arthritis by regulating Th cell differentiation, pro-inflammatory cytokine expression, the STING pathway, and necroptosis.
The immune-reinforcements of Lenvatinib plus anti-PD-1 and their rationale to unite with TACE for unresectable hepatocellular carcinoma treatment.
Jiang J, Zhang H, Ou Y … +6 more , Lai J, Huang Y, Cai W, Li C, Zhang L, Fu Y
Immunol Lett · 2025 Oct · PMID 40189154 · Publisher ↗
BACKGROUND: Despite encouraging clinical benefits have gained by anti-PD-1 and Lenvatinib combination, in-depth characterizations about the mechanisms of action remain poorly characterized. Furthermore, although the comb...
BACKGROUND: Despite encouraging clinical benefits have gained by anti-PD-1 and Lenvatinib combination, in-depth characterizations about the mechanisms of action remain poorly characterized. Furthermore, although the combination of systemic anti-PD-1 or Lenvatinib treatment and locoregional transcatheter arterial chemoembolization (TACE) is widely carried out to treat unresectable HCC in clinical, the efficacies of different combination regimens are uncertain due to limited researches. METHODS: We firstly generated murine HCC models to validate the enhanced anti-tumor effects of anti-PD-1 and Lenvatinib combination therapy. Then single cell mass cytometry (CyTOF) was employed to phenotypically reveal their mechanisms of action. After that, we further compared the effectiveness of TACE plus Lenvatinib (i.e., TACE-Len) dual therapy with TACE, Lenvatinib plus anti-PD-1 (i.e., TACE-Len-PD-1) triple therapy as conversion therapy for unresectable HCC. RESULTS: Lenvatinib and anti-PD-1 combination could generate activated immune profiles not only by increasing systemic CD4, CD8T cells and B cells proportions, but also by weakening the immune-tolerance functions derived from both immunosuppressive cells (i.e., MDSCs) and co-inhibitory mediators (i.e., PD-L1 and LAG-3). Meanwhile, our study also suggested that TACE-Len-PD-1 triple therapy could achieve better clinical responses with powerful immune profiles for unresectable HCC compared to TACE-Len dual therapy. CONCLUSIONS: Our study provided a delicate immune landscape of anti-PD-1and Lenvatinib combination, and we also offered scientific evidences that TACE-Len-PD-1 triple therapy could fulfill better clinical benefits than TACE-Len dual therapy, which is anticipated to provide objective and effective evidences for clinical use.
Functional alterations in colonic CD4+T and regulatory T cells drive immune imbalance in ulcerative colitis.
Long Y, Xia C, Zheng X … +6 more , Feng J, Li W, Ma Y, Sun Y, Zeng X, Liu C
Immunol Lett · 2025 Oct · PMID 40187693 · Publisher ↗
Immune imbalance plays a key role in the pathogenesis of ulcerative colitis (UC). The changes in CD4+ T cells and regulatory T cells (Tregs) in colonic T cells have an important relationship with UC. It is of great signi...
Immune imbalance plays a key role in the pathogenesis of ulcerative colitis (UC). The changes in CD4+ T cells and regulatory T cells (Tregs) in colonic T cells have an important relationship with UC. It is of great significance to elucidate the functional characteristics of CD4+ cells andTregs in UC patients. This study aimed to inquire into changes in functional markers of CD4+T cells and Tregs, including Helios, Bcl6, CTLA-4, CD226, TIGIT, PD-1 and ICOS. DSS-induced colitis was established in Balb/c mice and lymphocytes from spleen, mesenteric lymph nodes (MLNs), peripheral blood, and colon tissue were obtained. CD4+T cells and Tregs were analyzed by flow cytometry. We found that Helios+ and Bcl-6+ proportions were increased in colonic CD4+T cells of DSS-induced colitis mice. CD4+FoxP3+CXCR5-Tregs were significantly elevated in the colon of colitis mice, with CTLA-4+ percentages increased. Naïve subsets in colonic CD4+T and Tregs were significantly reduced, while effector T-cell subsets were increased in colitis mice. TIGIT+ and CD226+ percentages were significantly increased in both colonic CD4+T cells and Tregs of colitis mice. Both PD-1+ and ICOS+ percentages in colonic CD4+T cells and the ICOS+ percentage in colonic Tregs were significantly increased in colitis mice. In conclusion, functional molecules related to CD4+T cells and Tregs in colonic T cells are altered in UC, often adopting an activated phenotype. These changes may be associated with the pathogenesis of UC and could potentially serve as clinical therapeutic targets.
Heparanase inhibition mitigates bleomycin-induced pulmonary fibrosis in mice by reducing M2 macrophage polarization.
He L, Lv Q, Luo J … +4 more , Guo YD, Sun H, Zong M, Fan LY
Immunol Lett · 2025 Aug · PMID 40180131 · Publisher ↗
OBJECTIVE: This study investigates the involvement of heparanase in IPF pathogenesis and evaluates the therapeutic potential of heparanase inhibition. METHODS: Plasma heparanase levels were measured in IPF patients and h...
OBJECTIVE: This study investigates the involvement of heparanase in IPF pathogenesis and evaluates the therapeutic potential of heparanase inhibition. METHODS: Plasma heparanase levels were measured in IPF patients and healthy controls. Macrophage infiltration and heparanase expression in bronchoalveolar lavage fluid (BALF) were analyzed using immunofluorescence. Bleomycin (BLM)-induced pulmonary fibrosis mouse models were treated with the heparanase inhibitor OGT2115. Disease severity, macrophage polarization, and heparanase expression were assessed through histological staining, hydroxyproline content measurement, flow cytometry, immunofluorescence, Transmission Electron Microscopy and Western blot analysis. RESULTS: Elevated heparanase levels were found in the plasma of IPF patients and in macrophages from BALF. In BLM-induced mice, heparanase was predominantly expressed in M2 macrophages. OGT2115 treatment significantly reduced mortality, body weight loss, and fibrosis severity. Additionally, OGT2115 decreased M2 macrophage infiltration, attenuated lung fibrosis, and reduced autophagy markers LC3 I/II and P62. CONCLUSION: Heparanase plays a crucial role in modulating M2 macrophage polarization and the progression of IPF. Targeting heparanase with OGT2115 effectively ameliorates pulmonary fibrosis and represents a promising therapeutic strategy for IPF management.
BENTA disease or CARD11 gain-of-function? A novel variant with atypical features and a literature review.
Baldini L, Keller B, Dewitte L … +7 more , Passarelli C, Ginevrino M, Carli D, Montin D, Bossuyt X, Warnatz K, Licciardi F
Immunol Lett · 2025 Oct · PMID 40157432 · Publisher ↗
INTRODUCTION: The CARD11 (Caspase Recruitment Domain Family Member 11) gene encodes a scaffold protein critical for NF-κB signaling, regulating B-cell differentiation and T-cell effector functions. Gain-of-function (GOF)...
INTRODUCTION: The CARD11 (Caspase Recruitment Domain Family Member 11) gene encodes a scaffold protein critical for NF-κB signaling, regulating B-cell differentiation and T-cell effector functions. Gain-of-function (GOF) mutations in CARD11 cause BENTA disease (B cell Expansion with NF-κB and T cell Anergy), an autosomal dominant disorder typically presenting with early-onset polyclonal B-cell lymphocytosis, splenomegaly, lymphadenopathy, and recurrent infections. METHODS: We describe three related patients harboring a novel CARD11-GOF mutation (D357E), presenting with a BENTA phenotype with atypical features, including high IgM levels and a normal B-cell count, with life-threatening HLH in one case. Additionally, we conducted a systematic literature review using PubMed and EMBASE to identify previously reported cases of CARD11 GOF mutations. RESULTS: In vitro functional analysis demonstrated that the D357E variant activates the NF-κB signaling pathway in primary lymphocytes and in HEK293T cells transfected with mutant CARD11. Our literature review identified 13 studies describing 29 patients. Notably, HLH emerged as a common complication of CARD11 GOF mutations (18.8 %), while B-lymphocytosis -though frequent- was not universally present. CONCLUSION: We identified a novel pathogenic CARD11 variant and described its atypical phenotype, further expanding the clinical spectrum of CARD11 GOF disorders. These findings underscore the need for increased awareness of HLH risk in patients with CARD11 GOF mutations.
Virus-specific antibody responses in severe acute respiratory syndrome coronavirus 2-infected and vaccinated individuals.
Trier NH, Zivlaei N, Ostrowski SR … +6 more , Sørensen E, Larsen M, Slibinskas R, Ciplys E, Frederiksen JL, Houen G
Immunol Lett · 2025 Aug · PMID 40157431 · Publisher ↗
BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can have a serious course with many complications, especially in immunocompromised individuals. In such persons, other latent virus infec...
BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can have a serious course with many complications, especially in immunocompromised individuals. In such persons, other latent virus infections may contribute to disease pathology, in particular viruses which infect immune cells such as Epstein-Barr virus (EBV) and cytomegalovirus (CMV). METHODS: In this study, serology-based assays were conducted to analyse antibody responses to SARS-CoV-2 spike protein (SP), EBV Epstein-Barr nuclear antigen (EBNA)-1 and CMV phosphoprotein (pp)52 in naturally SARS-CoV-2-infected individuals, non-infected healthy controls (HCs) and vaccinated healthy controls (VHCs) to identify an association between SARS-CoV-2 antibodies and EBV and CMV antibodies in order to determine whether latent EBV and CMV infected individuals are more prone to become infected with SARS-CoV-2. Moreover, SARS-CoV-2, EBV, and CMV antibody responses were characterized in serum from patients with relapsing-remitting multiple sclerosis (RRMS), a chronic inflammatory disease strongly associated with EBV infections, to determine whether the serologic virus antibody profile varies in immunocompromised RRMS individuals upon SARS-CoV-2 vaccinations compared to VHCs. RESULTS: Significantly elevated SP IgG, IgM and IgA levels were identified in SARS-CoV-2-infected immunocompetent individuals when compared to non-infected HCs. However, no correlation was found to serum antibodies between SARS-CoV-2, EBV, and CMV in individuals infected with SARS-CoV-2 and in VHCs, suggesting that latent infections with neither EBV nor CMV associates to SARS-CoV-2 infection. Moreover, no significant difference in SP IgG, IgA and IgM levels was observed between vaccinated RRMS patients and VHCs, indicating that the immune system of immune deficient RRMS patients and VHCs respond identical to SARS-CoV-2 vaccinations. CONCLUSION: Collectively, SARS-CoV-2 SP antibody levels reflect the vaccination and infection history and do not associate with EBV and CMV serostatus.
Autoantibodies and therapeutic antibodies against complement factor H.
Nugteren S, Wang H, van Kooten C … +2 more , Gelderman KA, Trouw LA
Immunol Lett · 2025 Aug · PMID 40118156 · Publisher ↗
The complement system is a crucial part of our immune defense as, upon recognition, it can kill pathogens fast and effectively. However, misguided complement activation could cause damage to host tissues. Therefore, a we...
The complement system is a crucial part of our immune defense as, upon recognition, it can kill pathogens fast and effectively. However, misguided complement activation could cause damage to host tissues. Therefore, a well-controlled regulation of the complement system is a necessity to prevent collateral damage. Regulation is achieved by several complement inhibitory proteins, acting at different levels of the complement system. One of these complement regulators is factor H, the main regulator of the alternative complement activation pathway. Factor H can regulate the complement system both in fluid-phase and on the host cell surface by, for example, acting as co-factor for factor I, inactivating C3b. The functional properties of factor H are located within different regions of the protein. Functional impairment of factor H, either because of genetic variants, competing proteins such as the factor H-related proteins and proteins from certain pathogens, but also the presence of autoantibodies will impact on complement activation. However, exact consequences are dependent on the region within factor H that is affected. Autoantibodies binding to factor H have been shown to inhibit several regulatory functions of factor H, which is observed in diseases such as membranoproliferative glomerulonephritis and atypical hemolytic uremic syndrome. As more recently the presence of anti-factor H autoantibodies has also been discovered in several other diseases, ranging from autoimmune diseases to cancer, this review provides an overview of the presence of factor H autoantibodies described in these diseases. Factor H autoantibodies are reported to have inhibitory, or enhancing, effects on factor H, depending on the epitopes that are recognized. Formal conclusions about the pathogenicity of the factor H autoantibodies in some of these diseases cannot be drawn yet. Importantly, understanding the binding and functional impact of anti-factor H (auto)antibodies will allow targeted interventions to diminish pathological consequences of anti-factor H autoantibodies but may also open up additional avenues for the use of anti-factor H antibodies as therapeutic agents.
Connecting the dots: Mitochondrial transfer in immunity, inflammation, and cancer.
Artusa V, De Luca L, Clerici M … +1 more , Trabattoni D
Immunol Lett · 2025 Aug · PMID 40054017 · Publisher ↗
Mitochondria are more than mere energy generators; they are multifaceted organelles that integrate metabolic, signalling, and immune functions, making them indispensable players in maintaining cellular and systemic healt...
Mitochondria are more than mere energy generators; they are multifaceted organelles that integrate metabolic, signalling, and immune functions, making them indispensable players in maintaining cellular and systemic health. Mitochondrial transfer has recently garnered attention due to its potential role in several physiological and pathological processes. This process involves multiple mechanisms by which mitochondria, along with mitochondrial DNA and other components, are exchanged between cells. In this review, we examine the critical roles of mitochondrial transfer in health and disease, focusing on its impact on immune cell function, the resolution of inflammation, tissue repair, and regeneration. Additionally, we explore its implications in viral infections and cancer progression. We also provide insights into emerging therapeutic applications, emphasizing its potential to address unmet clinical needs.
The regulatory effect and molecular mechanism of Epstein-Barr virus protein LMP-1 in SLE susceptibility gene expression.
Zhang X, Hu S, Luo P … +6 more , Li Z, Chen Z, Xia C, Fan L, Li R, Chen H
Immunol Lett · 2025 Jun · PMID 40023262 · Publisher ↗
The development of systemic lupus erythematosus (SLE) involves both genetic and environmental factors. Epstein-Barr virus (EBV) infection has been implicated in SLE pathogenesis, particularly through the activity of late...
The development of systemic lupus erythematosus (SLE) involves both genetic and environmental factors. Epstein-Barr virus (EBV) infection has been implicated in SLE pathogenesis, particularly through the activity of latent membrane protein 1 (LMP-1). This study aimed to explore the role of LMP-1 in regulating susceptibility gene expression in SLE. Peripheral blood mononuclear cells (PBMCs) from SLE patients and H9 T cells were used to investigate this mechanism both in vivo and in vitro. RNA-seq analysis revealed that LMP-1 and the SLE susceptibility gene AT-rich interactive domain 5B (ARID5B) were significantly upregulated in SLE. Overexpression of LMP-1 in H9 T cells further increased ARID5B expression. Histone H3K27 methylation, catalyzed by enhancer of zeste homolog 2 (EZH2), was significantly elevated, suggesting epigenetic modifications play a role in this regulation. H3K27 methylation was studied due to its known involvement in transcriptional repression and chromatin remodeling in autoimmune diseases. Furthermore, phosphorylated p65 (p-p65), a marker of nuclear factor-kappa-B (NF-κB) pathway activation, was increased. Blocking the NF-κB signaling pathway reduced ARID5B expression, indicating that LMP-1 may regulate susceptibility genes through NF-κB signaling and histone modifications. These findings suggest that EBV LMP-1 contributes to SLE pathogenesis by epigenetically modulating susceptibility gene expression and activating inflammatory pathways.
SLAMF8 regulates Fc receptor-mediated phagocytosis in mouse macrophage cells through PI3K-Akt signaling.
Liu Z, Hu J, Han X … +8 more , Li L, Niu H, Zhang X, Wang N, Shi X, Sang L, Zhang Q, Qian X
Immunol Lett · 2025 Jun · PMID 39983459 · Publisher ↗
Emerging studies have demonstrated that phagocytosis checkpoints, which promote tumor-mediated immune evasion, are potential targets for cancer immunotherapy. In this study, the TCGA colorectal cancer (CRC) dataset and o...
Emerging studies have demonstrated that phagocytosis checkpoints, which promote tumor-mediated immune evasion, are potential targets for cancer immunotherapy. In this study, the TCGA colorectal cancer (CRC) dataset and our RNA sequencing dataset suggested that SLAMF8 expression is significantly positively correlated with the expression levels of multiple phagocytosis checkpoint molecules. In vitro, we confirmed that SLAMF8 significantly regulated the phagocytosis of mouse CRC cells. RNA sequencing revealed that the expression of genes that promote Fc receptor (FcR)-mediated phagocytosis, such as FCGR1, FCGR3, FCGR2b, FCGR4, and ITGAM, was significantly upregulated after SLAMF8 knockdown. The Kyoto Encyclopedia of Genes and Genomes (KEGG) results suggested that the significantly enriched signaling pathways after SLAMF8 knockdown or overexpression included the PI3K-Akt signaling pathway. The protein expression levels of p-PI3K and p-Akt were significantly increased after SLAMF8 knockdown. When PI3K inhibitors and Fc blockers were added after SLAMF8 knockdown, mouse macrophage phagocytosis, and FcR expression decreased. Our results suggest that SLAMF8 may impair FcR-mediated phagocytosis through the PI3K-Akt signaling pathway and negatively regulate the antitumor immune response.
Neutrophil extracellular traps and reactive oxygen species: Predictors of prognosis in bladder cancer.
Mansourabadi Z, Assarehzadegan MA, Mehdipour F … +3 more , Ariafar A, Faghih Z, Safari E
Immunol Lett · 2025 Jun · PMID 39971199 · Publisher ↗
Neutrophils, the most abundant leukocytes in circulation, have become the subject of intensive research due to growing evidence of their role as modulators of cancer with both anti- and pro-tumorigenic effects. However,...
Neutrophils, the most abundant leukocytes in circulation, have become the subject of intensive research due to growing evidence of their role as modulators of cancer with both anti- and pro-tumorigenic effects. However, their prognostic function related to the release of neutrophil extracellular traps (NETs) and production of reactive oxygen species (ROS) has not yet been elucidated in the context of bladder cancer (BC). This study aimed to evaluate the ability of circulating neutrophils from BC patients to undergo NETosis and produce ROS-both spontaneously and following activation with phorbol 12-myristate 13-acetate (PMA)-using flow cytometry and immunofluorescence techniques. Their relevance to clinicopathological characteristics was also evaluated. Our results showed that PMA-treated neutrophils had increased early NETosis in patients with stage II (P = 0.048) and T2 (P = 0.014) compared to those with stage III and T3, respectively. These cells also showed a significant increase in ROS production in patients with T2 compared to those with T3 (P = 0.026) and T4 (P = 0.014), as well as in patients with stage II compared to stage IV (P = 0.048). Additionally, spontaneous ROS production was higher in patients without lymphovascular invasion than in those with invasion (P = 0.013). The increased activity of neutrophils observed in earlier stages (stage II and T2) suggests a potential protective mechanism in the early phases of cancer progression. It also highlights NETosis and ROS production by neutrophils as possible biomarkers for assessing disease progression. These findings provide insights into the complex interactions of neutrophils within the tumor microenvironment and lay the groundwork for further investigations into targeted therapies, potentially improving prognostic evaluations and treatment outcomes for patients.
Nobiletin ameliorates monosodium urate-induced gouty arthritis in mice by enhancing AMPK/mTOR-mediated autophagy to inhibit NF-κB/NLRP3 inflammasome activation.
Liu Z, Chu A, Bai Z … +1 more , Yang C
Immunol Lett · 2025 Aug · PMID 39965668 · Publisher ↗
BACKGROUND: Gouty arthritis (GA) is a common rheumatic disease caused by the release of monosodium urate crystal (MSU) deposits into joint space. Nobiletin is a polymethoxylated flavonoid isolated from citrus fruits and...
BACKGROUND: Gouty arthritis (GA) is a common rheumatic disease caused by the release of monosodium urate crystal (MSU) deposits into joint space. Nobiletin is a polymethoxylated flavonoid isolated from citrus fruits and has many beneficial activities. This study aimed to elucidate the therapeutic efficacy of nobiletin in GA and to reveal its potential mechanisms. METHODS: Phorbol-12-myristate-13-acetate (PMA)-differentiated THP-1 macrophages were primed with lipopolysaccharide (LPS) and then stimulated with MSU crystals in the presence or absence of nobiletin. Cell viability as well as the levels of proinflammatory cytokines, pathway-related proteins, NLRP3 inflammasomes, and autophagy-related proteins were evaluated. MSU was used to induce GA in mice. Hematoxylin-eosin staining was conducted to assess histological morphology changes. Immunofluorescence staining was performed to measure LC3 expression in THP-1 cells and ankle joint tissues. RESULTS: For in vitro analysis, nobiletin reduced LPS and MSU-induced cell viability inhibition. Additionally, nobiletin inhibited inflammation and NF-κB/NLRP3 pathway in THP-1 cells. Moreover, nobiletin inhibited the activation of NLRP3 inflammasome by promoting AMPK/mTOR-mediated autophagy. For in vivo analysis, nobiletin attenuated MSU-induced GA in mice. Additionally, nobiletin suppressed inflammation and NF-κB/NLRP3 pathway and promoted tissue autophagy in GA mice. CONCLUSION: Nobiletin prevents MSU-induced GA in mice by inhibiting NF-κB/NLRP3 inflammasome activation through AMPK/mTOR-mediated autophagy.
USP7 - A novel target for controlling periodontal inflammation through modulation of macrophage polarization.
Wang Y, Mu H, Yang B … +3 more , Yang C, Dong W, Wang J
Immunol Lett · 2025 Jun · PMID 39946796 · Publisher ↗
Disruption of local microbial irritation and host immune response can result in inflammation and tissue destruction in periodontitis. Studies on the modulation of macrophage polarization could help attenuate immune respo...
Disruption of local microbial irritation and host immune response can result in inflammation and tissue destruction in periodontitis. Studies on the modulation of macrophage polarization could help attenuate immune responses in periodontal tissues. To investigate the effect of ubiquitin-specific protease-7 (USP7) and its inhibitor P5091 on the polarization of macrophages in periodontitis, gene expression in periodontitis tissues and normal control were analyzed via single-cell RNA sequencing data and mice model experimental periodontitis. RAW264.7 cells were induced to M1 polarization with LPS + IFN-γ and M2 polarization with IL-4. USP7 was knocked down using lentivirus, and the effect of USP7 inhibitor P5091 on macrophage polarization was comparatively analyzed. The expression of Usp7 and polarization markers were detected by qRT-PCR. Western blot was used to examine the polarization markers and pathway-associated proteins. Results indicated that USP7 expression was elevated in tissues affected by periodontitis. Periodontitis macrophages and M1 polarized macrophages had higher USP7 expression. Knockdown of USP7 revealed an inhibition of both M1 and M2 macrophage polarization. Inhibition of USP7 with P5091 resulted in the decreased expression of M1 polarization markers and phosphorylation of P65, but the increased expression of M2 polarization markers and phosphorylation of STAT6. In conclusion, USP7 is involved in regulating macrophage polarization in periodontitis and its inhibitor P5091 may contribute to the prevention of periodontitis.
Efficacy and safety of efgartigimod in patients with neurological autoimmune diseases.
Qin J, Li W, Yuan L … +3 more , Liu H, Pang R, Zhang J
Immunol Lett · 2025 Jun · PMID 39938695 · Publisher ↗
OBJECTIVE: Myasthenia gravis (MG) is an autoimmune disease characterized by disrupted neuromuscular synaptic transmission. Efgartigimod, a human Fc receptor antagonist, has been approved for patients with MG. Its potenti...
OBJECTIVE: Myasthenia gravis (MG) is an autoimmune disease characterized by disrupted neuromuscular synaptic transmission. Efgartigimod, a human Fc receptor antagonist, has been approved for patients with MG. Its potential use for other IgG-mediated neurological autoimmune diseases is unclear. This study aimed to retrospectively evaluate the efficacy and safety of efgartigimod in patients with neurological autoimmune diseases. METHODS: This retrospective study investigated patients with neurological autoimmune diseases who were treated with efgartigimod in the Henan Provincial People's Hospital. The efficacy of the medication was analyzed using the quality-of-life improvement score and the IgG level pre- and post-efgartigimod treatment. The safety of the medication was assessed by considering adverse events and blood parameters. The blood parameters, including routine blood parameters, coagulation, liver, kidney, and immune function. RESULTS: Seventeen patients received efgartigimod in the Henan Provincial People's Hospital from September 1, 2023, to January 31, 2024. In MG patients, myasthenia gravis activities of daily living (MG-ADL) reduced after efgartigimod treatment for 4 weeks compared with baseline (P < 0.05). Autoimmune encephalitis (AE) is a group of inflammatory disease with antibodies against neuronal synaptic and cell surface antigens. Similarly, patients with AE had a statistically significant reduction in modified Rankin scale (mRS) after efgartigimod treatment for 4 weeks compared with baseline (P < 0.05). Guillain Barre syndrome (GBS) is an immune-mediated disease of the peripheral nerves and nerve roots. However, the inflammatory neuropathy cause and treatment (INCAT) scale score didn't statistically differ in GBS patients before and after efgartigimod treatment (P > 0.05). The IgG levels significantly reduced after the first infusion and gradually decreased after multiple infusions (P < 0.05). Most subjects did not have increased IgG serum levels before treatment. IgA, IgM, and complement levels didn't differ significantly with efgartigimod treatment (P > 0.05). There were no changes in blood parameters during the treatment (P > 0.05). CONCLUSIONS: Efgartigimod was effective and safe in neurological IgG-mediated autoimmune diseases, even in patients without increased IgG serum levels.
Systemic and cerebrospinal fluid immune mediators coordinate a dichotomic microenvironment in parturients with acute or convalescent phases of COVID-19.
Sasaki LMP, Canellas-de-Castro ME, Fernandes GM … +33 more , Motta F, Araújo Júnior DA, Schulte HL, Jardim-Santos GP, Silva ÂP, Carvalho AO, Pereira YR, Siracusa CC, Rabelo IP, Santos Junior ACM, Alves CO, Lauand L, Nery RR, Mendonça-Silva DL, Tristão R, Jesus JAL, Costa KN, Castro LCG, Kurizky PS, Nóbrega OT, Espindola LS, Coelho-Dos-Reis JGA, Brito-de-Sousa JP, Costa-Rocha IA, Campi-Azevedo AC, Peruhype-Magalhães V, Teixeira-Carvalho A, Gomes CM, Albuquerque CP, Soares AASM, Zaconeta AM, Martins-Filho OA, Mota LMH
Immunol Lett · 2025 Aug · PMID 39933603 · Publisher ↗
The present study intended to characterize the profile of soluble immune mediators in serum samples and in the cerebrospinal fluid (CSF) microenvironment from parturients with acute and convalescent COVID-19 as compared...
The present study intended to characterize the profile of soluble immune mediators in serum samples and in the cerebrospinal fluid (CSF) microenvironment from parturients with acute and convalescent COVID-19 as compared to healthy controls (HC), during the circulation of B.1.1.28 and B.1.1.33 SARS-CoV-2 strains, which were identified during the initial spread of COVID-19 in Brazil. Data demonstrated increased levels of immune mediators in serum at acute infection with a clear waning during convalescent COVID-19. Conversely, a progressive increase of immune mediators was observed in CSF from acute infection towards convalescent COVID-19. Immune mediator signatures and integrative correlation circuits further confirmed these findings and supported the existence of dichotomic microenvironments in the serum and CSF compartments. While a waning of correlations involving pro-inflammatory cytokines with increased connectivity of regulatory cytokines was observed in serum samples from acute towards convalescent COVID-19, an increasing frequency of correlations mediated by pro-inflammatory cytokines with decreased connectivity of regulatory cytokine was the hallmark of CSF. Correlations analysis identified a set of molecules associated with the dichotomic crosstalk between serum and CSF compartments, including chemokines (CXCL8, CCL5, CXCL10) and regulatory cytokines (IL-4 and IL-9). These immune biomarkers may represent potential targets for therapeutic strategies in parturients with COVID-19. Together, these findings demonstrated the existence of a divergent landscape of soluble immune mediators in serum and CSF, emphasizing the relevance of understanding the systemic and compartmentalized immune response elicited by SARS-CoV-2 infection during pregnancy.
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