Noack M, Bailly M, Durix L
… +2 more, Pin JJ, Miossec P
Clin Exp Immunol
· 2025 Jan · PMID 40719067
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INTRODUCTION: Stromal-immune cell interactions promote pro-inflammatory cytokine secretion such as IL-17. IL-17 is involved in several chronic inflammatory diseases, affecting joints and skin. Podoplanin has been already...INTRODUCTION: Stromal-immune cell interactions promote pro-inflammatory cytokine secretion such as IL-17. IL-17 is involved in several chronic inflammatory diseases, affecting joints and skin. Podoplanin has been already identified as partially involved in high IL-17 secretion resulting from these cell interactions. METHODS: The aim of this study was to identify new molecules, using co-cultures of activated peripheral blood mononuclear cells and synoviocytes (5:1 ratio). Cell interactions were critical to induce a high IL-17 production. The blockade of podoplanin inhibited this production, approximately 40%, confirming the contribution of other molecules. A battery of mouse monoclonal anti-human RA synoviocyte antibodies were tested in co-cultures and several were selected for their inhibitory effect on IL-17. RESULTS: Cloning by expression allowed identifying the target of the selected 8350 antibody, a truncated isoform of CD74. CD74 blockade in co-cultures by 8350 antibody and a commercial antibody inhibited IL-17 production by 40%, but 8350 antibody had a limited effect on IL-10 inhibition. Furthermore, cell interactions increased CD74 expression, at mRNA and protein levels. CONCLUSION: This study identified truncated CD74 isoform as a novel molecule directly involved in high IL-17 secretion resulting from cell interactions. Inhibition of this truncated CD74 could represent a new therapeutic option for diseases with IL-17 involvement.
Tamaru T, Katayama R, Momokino J
… +7 more, Maruoka Y, Ueda A, Kanegane H, Wada T, Bukhari STA, Banday AZ, Akagi T
Clin Exp Immunol
· 2025 Jan · PMID 40581342
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INTRODUCTION: Specific granule deficiency (SGD)-a rare innate immune disorder-is classified into types 1 and 2 (SGD-1 and -2). SGD-1 is caused by variants of the CCAAT/enhancer-binding protein epsilon (C/EBPε) gene. METH...INTRODUCTION: Specific granule deficiency (SGD)-a rare innate immune disorder-is classified into types 1 and 2 (SGD-1 and -2). SGD-1 is caused by variants of the CCAAT/enhancer-binding protein epsilon (C/EBPε) gene. METHODS: We assessed the molecular mechanisms underlying C/EBPε dysfunction in SGD-1, caused by the frameshift variant (c.655_665del; del11) that we previously reported. We compared the functions of del11 with those of the previously reported p.Arg247_Ser248del (ΔRS) variant and wild-type (WT) C/EBPε. RESULTS: Forced expression in embryonic stem cells revealed that both the del11 and ΔRS variants inhibited C/EBPε-mediated target gene induction, indicating a loss of transcriptional activity. In NIH3T3 cells, WT and ΔRS C/EBPε were localized to the nucleus, whereas del11 C/EBPε showed cytoplasmic retention and induced morphological changes in expressing cells. Protein-protein interaction analyses demonstrated that both mutants failed to interact with the transcription factors GATA-binding protein 1 and purine-rich box-1. DNA-binding assays revealed that del11 C/EBPε completely lost its ability to bind to target DNA sequences, whereas WT and ΔRS C/EBPε retained binding capacity. Thus, del11 disrupts multiple C/EBPε functions, including nuclear localization, DNA-binding, and protein interactions. CONCLUSION: Based on these functional differences, we propose a novel classification of SGD-1 into types 1a and 1b (SGD-1a and -1b). Patients with SGD-1b,-associated with nonsense and frameshift variants, such as del11,-exhibit more severe clinical phenotypes than those with SGD-1a,-associated with missense variants and in-frame deletions. This study offers novel insights into the pathogenesis of SGD and genotype-phenotype correlations, potentially informing the development of future therapeutic strategies.
Aziz S, Pellegrino R, Buono P
… +9 more, Creoli M, Torre D, Chiantese C, Colucci A, Casertano M, Ciamarra P, Federico A, Gravina AG, Strisciuglio C
Clin Exp Immunol
· 2025 Jan · PMID 40581073
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Eosinophilic Esophagitis (EoE) is a chronic disease primarily driven by immune-mediated pathogenesis, characterized by eosinophil-driven inflammation of the oesophagus, leading to organ dysfunction and fibrosis. Although...Eosinophilic Esophagitis (EoE) is a chronic disease primarily driven by immune-mediated pathogenesis, characterized by eosinophil-driven inflammation of the oesophagus, leading to organ dysfunction and fibrosis. Although initially considered a rare disorder, EoE is now recognized as one of the leading causes of food impaction and dysphagia. Advances in knowledge and diagnostic techniques have contributed to its increased detection; however, epidemiologic data suggest that the surge in incidence represents an actual rise in disease prevalence rather than solely increased awareness. The pathogenesis of EoE remains largely unclear, but it is believed to involve a complex interplay of genetic predisposition, environmental factors, diet-derived allergens, and immune dysregulation. A significant role in the pathogenesis of EoE is attributed to environmental and, particularly, food allergens, with mechanisms that extend beyond IgE-mediated pathways, as evidenced by the lack of efficacy of anti-IgE therapies such as omalizumab in clinical trials. A key pathogenic feature is the dysregulated activation of pathways mediated by T-helper type 2 (Th2) lymphocytes. Supporting the role of the Th2 system in EoE inflammation is the demonstrated efficacy of monoclonal inhibitors of interleukin 4 and 13 (i.e. dupilumab), currently the only approved biological therapy for this condition. Additionally, the role of autophagic processes in EoE pathogenesis is becoming increasingly evident. This review aims to provide a concise overview of the key pathogenic mechanisms of EoE and the currently available diagnostic approaches, both invasive and non-invasive, for managing this disorder.
O'Byrne AM, Grasso C, de Winde CM
… +8 more, Mikula AM, Gago da Graça C, Semmelink JF, Remmerswaal EBM, Bolt JW, van de Sande MGH, Mebius RE, van Baarsen LGM
INTRODUCTION: Murine studies have demonstrated that lymph node fibroblasts can present self-antigens via major histocompatibility complex class II molecules, inducing functional regulatory T cells and contributing to per...INTRODUCTION: Murine studies have demonstrated that lymph node fibroblasts can present self-antigens via major histocompatibility complex class II molecules, inducing functional regulatory T cells and contributing to peripheral tolerance. METHODS: To investigate this phenomenon in humans, we developed an in vitro system co-culturing human lymph node fibroblasts with autologous CD4+ T cells. RESULTS: Our results reveal that lymph node fibroblasts upregulate human leukocyte antigen-DR (HLA-DR) upon contact with CD4+ T cells and maintain FoxP3+ regulatory T cells. This maintenance is lost upon blockade of HLA-DR or interleukin-2, and regulatory T cells are lost in the absence of lymph node fibroblasts. Furthermore, we demonstrate that lymph node fibroblasts directly isolated from rheumatoid arthritis patients exhibit a significant reduction in the frequency of HLA-DR+ cells compared to those from individuals at risk of developing the disease. CONCLUSION: These findings highlight a crucial role for HLA-DR-expressing lymph node fibroblasts in maintaining peripheral tolerance within lymph nodes, a function that may be impaired in autoimmunity. Our study provides novel insights into the intricate cellular interactions within human lymph nodes and their potential implications in autoimmune disorders, opening new avenues for understanding and potentially treating these conditions.
Heather JM, Kim DW, Sepulveda SM
… +5 more, van Seventer EE, Fish MG, Corcoran R, Hong TS, Cobbold M
Clin Exp Immunol
· 2025 Jan · PMID 40574667
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BACKGROUND: Radiation therapy has long been a cornerstone of cancer treatment. More recently, immune checkpoint blockade has also been applied across a variety of cancers, often leading to remarkable response rates. Howe...BACKGROUND: Radiation therapy has long been a cornerstone of cancer treatment. More recently, immune checkpoint blockade has also been applied across a variety of cancers, often leading to remarkable response rates. However, photon-based radiotherapy-which accounts for the vast majority-is also known to frequently induce profound lymphopenia, which might limit the efficacy of immune system-based combinations. Proton beam therapy is known to produce a less drastic lymphopenia, which raises the possibility of greater synergy with immunotherapy. In this study, we aimed to explore the exact nature of the differential impact of the two radiation modalities upon the immune system. METHODS: We used multiparametric flow cytometry and deep sequencing of rearranged TCRb loci to investigate a cohort of 20 patients with gastrointestinal tumors who received either therapy and developed lymphopenia. RESULTS: Proton-treated patients remained relatively stable throughout treatment by most metrics considered, whereas those who received photons saw a profound depletion in naïve T cells, an increase in effector/memory populations, and a loss of TCR diversity. The repertoires of photon-treated patients underwent an oligoclonal expansion after their lymphocyte count nadirs, particularly of CD8+ Temra cells, driving this reduction in diversity. Across the entire cohort, this reduction in post-nadir diversity is inversely correlated with the overall survival time of those patients who died. CONCLUSION: This raises the possibility that increased adoption of proton-based or other lymphocyte-sparing radiotherapy regimes may lead to better survival in cancer patients.
Clin Exp Immunol
· 2025 Jan · PMID 40554686
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Myasthenia gravis (MG) is an autoimmune disease commonly associated with immune disorders in thymoma. The role of thymus myoid cells (TMCs) in the pathogenesis of autoimmune diseases has attracted much attention. Therefo...Myasthenia gravis (MG) is an autoimmune disease commonly associated with immune disorders in thymoma. The role of thymus myoid cells (TMCs) in the pathogenesis of autoimmune diseases has attracted much attention. Therefore, the present study was designed to reveal the impact of TMCs on the pathophysiology of tumor-associated MG (TAMG). This study included clinical patients and healthy volunteers and validated the potential role of TMCs in TAMG progression using a TMCs-deficient mouse model. Correlative findings showed that TMCs deletion affected thymic architecture in MG patients, as evidenced by the expression of key myogenic factors as well as AChR and RyRs receptors in the thymus. Further experimental validation showed that TMCs deletion increased the levels of Th1 and Th17 cells, decreased the levels of Th2 and Treg cells, and altered the secretion of corresponding cytokines, including IL-2, IL-4, IL-17, IL-22, and TGF-β concentrations. Co-culture of CD4+ T cells with Thy0517 cells or CD4+ T cells with a myoblastoid cell line using the Transwell system demonstrated that deletion of TMC inhibited the differentiation of CD4+ T cells to Treg cells. In this study, we hypothesized that TMCs are involved in TAMG progression by regulating CD4+ T cell differentiation.
Zhu G, Yue H, He J
… +17 more, Wang C, Xu C, Jia C, Wang X, Yan Y, Wang B, Zhang H, Chen X, Qiu J, Gao L, Zheng J, Lv G, Yang J, Luo Y, Qin M, Gui J, Mou W
Clin Exp Immunol
· 2025 Jan · PMID 40531141
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Leukocyte adhesion deficiency I (LAD-I) is an autosomal recessive immunodeficiency caused by mutations in the ITGB2 gene, characterized by recurrent severe infections, impaired pus formation, and delayed wound healing. I...Leukocyte adhesion deficiency I (LAD-I) is an autosomal recessive immunodeficiency caused by mutations in the ITGB2 gene, characterized by recurrent severe infections, impaired pus formation, and delayed wound healing. In this study, we describe a late-onset presentation of LAD-I in a 22-year-old male who initially exhibited marked leukocytosis and neonatal omphalitis, followed by recurrent upper respiratory tract infections from 9 months of age. At age 13, the patient developed abdominal and left iliac fossa abscesses, which progressed to a vesicocutaneous fistula after a prolonged febrile episode. Extended catheterization and antibiotic treatment led to the formation of characteristic tin foil-like scarring. Recurrent purulent skin and soft tissue infections led to widespread scarring and pigmentary changes. Next-generation sequencing (NGS) identified a novel homozygous splice-site mutation in ITGB2 (NM_000211.5, c.1225-1G > A, IVS10-1G > A). In silico analysis predicted disruption of the acceptor site, while a minigene assay demonstrated two aberrant splicing events, namely a 12-bp deletion and complete skipping of exon 11 (188 bp). Flow cytometry analysis at age 13 showed CD18 expression reduced to less than 1% across granulocytes, monocytes, and lymphocytes, with concomitant decreases in β2-integrin α subunits (CD11a, CD11b, and CD11c). At 15 years of age, the patient underwent hematopoietic stem cell transplantation (HSCT) from a fully HLA-matched (10/10) heterozygous sister donor following a modified myeloablative conditioning regimen. Although initial chimerism fluctuated, full donor chimerism was ultimately achieved, restoring CD18 expression and normalizing ɑ-integrin levels. This study highlights the therapeutic efficacy of HSCT in correcting the molecular defects associated with LAD-I.
van Linge CCA, Michels EHA, Pereverzeva L
… +10 more, de Beer R, Klarenbeek AM, Schomakers BV, van Weeghel M, Houtkooper RH, Wiersinga WJ, Bonta PI, Annema JT, van der Poll T, de Vos AF
Clin Exp Immunol
· 2025 Jan · PMID 40515396
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INTRODUCTION: Alveolar macrophages (AMs) play an essential role in maintaining homeostasis in the lung and in innate immunity for host defense. To fuel inflammatory responses, AMs do not rely on glycolysis, but require o...INTRODUCTION: Alveolar macrophages (AMs) play an essential role in maintaining homeostasis in the lung and in innate immunity for host defense. To fuel inflammatory responses, AMs do not rely on glycolysis, but require oxidative phosphorylation. However, which nutrients AMs use to fuel their energy demand during inflammatory responses, is still unknown. The present study aimed to determine the contribution of three key metabolic pathways; fatty acid oxidation, glutaminolysis, and glycogenolysis, to the inflammatory response of AMs. METHODS: Primary AMs were isolated from healthy human volunteers and stimulated with lipopolysaccharide (LPS). After 24 hours, cells were subjected to analyses of metabolic flux, expression of genes involved in these metabolic pathways, and inflammatory cytokine secretion in the presence of metabolic inhibitors. RESULTS: The results of our study show that human AMs display expression of genes involved in fatty acid and glutamine metabolism and are capable of metabolizing oleic acid and glutamine during homeostasis, but do not use these metabolites to fuel the production of inflammatory cytokines. We demonstrate that AMs, while residing in a glucose-deprived environment, contain glycogen and use glycogenolysis to fuel inflammatory cytokine secretion, as reflected by reduced TNF, IL-1β and IL-6 levels in supernatant of LPS-stimulated AMs treated with the glycogenolysis inhibitor CP316819. Moreover, AMs display marked expression of genes involved in glycogenesis, including FBP1 and GYS. CONCLUSIONS: Taken together, these results indicate that primary human AMs are equipped to use different nutrients to fuel their metabolic demands. Moreover, our findings suggest that glycogenolysis is critical for the inflammatory response of AMs.
Schiffmann S, Henke M, Weber F
… +1 more, Parnham MJ
Clin Exp Immunol
· 2025 Jan · PMID 40512144
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Spindlin-1, a multivalent epigenetic reader, is a new target for cancer therapy. Beside the anticancer effect, modulation of the recognition of methyl marks of histones may impact the immune system, which plays an import...Spindlin-1, a multivalent epigenetic reader, is a new target for cancer therapy. Beside the anticancer effect, modulation of the recognition of methyl marks of histones may impact the immune system, which plays an important role in the anticancer strategy of the human organism. Two Spindlin-1 inhibitors (A366, MS31) were characterized to differentiate between drug and target-specific effects. We performed a comprehensive study regarding the influence of Spindlin-1 inhibition on various immune cells. A366 and MS31 showed immune cell type-dependent cytotoxicity with IC50 values in the ranges of 37-143 µM and 11-3122 µM, respectively, macrophages tending to be less susceptible than lymphocytes. A366 had only minor effects on M1 polarization, whereas MS31 shifted the M1 to a M2 phenotype, as shown by regulated cytokines and surface marker expression. Both A366 and MS31 weakened the polarization of predifferentiated M2 macrophages by reducing surface marker expression, cytokines, and inflammatory markers. A366 and MS31 had no effect on activation and energy metabolism of CD4+ T cells. Interestingly, 5 µM A366 and 2.5 µM MS31 clearly prevented B cell activation, as shown by reduced proliferation, plasmablast formation, and release of immunoglobulins A and G. Additionally, A366 increased energy metabolism in B cells. In conclusion, the inhibition of Spindlin-1 had only minor effects on polarization of macrophages and T cell proliferation but profoundly prevented B cell activation at low concentrations. This suggests that Spindlin-1 inhibitors, while mediating anticancerogenic effects, may also suppress the humoral immune response and increase infection risk.
Colombo SAP, Gago S, Chamula M
… +3 more, Lord R, MacDonald AS, Kosmidis C
Clin Exp Immunol
· 2025 Jan · PMID 40503945
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BACKGROUND: Growing evidence links immune dysfunction, notably impaired IFNγ production, to chronic pulmonary aspergillosis (CPA), but understanding of the immune phenotype in CPA patients remains limited. METHODS: To in...BACKGROUND: Growing evidence links immune dysfunction, notably impaired IFNγ production, to chronic pulmonary aspergillosis (CPA), but understanding of the immune phenotype in CPA patients remains limited. METHODS: To investigate this, we recruited 25 CPA patients and 25 controls with bronchiectasis, isolating immune cells from peripheral blood for detailed flow cytometric phenotyping at resting state and after ex vivo stimulation with the TLR2/Dectin-1 agonist Zymosan. RESULTS: CPA patients exhibited pronounced neutrophilia and a reduced frequency of conventional dendritic cell (DC) subsets at baseline compared to bronchiectasis controls. Post-stimulation, DC and monocyte subsets in CPA patients showed significantly lower expression of activation markers. Notably, cDC1s displayed reduced IL-12p40, TNFα, and CD86 expression. CPA patients with a history of tuberculosis (TB) had significantly higher frequencies of activated cDC1s. Machine learning analysis validated these immunological parameters as predictive of CPA status. CONCLUSION: Our findings suggest that immune dysfunction in CPA involves DC and monocyte impairments, potentially contributing to IFNγ deficiency through reduced IL-12 production and co-stimulatory capacity in cDC1s. These results also hint at the presence of innate immune memory in CPA patients with prior TB. Our study advances understanding of the immune dysfunction underlying CPA.
Trattner R, Iordanou M, Ohlsson S
… +3 more, Martin M, Segelmark M, Blom AM
Clin Exp Immunol
· 2025 Jan · PMID 40440129
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BACKGROUND: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of rare, autoimmune diseases causing inflammation in the vessel wall. Many organs can be affected, and kidney involvement is...BACKGROUND: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of rare, autoimmune diseases causing inflammation in the vessel wall. Many organs can be affected, and kidney involvement is a common and serious manifestation. Complement activation is important in disease development and has also been detected in patients in remission. The reason for increased complement activation also without active disease is not understood. METHODS: In this study, 65 AAV patients in remission, contributing with a total of 147 plasma samples, were included. Biomarkers of complement activation such as C4d (classical and lectin pathways), C3bBbP (alternative pathway), and soluble terminal complement complex (sTCC) (common terminal pathway) were measured with ELISA. For C4d measurement, an improved assay with an antibody targeting a cleavage neoepitope solely exposed during complement activation was used. RESULTS: Our first hypothesis was that patients prone to recurrent flares might have an increased complement activation even when beeing in remission. However, we found no significant difference between those who did and did not develop flares during follow-up, nor any correlation between the total number of flares and any of the complement biomarkers. Interestingly, higher sTCC levels in remission correlated significantly to kidney involvement at the time of diagnosis and plasma creatinine levels at the time of sampling. Also, the diagnosis of microscopic polyangiitis (MPA), compared to granulomatosis with polyangiitis (GPA), yielded higher sTCC levels, and plasma C-reactive protein levels correlated significantly to sTCC. CONCLUSION: These findings suggest that persistent complement activation during remission in AAV may reflect underlying disease severity and organ involvement rather than predicting future flares.
Clin Exp Immunol
· 2025 Jan · PMID 40435290
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Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome characterized by an aberrant immune response against host tissues. It can arise from diverse triggers like infection, inflammation, malignan...Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome characterized by an aberrant immune response against host tissues. It can arise from diverse triggers like infection, inflammation, malignancy, genetic defects, or therapy-related factors. Cytokine storm, capillary leak syndrome, cytokine release syndrome, and macrophage activation syndrome are the different faces of this chimera, and each of them displays significant clinical variability associated with high mortality. The pathogenesis of both primary and secondary HLH generally follows a similar pattern, involving excessive activation of macrophages and uncontrolled destruction of reticuloendothelial tissues. Environmental triggers cause exaggerated activation of innate immune cells in genetically predisposed individuals. This process is further driven by the release of multiple cytokines and soluble mediators that sustain ongoing inflammation and cause subsequent target organ damage. Biomarkers, including cytokines and inflammatory mediators, are crucial for early detection and monitoring treatment response. Persistent immune activation and inadequate resolution mechanisms result in a destructive inflammatory cascade or "immunological massacre". Animal models of HLH and MAS elucidate the roles of impaired cytotoxicity, IFN-γ, TLR signaling, and inflammatory cytokines in disease pathogenesis. Trigger-specific differences highlight the involvement of CD8+ T cells, NK cells, macrophages, and cytokines. Therapeutic strategies include cytokine neutralization, adoptive T-cell transfer, and mTOR inhibition. Timely diagnosis and prompt initiation of therapy are essential to mitigate the serious consequences of HLH and improve long-term outcomes.
Chowdhury K, Kumar U, Chaudhuri J
… +8 more, Kumar P, Das S, Kanjilal M, Ghosh P, Basyal RK, Kanga U, Bandyopadhaya S, Mitra DK
Clin Exp Immunol
· 2025 Jan · PMID 40434878
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BACKGROUND: Despite their synovial enrichment, regulatory T cells (Treg) fail to alleviate the joint inflammation in rheumatoid arthritis (RA). This indicates their functional impairment in the synovial milieu of RA pati...BACKGROUND: Despite their synovial enrichment, regulatory T cells (Treg) fail to alleviate the joint inflammation in rheumatoid arthritis (RA). This indicates their functional impairment in the synovial milieu of RA patients. RESULTS: Here, we demonstrate that a deficit in the PD-1 pathway incapacitates the synovial Treg cells, and engaging programmed cell death protein-1 (PD-1) restores their suppressive function (interleukin 10, transforming growth factor beta secretion), which in turn suppresses the synovial inflammatory T cells (IFN-γ+, IL-17+ TNF-α+). We also showed that a deficit in programmed death ligand-1 expression on RA synovial macrophages contributes to impaired Treg cell function. CONCLUSION: Rejuvenating synovial Treg cell function via PD-1 engagement may be a potential strategy to ameliorate the synovial inflammation in RA patients.
Clin Exp Immunol
· 2025 Jan · PMID 40397507
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The human response to vaccination exhibits considerable variability due to a complex interplay of heritable and environmental factors. This review examines the current understanding of the role of human genetics in vacci...The human response to vaccination exhibits considerable variability due to a complex interplay of heritable and environmental factors. This review examines the current understanding of the role of human genetics in vaccine responses, encompassing both rare adverse events following immunization as well as immunogenicity and efficacy. We highlight recent studies including from the coronavirus disease 2019 (COVID-19) pandemic, which provided a unique opportunity to study vaccine genetics at scale for a newly emerging infection and revealed significant associations between HLA alleles and responses to SARS-CoV-2 vaccines. Understanding genetic contributions to vaccine responses holds promise for enhancing vaccine safety and efficacy, and the development of personalized vaccination strategies.
Clin Exp Immunol
· 2025 Jan · PMID 40371966
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Reactive oxygen species (ROS) are produced in immune cells by the phagocyte NADPH oxidase (NOX2) system that carries out coordinated transfer of electrons to molecular oxygen. The importance of the system in host defence...Reactive oxygen species (ROS) are produced in immune cells by the phagocyte NADPH oxidase (NOX2) system that carries out coordinated transfer of electrons to molecular oxygen. The importance of the system in host defence and immunoregulation is underlined by chronic granulomatous disease (CGD), a severe monogenic immunodeficiency caused by mutations in genes encoding individual components of NOX2. CGD also leads to inflammatory manifestations due to the regulatory role of ROS in multiple signalling processes. We describe the system in detail, from its discovery to our current understanding of the oxidase. We also describe CGD and illustrate how recent insights into this disease shed light on physiology.
Zhao LP, Tan LL, Xia YM
… +7 more, Ma XY, Li T, Zhou SY, Wu J, Li MA, Zhao WJ, Shen YQ
Clin Exp Immunol
· 2025 Jan · PMID 40355363
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INTRODUCTION: Mood disorders such as anxiety are important extraintestinal manifestations of inflammatory bowel disease (IBD) and are more prevalent in active IBD. Studies have shown that pharmacologically induced anxiet...INTRODUCTION: Mood disorders such as anxiety are important extraintestinal manifestations of inflammatory bowel disease (IBD) and are more prevalent in active IBD. Studies have shown that pharmacologically induced anxiety was correlated with changes in plasma Kynurenine (Kyn) concentrations. Our previous study also found that Kyn was abnormally increased in the serum and brain of mice with acute colitis. This study aimed to investigate the role and possible mechanism of Kyn in anxiety-like behavior induced by colitis. METHODS: Therefore, we established a 3% dextran sulfate sodium-induced mouse model of acute colitis. Kyn is produced by tryptophan metabolism in the presence of indoleamine 2,3-dioxygenase (IDO, rate-limiting enzyme). Furthermore, 1-methyl-tryptophan (1-MT), as an IDO inhibitor, was used to reduce Kyn synthesis in this study. RESULTS: We found that 1-MT significantly improved anxiety-like behaviors in mice with colitis, as assessed by the marbles burying test. Moreover, our study demonstrated that 1-MT reduced the level of pro-inflammatory cytokine IL-1β and the activation of glial cells in the mouse brain, indicating the anti-inflammatory effect of 1-MT. Similarly, 1-MT inhibited lipopolysaccharide-induced inflammatory responses in BV2 cells, which was consistent with the in vivo results. Furthermore, 1-MT reversed the low expression of doublecortin (DCX) and proliferating cell nuclear antigen (PCNA) in the hippocampus caused by colitis, suggesting a pro-neurogenesis and pro-proliferation effect. In addition, we found that Kyn promoted apoptosis by regulating the Bax/Bcl2 signaling cascade through in vitro and in vivo experiments. CONCLUSION: Overall, these results suggest that 1-MT improved anxiety-like behaviors in mice with colitis by decreasing neuroinflammation, promoting neurogenesis and cell proliferation, and reducing apoptosis.
de Jong TA, Semmelink JF, Bolt JW
… +4 more, Grasso C, Hoebe RA, Krawczyk PM, van Baarsen LGM
Clin Exp Immunol
· 2025 Jan · PMID 40336246
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Cellular senescence, a state of proliferation arrest, is implicated in the pathogenesis of age-related diseases such as rheumatoid arthritis (RA). The pathogenesis of RA, characterized by immune dysregulation and systemi...Cellular senescence, a state of proliferation arrest, is implicated in the pathogenesis of age-related diseases such as rheumatoid arthritis (RA). The pathogenesis of RA, characterized by immune dysregulation and systemic autoimmunity preceding clinical onset of disease, may involve early accumulation of senescent lymph node (LN) fibroblasts driving immune tolerance breakdown. This study aims to explore the hallmarks of senescence in LN fibroblasts during the earliest phases of RA and evaluate the effects of dasatinib. Human LN fibroblasts were isolated from inguinal LN needle biopsies from autoantibody-positive individuals at risk of developing RA (RA-risk individuals), RA patients, and seronegative healthy volunteers. Senescence hallmarks and the effects of dasatinib treatment were assessed using quantitative gene expression analysis, flow cytometry, microscopy, and live-cell imaging. Cell size, granularity, and autofluorescence were significantly greater in RA LN fibroblasts compared with controls. Altered gene expression of senescence-associated genes was observed in RA LN fibroblasts. Elevated senescence-associated β-galactosidase activity, more lipofuscin-positive granules, and DNA damage were observed in RA-risk and RA LN fibroblasts. Notably, RA(-risk) LN fibroblasts presented impaired DNA damage repair capacity. Dasatinib treatment significantly improved the size and ability of the LN fibroblast pool to repair DNA damage. We observed multiple senescence hallmarks in RA LN fibroblasts and, to a lesser extent, in RA-risk LN fibroblasts, which could be partially restored by senescent cell removal via dasatinib treatment. These findings suggest a role for senescent LN fibroblasts in RA pathogenesis and highlight the potential of dasatinib as a potential therapeutic intervention to mitigate senescence-associated defects in RA.