Clinical And Experimental Immunology[JOURNAL]
Sun
200 papers
Nebivolol prevents exhausted T cells and enhances cytotoxicity against MCF-7 breast cancer cells in a β2-adrenergic receptor-dependent manner.
Hajiaghayi M, Gholizadeh F, Rahbari N … +3 more , Emamnia N, Shih SCC, Darlington PJ
Clin Exp Immunol · 2026 Jan · PMID 41906691 · Full text
INTRODUCTION: Cancers often drive T cells toward an exhausted state characterized by impaired cytotoxicity and upregulation of inhibitory receptors (PD-1, TIM-3, CD38) and transcriptional regulators (TOX, NFATc1). Repeat...
INTRODUCTION: Cancers often drive T cells toward an exhausted state characterized by impaired cytotoxicity and upregulation of inhibitory receptors (PD-1, TIM-3, CD38) and transcriptional regulators (TOX, NFATc1). Repeated stimulation in vitro is used to model this process, reflecting chronic antigen exposure in the tumor microenvironment. Stress-derived catecholamines further drive dysfunction through β-adrenergic receptor (β-AR) signaling. Here, we examined the impact of nebivolol, an atypical β1-AR blocker with β2-biased agonist activity, on T-cell exhaustion and cytotoxicity against breast cancer cells. METHODS: Human CD3+ T cells from healthy participants were activated once (early activation) or four times (repeated activation) using CD3/CD28/CD2 T cell activator. Cells were treated in vitro with nebivolol, terbutaline (β2-agonist), isoproterenol (β1/β2-agonist), and metoprolol (β1-blocker). Exhaustion markers, including PD-1, TIM-3, CD38, and TOX, were measured by flow cytometry and RT-qPCR; NFATc1 by western blot; TNF and IFN-γ by ELISA, and cytotoxicity against MCF-7 breast carcinoma cells by co-culture assays. Disruption of the β2-AR gene (ADRB2) was achieved using CRISPR/Cas9. RESULTS: Nebivolol reduced the proportion of TIM-3+CD38+PD-1+ T cells, downregulated TOX and nuclear NFATc1, and restored ADRB2 expression under repeated activation conditions. Nebivolol enhanced TNF secretion and improved cytotoxicity against MCF-7 cells. In contrast, terbutaline and isoproterenol had no significant effect on exhaustion markers or cytotoxicity. Metoprolol did not inhibit nebivolol's activity, indicating that its effects are not β1-AR-dependent. Disruption of ADRB2 indicated that nebivolol's anti-exhaustion effects are mediated by β2-AR. DISCUSSION: These findings show that nebivolol reinvigorates CD4+ and CD8+ T cells following repeated activation, restoring their cytotoxic function against breast cancer cells in vitro. The immunomodulatory activity of Nebivolol is independent of β1-AR and mediated through β2-AR, suggesting that biased β2-AR signaling may represent a potential strategy for modulating T cell exhaustion in the tumor microenvironment.
Altered neutrophil signalling linked to impaired chemotaxis and increased ROS and NET production in older people with frailty.
Abdullah GA, Walsh J, Sellin A … +4 more , McLean C, Akpan A, Phelan MM, Wright HL
Clin Exp Immunol · 2026 Jan · PMID 41906686 · Full text
Immune function alters with age, and is often accompanied by low-grade inflammation (inflammageing). In individuals with frailty, inflammageing is increased, dysregulating immune function and increasing susceptibility to...
Immune function alters with age, and is often accompanied by low-grade inflammation (inflammageing). In individuals with frailty, inflammageing is increased, dysregulating immune function and increasing susceptibility to serious outcomes from infection. In this study, we investigated the changes that take place in human neutrophils during healthy ageing and ageing with frailty (FR) using RNAseq and functional assays. We also compared neutrophil phenotype in frailty with rheumatoid arthritis (RA). RNAseq data were analysed using IDEP2 and Ingenuity Pathway Analysis (IPA). Neutrophil phenotype was assessed for reactive oxygen species (ROS) production, neutrophil extracellular trap (NET) release, chemotaxis, and bacterial killing capacity. Experimental data were analysed by ANOVA in R (v4.5.1). RNAseq identified activation of G-protein coupled receptors, interferon and cytokine receptor signalling, and chemotaxis pathways in frail individuals (n = 10) compared with healthy older (n = 9) and healthy younger people (n = 8, adj. P < 0.05). FR neutrophils expressed more IL-8 receptors (CXCR1 and CXCR2) and CD177 on their surface (n = 5-8, P < 0.05). FR and RA neutrophils released significantly more ROS (n = 6-7) and had impaired chemotaxis (n = 8-9) and bacterial killing capacity (n = 5, P < 0.05) compared with both healthy groups. FR neutrophils also released significantly more NETs in response to LPS (10 ng/ml, n = 6-7, P < 0.05). This work provides novel insight into the altered neutrophil phenotype associated with ageing in good health and ageing with frailty, and highlights similarities between inflammageing in frailty and chronic inflammation in RA. This may be important in the development of therapeutics and/or health management strategies to support healthy living as we age.
Reduced IL-10 production by FoxP3+IL-10+ Treg cells is partially compensated by complosome-associated induction of regulatory FoxP3-IL-10+ T cells in allergic eosinophilic asthma.
Stichova J, Slanina P, Chovancova Z … +4 more , Baros J, Litzman M, Litzman J, Vlkova M
Clin Exp Immunol · 2026 Jan · PMID 41875927 · Full text
Role of the anti-inflammatory cytokine IL-10 in allergic eosinophilic asthma (AEA) remains controversial, with studies reporting inconsistent findings. Nevertheless, reduced IL-10 production has been described and may co...
Role of the anti-inflammatory cytokine IL-10 in allergic eosinophilic asthma (AEA) remains controversial, with studies reporting inconsistent findings. Nevertheless, reduced IL-10 production has been described and may contribute to the pathophysiologic features of the disease. Here, we compared FoxP3+IL-10+ Treg cells with the complosome-CD46-induced regulatory FoxP3-IL-10+ T cell capacity to produce IL-10 in AEA. We analyzed CD4+ T cells from 58 adults with controlled AEA and 49 healthy donors using ex vivo phenotypic characterization combined with a defined αCD3/αCD46/IL-2 activation model. CD4+ T cells from patients with controlled AEA showed a predominance of memory CD4+ T cells, reduced frequencies of FoxP3+ Treg cells and increased IFN-γ plasma levels. After CD46-mediated activation in vitro, CD4+FoxP3- T cells from AEA patients exhibited enhanced IFN-γ production together with altered expression of complosome-associated components, including increased CD46 expression and reduced surface C3bIn parallel, reduced frequencies of CD4+FoxP3+ Treg cells with impaired IL-10-producing capacity and normal levels of regulatory FoxP3-IL10+CD49b+ T cells were observed in AEA. The inducible regulatory response within the FoxP3- compartment was primarily driven by increased IL-10 secretion at the single-cell level rather than by an increased frequency of IL-10+ cells. Together, these findings define ex vivo features of complosome-associated CD4+ T cell activation in controlled AEA and indicate that impaired FoxP3+ T cells with diminished IL-10-producing capacity can be partially compensated by complosome-CD46 driven differentiation of CD4+FoxP3- T cells with stronger IL-10 secretion despite overall increase in T1 responses under defined experimental conditions.
In vitro pharmacological modulation of NKG2D expression in immune cells from Behçet syndrome patients.
Bonacini M, Muratore F, Albertazzi L … +5 more , Cimino L, Colla R, Zerbini A, Salvarani C, Croci S
Clin Exp Immunol · 2026 Jan · PMID 41849662 · Full text
Glucocorticoids, interferon-2α, colchicine, and azathioprine are recommended by EULAR for various manifestations of Behçet syndrome (BS). Curcumin is a natural compound with anti-inflammatory activities. NKG2D is a recep...
Glucocorticoids, interferon-2α, colchicine, and azathioprine are recommended by EULAR for various manifestations of Behçet syndrome (BS). Curcumin is a natural compound with anti-inflammatory activities. NKG2D is a receptor expressed by NK, NKT, and CD8pos T cells implicated in recognizing stressed cells. This study aimed to: (i) evaluate the effects of selected drugs used in the management of BS plus curcumin on NKG2D expression by lymphocytes; (ii) test the effects of these drugs on immune cell subsets; and (iii) determine whether immune cells from BS patients respond differently to those from healthy controls (CTR). Peripheral blood mononuclear cells from BS patients and CTR were treated with dexamethasone, interferon-2α, colchicine, azathioprine, or curcumin for 48 h in the presence or absence of IL-15. NKG2D expression on NK, NKT, and CD8pos T cells and the percentages/absolute counts of NK, NKT, T, and B cells were evaluated by flow cytometry. All drugs down-regulated NKG2D expression. The reduction was more pronounced in CTR than in BS patients following dexamethasone treatment, in BS patients than in CTR following colchicine treatment. Dexamethasone reduced NK cells in the absence of IL-15, but increased them in its presence. Colchicine reduced B cells regardless of IL-15 stimulation. Azathioprine also down-regulated B cells, but only in the presence of IL-15 stimulation. Drugs used in the management of BS reduced NKG2D expression, potentially decreasing the activation of cytotoxic cells. Immune cells from BS patients responded differently to dexamethasone and colchicine compared to those from CTR.
A novel fusion protein reduces kidney complement in experimental C3 glomerulopathy.
Malik TH, Kwiatkowska K, Lomax-Browne HJ … +7 more , Bottomley CM, Bright M, Tean ZS, Akturk AK, Alexander IE, Logan GJ, Pickering MC
Clin Exp Immunol · 2026 Jan · PMID 41810513 · Full text
Complement activation contributes to kidney damage in many types of glomerulonephritis and complement inhibition therapy is approved for IgA nephropathy and C3 glomerulopathy. However, inhibition is not specific to the k...
Complement activation contributes to kidney damage in many types of glomerulonephritis and complement inhibition therapy is approved for IgA nephropathy and C3 glomerulopathy. However, inhibition is not specific to the kidney resulting in unnecessary systemic complement inhibition and increased infection risk. To develop an effective inhibitor of glomerular complement we combined complement factor H-related protein 5 (FHR51-9), which binds to glomerular complement C3, with the complement regulatory domains of the key negative regulator of C3 activation complement factor H (FH1-5). One week after adeno-associated virus (AAV) mediated expression of the FHR51-9FH1-5 fusion protein in factor H (FH)-deficient mice, glomerular C3b/iC3b/C3c was significantly reduced and properdin resolved completely compared to controls. There was no change to circulating C3 levels and FHR51-9FH1-5 was detected in glomeruli in association with C3d. Six and twenty weeks after AAV8-FHR51-9FH1-5 treatment in hFH-FHR5mut mice (a mouse model of CFHR5 nephropathy) glomerular C3b/iC3b/C3c, C3d, and C5 were significantly reduced and properdin resolved completely compared to controls. Pre-administration of AAV-FHR51-9FH1-5 also ameliorated abnormal glomerular C3b/iC3b/C3c, C3d, C5, and properdin in a triggered CFHR5 nephropathy model. In vitro FHR51-9FH1-5 showed dose-dependent binding to surface-immobilized C3, C3b, iC3b, and C3d; factor I cofactor activity; and reduced C3a generation in an alternative pathway convertase assay. Taken together, the FHR51-9FH1-5 protein reduced glomerular C3 in experimental models of C3 glomerulopathy driven by either FH deficiency or mutated FHR5. These preclinical data indicate that FHR51-9FH1-5 protein represents a novel treatment strategy for complement-mediated kidney disease.
Evolving understandings for the roles of CD38 protein in autoimmunity and autoimmune disease.
Ye X, Zhang J, Song M … +9 more , Wang P, Ares I, Lopez-Torres B, Martínez M, Martínez-Larrañaga MR, Maximiliano JE, Anadón A, Wang X, Martínez MA
Clin Exp Immunol · 2026 Jan · PMID 41810503 · Full text
Autoimmune diseases are chronic idiopathic disorders characterized by inflammatory responses. Cluster of differentiation 38 (CD38), a surface molecule with enzymatic and signalling capabilities, contributes to the regula...
Autoimmune diseases are chronic idiopathic disorders characterized by inflammatory responses. Cluster of differentiation 38 (CD38), a surface molecule with enzymatic and signalling capabilities, contributes to the regulation of NAD+ metabolism and mediates various intracellular pathways. Recent research has revealed the influence of the CD38 protein in the pathogenesis of autoimmune diseases. During inflammation, CD38 is involved in regulating biological processes such as cell recruitment, cell activation, cytokine and chemokine release, antigen presentation, and phagocytosis. Dysfunctional CD38 induces autoimmune diseases. CD38 is expressed at low levels in various haematopoietic systems and tissues but exhibits elevated expression in multiple myeloma and plasma cells. CD38-targeted monoclonal antibodies with favourable therapeutic effects have been discovered, such as isatuximab, daratumumab, and mezagitamab. Although CD38-targeted antibodies were originally developed to eliminate malignant immune cells and inhibit their strong activation, these monoclonal antibodies can also inhibit autoantibodies production in autoimmune diseases. CD38 protein is a promising biomarker of autoimmune disease diagnosis and a potential therapeutic target for the treatment of autoimmune diseases. In this review article, we will focus on the latest findings on the involvement of CD38 in autoimmunity and autoimmune disease and assess the value of research and therapeutic application of CD38 in disease control.
An imbalance between CD80 and CD86 levels and CD4 regulatory T cell number and transendocytosis function exists in the liver in autoimmune hepatitis.
Halliday N, Kennedy A, Williams C … +5 more , Soskic B, Hinze C, Pinzani M, Thorburn D, Sansom DM
Clin Exp Immunol · 2026 Jan · PMID 41807245 · Full text
Impairment in Regulatory CD4 T cells (Treg) number and function have been implicated in autoimmune hepatitis (AIH). Treg are critical regulators of CD28 costimulation through CTLA4-mediated CD80 and CD86 control. We soug...
Impairment in Regulatory CD4 T cells (Treg) number and function have been implicated in autoimmune hepatitis (AIH). Treg are critical regulators of CD28 costimulation through CTLA4-mediated CD80 and CD86 control. We sought evidence for hepatic Treg frequency, phenotype, and function, and CD80/CD86 availability in AIH. Hepatic immune cells were isolated from eight patients with AIH and compared with cirrhotic and non-cirrhotic controls. Cells were assessed by flow cytometry and function was assessed by acquisition of CD80 from model antigen-presenting cells (APCs). We observed that Treg frequency was increased in AIH liver. Treg had an activated phenotype with a high CTLA4 expression and higher frequency of CTLA4 + PD1+ cells compared to non-AIH. Conventional CD4 T cells (Tcon) had an activated phenotype with increased HLA-DR expression, despite patients being in biochemical and histological remission. CD80 and CD86 expressions on B cells and monocytes were maintained or increased despite the excess of Treg, suggesting an imbalance between Treg and CD28 ligand availability. Hepatic Treg in AIH had preserved function for transendocytosis of CD80, which was enhanced by IL2 or IL10, demonstrating capacity for CD28 control. Overall, hepatic Treg have an activated phenotype and we did not observe reduced frequency or transendocytosis function of Treg in cirrhotic liver or (sub)acute liver failure from AIH. However, there is an imbalance between Treg function and CD80 and CD86 availability, with Tcon activation. This suggests that advanced AIH is not associated with reduced Treg frequency or function in the liver, but with an excess of CD80 and CD86.
Neutrophil extracellular traps in rheumatoid arthritis: biomarkers, drivers, and emerging therapeutic targets.
Kumari S, Pardali K, Meldrum E … +2 more , Lood C, Kraan M
Clin Exp Immunol · 2026 Jan · PMID 41703739 · Full text
Neutrophil extracellular traps (NETs) are web-like structures composed of DNA, histones, and granule proteins released by activated neutrophils. While originally characterized as part of the innate immune response, NETs...
Neutrophil extracellular traps (NETs) are web-like structures composed of DNA, histones, and granule proteins released by activated neutrophils. While originally characterized as part of the innate immune response, NETs are now recognized as contributors to the pathogenesis of immune-mediated inflammatory diseases, including rheumatoid arthritis (RA). This review summarizes current clinical evidence linking NETs to RA, with a focus on their utility as biomarkers for disease activity and treatment response and their potential mechanistic role in disease progression. Elevated levels of NET components, such as myeloperoxidase-DNA complexes, citrullinated histones, and calprotectin, have been reported in RA and correlate with inflammatory markers and clinical disease activity scores. Treatment with biological disease-modifying anti-rheumatic drugs, including tumour necrosis factor alpha and interleukin-6 inhibitors, reduces NET markers, whereas persistent NET formation is associated with poor response. NETs also promote pathogenic processes, including anti-citrullinated protein antibody formation, Th17 activation, and osteoclastogenesis. Although no therapies currently target NET formation directly, preclinical studies using PAD4 inhibitors and antibodies against citrullinated histones show promising effects. Standardizing NET biomarkers and conducting longitudinal studies will be essential for clinical translation. Overall, NETs represent both a biomarker and a mechanistic driver in RA, offering a novel opportunity for therapeutic intervention.
Eosinophils ETosis as a novel contributor to the pathogenesis of granulomatosis with polyangiitis.
Hashimoto T, Ueki S, Nishiyama S … +9 more , Hizuka K, Kodama S, Minagawa Y, Abe T, Tamura M, Furukawa T, Hirota S, Azuma N, Matsui K
Clin Exp Immunol · 2026 Jan · PMID 41700945 · Full text
Granulomatosis with polyangiitis (GPA) is traditionally regarded as a neutrophil-driven necrotizing vasculitis. However, the potential involvement of eosinophilic inflammation has not been fully elucidated. We investigat...
Granulomatosis with polyangiitis (GPA) is traditionally regarded as a neutrophil-driven necrotizing vasculitis. However, the potential involvement of eosinophilic inflammation has not been fully elucidated. We investigated the contribution of eosinophilic inflammation to the pathogenesis of GPA, with a particular focus on eosinophil extracellular trap formation (EETosis). This retrospective study included 52 patients, including 25 with active GPA and 27 in remission. We recorded enzyme-linked immunosorbent assay-based serum concentrations of eosinophil-derived proteins (galectin-10, eosinophil cationic protein, and eosinophil-derived neurotoxin), neutrophil-derived proteins (myeloperoxidase), and a marker for extracellular traps (citrullinated histone H3) for these patients. EETosis in tissue samples of patients was examined by immunofluorescence staining. Serum-induced EETosis was evaluated in vitro. Serum concentrations of galectin-10, eosinophil cationic protein, eosinophil-derived neurotoxin, citrullinated histone H3, and C-reactive protein and antineutrophil cytoplasmic antibody titre of patients with active GPA were significantly higher than those in remission. Galectin-10 had the strongest correlation with the Birmingham Vasculitis Activity Score (r = 0.778, P < 0.001). Increased galectin-10 levels were identified to be associated with the active stage after adjustment for glucocorticoid dose and eosinophil count. Receiver operating characteristic analyses of galectin-10 to discriminate between the active and remission phases revealed an area under the curve of 0.923, with 85.2% sensitivity and 91.1% specificity. GPA lung tissue showed lytic eosinophils and EETosis. Additionally, serum from active GPA patients induced EETosis in vitro whereas that from remission patients did not. Eosinophil activation and EETosis may contribute to the disease activity of GPA, highlighting a previously underrecognized component of its pathogenesis.
Exosomal nanocarriers of immune fate: molecular insights into cancer immunity, pathogen defense, and emerging immunotherapies.
Adedokun KA, Bello A, Oyeniyi GM … +2 more , Oladejo MK, Adebisi TA
Clin Exp Immunol · 2026 Jan · PMID 41686698 · Full text
Exosomes, the nanoscale extracellular vesicles released by most cell types, are increasingly recognized as potent regulators of immune communication. This review provides a mechanistic and integrative perspective on the...
Exosomes, the nanoscale extracellular vesicles released by most cell types, are increasingly recognized as potent regulators of immune communication. This review provides a mechanistic and integrative perspective on the immunological functions of exosomes, highlighting their roles in both immune stimulation and suppression across physiological and pathological contexts. We begin by dissecting the molecular architecture of exosomes-focusing on immunologically active components such as ESCRT proteins, tetraspanins, RabGTPases, and lipid mediators-and explore how these elements contribute to exosome biogenesis and immune function. The review further examines exosomal cargo enriched in pattern recognition receptor (PRR) ligands, including damage-associated molecular patterns (DAMPs), pathogen-associated molecular patterns (PAMPs), and microRNAs, and discusses how these molecules activate toll-like receptors and other PRRs to orchestrate innate immune responses through endosomal and cytosolic signaling cascades. Special emphasis is given to MHC-mediated antigen presentation via exosomes, distinguishing classical and non-canonical pathways and their interplay with downstream immune signaling mechanisms. We present a dichotomous view of exosomes as both immunostimulatory and immunosuppressive agents, detailing their roles in T-cell cross-priming, dendritic cell maturation, tumor progression, and metastasis. Moreover, we review pathogen-driven hijacking of exosomal pathways and their implications for immune evasion. Finally, we discuss the therapeutic promise of exosomes in cancer immunotherapy and vaccine design, advocating for their strategic integration into next-generation immunomodulatory approaches.
Higher humoral response in ileal versus colonic Crohn's disease.
Vieujean S, Jacobs N, Fernández-Verdejo R … +7 more , Fraussen J, Baiwir D, Mazzucchelli G, Reenaers C, Van Kemseke C, Louis E, Pierre N
Clin Exp Immunol · 2026 Jan · PMID 41672733 · Full text
Despite its interest for the development of personalized medicine, the immunological differences between ileal and colonic Crohn's disease (CD) have been understudied. For unknown reasons, some circulating antibodies are...
Despite its interest for the development of personalized medicine, the immunological differences between ileal and colonic Crohn's disease (CD) have been understudied. For unknown reasons, some circulating antibodies are associated with CD location (ileal CD: anti-Saccharomyces cerevisiae antibodies, anti-flagellins antibodies, anti-granulocyte macrophage-colony stimulating factor autoantibodies, and some pancreatic autoantibodies; colonic CD: perinuclear antineutrophil cytoplasmic autoantibodies). Based on these observations, we hypothesized that, in tissues, the humoral response differs between ileal and colonic CD. This hypothesis was tested by analysing the expression of IgA1, IgA2, IgG1, IgG2, IgG3, IgM, and immunoglobulin J chain (IGJ) in our previous dataset comparing the proteome of ulcer edges and adjacent normal mucosa (paired design) in the ileum (4 428 proteins screened in 16 biopsies) and colon (5 204 proteins screened in 16 biopsies) of 16 patients with CD. All these proteins were increased in ileal ulcer edges compared with adjacent normal mucosa, whereas only IgG3 was increased in colonic ulcer edges compared with adjacent normal mucosa. These data highlight the distinct role of humoral immunity in ileal and colonic CD, thereby opening a new avenue of research for developing therapies tailored to CD location.
The dopamine D3 receptor regulates dopamine-induced activation and glycolytic metabolism of synovial fibroblasts in rheumatoid arthritis.
Xue L, Xu S, Li M … +7 more , Wang B, Kang P, Zhu J, Clanchy FIL, Williams RO, Abraham D, Geng Y
Clin Exp Immunol · 2026 Jan · PMID 41664410 · Full text
Increased glycolytic metabolism in synovial fibroblasts contributes to their activated phenotype in rheumatoid arthritis (RA). Our previous results revealed that the activation of the dopamine D3 receptor (D3R) in mast c...
Increased glycolytic metabolism in synovial fibroblasts contributes to their activated phenotype in rheumatoid arthritis (RA). Our previous results revealed that the activation of the dopamine D3 receptor (D3R) in mast cells reduced inflammation in a mouse model of RA. In this study, we explored the role of D3R in regulating dopamine-induced activation and glycolysis in synovial fibroblasts from patients with RA (RASFs). RASFs were cultured in the presence of dopamine. Pharmacological modulation of D3R-by-D3R agonist (7-OHDPAT) and antagonist (NGB2904) was used to investigate the regulatory role of D3R in dopamine-induced activation and glycolysis in RASFs. Dopamine stimulation induced a dose-dependent increase in cell viability and α-SMA expression in RASFs. Dopamine also caused significant and dose-dependent upregulation of glycolysis-related enzymes in RASFs. Treatment with 7-OH-DPAT inhibited dopamine-induced increases in α-SMA expression and inflammatory response in RASFs, whereas NGB2904 treatment resulted in the enhanced effects stimulated by dopamine. NGB2904 treatment upregulated glycolysis and the expression of glycolytic enzymes induced by dopamine, whereas 7-OH-DPAT treatment downregulated glycolysis and glycolytic enzymes in RASFs. NGB2904 attenuated the ability of 7-OH-DPAT to inhibit the dopamine-induced elevation in cAMP levels of RASFs. Involvements of the cAMP pathway was confirmed by findings that H89 (a PKA inhibitor) abrogated the upregulation of activation, glycolysis, and expression of glycolytic enzymes mediated by the D3R antagonist, NGB2904, in RASFs. D3R downregulates dopamine-induced activation and glycolysis of RASFs by suppressing PKA activity. Therefore, inhibition of glycolysis by manipulating the D3R pathway may provide a novel therapeutic strategy to reduce the activation of RASFs.
Rare STAT1 variants in Moroccan tuberculosis patients: insights into host genetic susceptibility.
Zaidi S, Rafik A, Skhoun H … +16 more , Elkarhat Z, Guennoun A, Tabehout F, Errami A, Abid A, Abderrhamani Ghorfi I, El Ouazzani H, Souhi H, Zegmout A, El Hassani A, Ailal F, Abilkassem R, Ouzzif Z, Benhsaien I, Bousfiha AA, El Baghdadi J
Clin Exp Immunol · 2026 Jan · PMID 41660815 · Full text
Tuberculosis (TB) remains a major public health concern, particularly in Morocco. The JAK/STAT signaling pathway, activated by interferon-gamma (IFN-γ), plays a crucial role in the immune response against intracellular m...
Tuberculosis (TB) remains a major public health concern, particularly in Morocco. The JAK/STAT signaling pathway, activated by interferon-gamma (IFN-γ), plays a crucial role in the immune response against intracellular mycobacteria. However, pathogenic variants in the STAT1 gene can lead to either impaired or dysregulated signaling, affecting host defense mechanisms. In this study, we investigated 245 patients for the contribution of rare heterozygous STAT1 variants in children and young adults with confirmed TB. Patients presented diverse clinical phenotypes, including both pulmonary and extrapulmonary forms of TB disease. Using an integrative approach combining next-generation sequencing, functional immunoassays targeting the IL-12/IL-23/IFN-γ axis, and in silico analyses, we identified eight rare missense variants among eight cases (one mutation per patient): p.Asp65Gly, p.Glu157Lys, p.Ala267Val, p.Gln340Arg, p.Phe364Leu, p.Leu498Val, p.Lys652Glu, and p.Met691Val. These variants were located in key functional domains of the STAT1 protein. Statistical analysis using Mann-Whitney U test demonstrated markedly reduced cytokine production in patient cells following BCG + IFN-γ stimulation (median: 1117 vs. 3328 in controls; P = 0.038), demonstrating a targeted deficiency in IFN-γ-mediated signaling. In silico predictions and 3D structural modeling indicated that these variants could destabilize the protein through altered hydrogen bonding and hydrophobic interactions. The previously reported variants, including the GOF variant p.Ala267Val and the LOF variants p.Glu157Lys, p.Leu498Val, and p.Met691Val, impair STAT1 activation or its nuclear translocation, thereby disrupting IFN-γ-mediated signaling and weakening host immune defense against Mycobacterium tuberculosis. Additionally, this study identified novel variants, comprising the GOF variant p.Asp65Gly and the LOF variants p.Gln340Arg, p.Phe364Leu, and p.Lys652Glu.
LncRNAs at the frontline of neuroimmune crosstalk in oral cancer.
Patel M, Jyotishi C, Prajapati S … +1 more , Gupta R
Clin Exp Immunol · 2026 Jan · PMID 41660801 · Full text
Oral squamous cell carcinoma (OSCC) is one of the most aggressive malignancies, marked by immune evasion and perineural invasion that fuel therapy resistance and poor prognosis. Long non-coding RNAs (lncRNAs) have emerge...
Oral squamous cell carcinoma (OSCC) is one of the most aggressive malignancies, marked by immune evasion and perineural invasion that fuel therapy resistance and poor prognosis. Long non-coding RNAs (lncRNAs) have emerged as key regulators of cancer progression, capable of shaping immune responses and promoting neural invasion. This review examines the developing concept of the nerve-immune-cancer axis, emphasizing new findings on neuroimmune interactions and how lncRNAs influence neuroinflammation. The review summarizes recent studies on the functions of lncRNAs in OSCC, particularly their role in neuroimmune interactions. This review explains how lncRNAs can influence both the immune system and nerve-related signals in OSCC. Unlike previous reviews that address neuronal or immune mechanisms in isolation, this work highlights the convergent neuroimmune pathways potentially regulated by lncRNAs and identifies critical gaps, including the lack of OSCC-specific functional studies, absence of spatial or single-cell resolution of lncRNA activity, and limited in vivo models assessing lncRNA-driven perineural invasion. By articulating these research gaps, this review outlines testable hypotheses regarding lncRNA-mediated regulation of neuroimmune crosstalk and proposes future directions such as functional genomics, spatial transcriptomics, and nerve-tumor co-culture models. Clarifying these mechanisms may enable the identification of novel biomarkers and therapeutic targets, ultimately improving the management of OSCC.
Elevated type I interferon signature in patients with chronic granulomatous disease.
Aggarwal R, Vignesh P, Dod A … +4 more , Vinay K, Sharma S, Singh S, Rawat A
Clin Exp Immunol · 2026 Jan · PMID 41559882 · Full text
Chronic granulomatous disease (CGD) patients develop repeated infections and inflammatory complications. Underlying pathogenesis of hyperinflammation in CGD is not clearly characterized. To assess type-1 interferon signa...
Chronic granulomatous disease (CGD) patients develop repeated infections and inflammatory complications. Underlying pathogenesis of hyperinflammation in CGD is not clearly characterized. To assess type-1 interferon signature and measure Siglec-1/CD169 expression on monocytes in patients with CGD. mRNA sequencing of PBMCs in five CGD patients and three controls was analysed for differentially expressed genes. Subsequently, 20 patients with CGD, 10 heterozygous carriers of CYBB mutations, 11 healthy controls and 11 patients of systemic lupus erythematosus (disease controls) were enrolled. Expression of CD169 on monocytes was measured using flowcytometry. Expression of five type 1 interferon signature genes (ISGs) was measured using RT-PCR. On transcriptome analysis of peripheral blood mononuclear cells, increased expression of type-1 ISGs were seen in CGD patients. Monocyte CD169 expression was compared across three subgroups of CGD patients (10 = inflammatory disease, 5 = infectious disease, 5 = asymptomatic disease). CD169 expression on monocytes (percentage and ΔMFI) was significantly high in inflammatory disease subgroup in comparison to asymptomatic disease subgroup of CGD (P = <0.001 and P = <0.001). Similarly, the expression was significantly high in inflammatory disease subgroup when compared to infection subgroup of CGD (P = 0.033 and P = 0.017). An elevated type-1 interferon score by RT-PCR was found in inflammatory disease subgroup in comparison to infection subgroup of CGD (P = 0.029) and healthy controls (P = 0.021). Percentage and ΔMFI of monocyte CD169 correlated with type 1 interferon scores, rp = 0.38 (P = 0.049) and rp = 0.46 (P = 0.017), respectively. CGD patients with hyperinflammatory manifestations exhibited a high type 1 interferon signature. CD169 is a reliable surrogate marker for estimation of type 1 interferon signature.
BAFF-R Expression as a Potential Biomarker Associated with COVID-19 Vaccine Non-Responsiveness in Antibody-Deficient Patients.
O'Callaghan E, Shields AM, Chang L … +6 more , Umpierrez M, Newton D, Burns SO, Richter AG, Doody G, Savic S
Clin Exp Immunol · 2026 Jan · PMID 41559870 · Publisher ↗
INTRODUCTION: Patients with primary and secondary antibody deficiencies exhibit variable responses to vaccination, with many failing to mount optimal immunity to SARS-CoV-2. Mechanisms underpinning vaccine non-responsive...
INTRODUCTION: Patients with primary and secondary antibody deficiencies exhibit variable responses to vaccination, with many failing to mount optimal immunity to SARS-CoV-2. Mechanisms underpinning vaccine non-responsiveness remain poorly defined and unpredictable. We hypothesised that B-cell-intrinsic features are associated with SARS-CoV-2 vaccine failure. METHODS: Peripheral B-cells from 49 patients enrolled in the COVID-19 in Antibody Deficiency (COV-AD) study underwent a validated in vitro B-cell differentiation assay. We assessed plasmablast and plasma cell (PC) generation, immunoglobulin production, immunoglobulin heavy chain (IGH) repertoire diversity, and BAFF-R expression. RESULTS: Vaccine non-responders displayed reduced IgA class-switched immunoglobulin production in vitro compared to healthy controls and responders. Moreover, while the relative percentage of PC output was comparable between groups, the overall number of cells obtained from non-responders was reduced. Most non-responders and a subset of responders exhibited reduced BAFF-R surface expression at baseline compared to healthy controls, though with considerable overlap between groups. BAFF-R transcript levels partially corresponded with surface expression but varied and did not clearly distinguish response. No compensatory upregulation of alternative BAFF receptors or elevated serum BAFF was observed. IGH repertoire analysis revealed preserved diversity among patients. CONCLUSIONS: Diminished BAFF-R expression is associated with vaccine non-responsiveness and may indicate underlying B-cell-intrinsic defects. BAFF-R shows potential as a candidate biomarker that merits further validation in larger, multicentre cohorts to determine its clinical utility for stratifying patients at risk of vaccine failure. These findings suggest that the BAFF/BAFF-R axis may play an important role in vaccine-induced humoral immunity in antibody-deficient patients, warranting further mechanistic investigation.
Hydrogen ameliorates psoriasis-like skin inflammation via inhibiting the cGAS-STING pathway.
Wu Y, Wang X, Sun Y … +5 more , Duan Y, Zhang M, Sang H, Yu P, Kong Q
Clin Exp Immunol · 2026 Jan · PMID 41533764 · Full text
Psoriasis is a chronic disease caused by abnormal immune system response, which is characterized by excessive keratinocyte proliferation and the activation of cytokine signaling pathways. In a previous study, we demonstr...
Psoriasis is a chronic disease caused by abnormal immune system response, which is characterized by excessive keratinocyte proliferation and the activation of cytokine signaling pathways. In a previous study, we demonstrated in a psoriasis mouse model that hydrogen-rich water, an effective reactive oxygen species (ROS) scavenger, significantly improves disease severity. However, the precise molecular mechanism by which hydrogen helps in psoriasis treatment remains inadequately understood. This study assessed the role of hydrogen in suppressing keratinocyte hyperproliferation. We observed that the cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon gene signaling was activated in psoriasis-like skin inflammation, which was dramatically inhibited by hydrogen treatment both in vitro and in vivo. Consistently, hydrogen decreased proliferative marker expression, including BCL2, BAX, and Ki-67, and significantly reduced ROS and inflammatory cytokines production. Our study suggests that molecular hydrogen could function as a potential treatment for psoriasis.
IL-33 blockade attenuates vascular inflammation in a mouse model of Kawasaki disease vasculitis.
Carvalho TT, Ross BL, Jena PK … +12 more , Atici AE, Gomez AC, Fishbein MC, Aubuchon EA, Lee Y, Lee RT, Jacobsen EA, Verri WA, Chen S, Crother TR, Arditi M, Noval Rivas M
Clin Exp Immunol · 2026 Jan · PMID 41533763 · Full text
The immune mechanisms underlying Kawasaki disease (KD), a febrile systemic vasculitis in children, are poorly understood. Reports indicate elevated levels of circulating IL-33 in acute KD patients; however, if IL-33 cont...
The immune mechanisms underlying Kawasaki disease (KD), a febrile systemic vasculitis in children, are poorly understood. Reports indicate elevated levels of circulating IL-33 in acute KD patients; however, if IL-33 contributes to the pathogenesis of KD vasculitis remains unclear. Here, we used the Lactobacillus casei cell wall extract (LCWE)-induced murine model of KD to determine the contribution of IL-33 to vasculitis development. We observed increased expression of Il33 transcripts and IL-33 protein in LCWE-induced cardiovascular lesions. Bone marrow chimera experiments suggest that IL-33 production by both hematopoietic and stromal cells is important for LCWE-induced KD vasculitis; however, single-cell RNA sequencing, spatial transcriptomics, and flow cytometric analysis revealed that stromal cells were the predominant sources of IL-33. Furthermore, immune cells infiltrating LCWE-induced cardiovascular lesions expressed Il1rl1 transcripts, coding for the IL-33 receptor ST2. In vitro stimulation of bone marrow-derived macrophages with IL-33 enhanced their production of IL-1b and TNF-α. In vivo blockade of IL-33, using either neutralizing IL-33 antibody or Il33-/- mice, effectively attenuated LCWE-induced cardiovascular inflammation. Our results indicate that IL-33 contributes to LCWE-induced vascular inflammation through redundant mechanisms across multiple immune cell subsets rather than a single population and highlight IL-33 as a potential therapeutic target.
Circulating T-lymphocyte subsets as biomarkers for immune checkpoint inhibitors in solid tumors.
Kong Y, Chen R, Zhang J … +1 more , Zhang L
Clin Exp Immunol · 2026 Jan · PMID 41530915 · Full text
Immune Checkpoint Inhibitors (ICIs) have become a mainstay in the treatment of various solid tumors. At present, commonly used predictive biomarkers include tumor mutation burden, programed death-ligand 1 expression leve...
Immune Checkpoint Inhibitors (ICIs) have become a mainstay in the treatment of various solid tumors. At present, commonly used predictive biomarkers include tumor mutation burden, programed death-ligand 1 expression levels, and microsatellite instability. However, these biomarkers face inherent limitations, such as the challenges associated with tumor tissue sampling and the inability to provide dynamic monitoring. In recent years, significant efforts have been undertaken for the precise characterization of circulating T-lymphocyte subsets, with their classification offering the potential to reflect the functional state of T cells and predict responses to ICI therapy. Its advantages in terms of sampling convenience and minimally invasive nature further highlight its feasibility as a dynamic monitoring tool. This review expounds on current research progress on the use of "circulating" T-lymphocyte subsets as predictors of ICI efficacy and discusses their reliability and potential as predictive tools.
CD40L and IL-4 lymph node-associated signals protect B cells from rituximab-induced ADCC via KIR and NKG2A.
Graham LV, Foxall RB, Ashton-Key M … +6 more , Khakoo SI, Sayegh S, Leandro M, Reddy VR, Cragg MS, Blunt MD
Clin Exp Immunol · 2026 Jan · PMID 41528734 · Full text
Autoreactive B cells that remain in lymphatic tissue after anti-CD20 antibody therapy are considered a major contributing factor to relapse in patients with autoimmune diseases. Natural killer (NK) cells contribute to th...
Autoreactive B cells that remain in lymphatic tissue after anti-CD20 antibody therapy are considered a major contributing factor to relapse in patients with autoimmune diseases. Natural killer (NK) cells contribute to the depletion of autoreactive B cells by anti-CD20 antibodies via antibody-dependent cellular cytotoxicity (ADCC). However, the impact of germinal centre-associated signals CD40 ligand (CD40L) and interleukin-4 (IL-4) on ADCC was unknown. This study used a combination of flow cytometry, immunohistochemistry, and ex vivo functional assays using peripheral blood mononuclear cells to investigate how CD40L and IL-4 affect NK cell-B cell interactions. CD40L and IL-4 significantly upregulate human leukocyte antigen (HLA)-E and total HLA Class I expression on the surface of B cells from healthy donors, as well as patients with rheumatoid arthritis and systemic lupus erythematosus. The upregulation of HLA-E and total HLA functions to inhibit B-cell depletion by NK cell-mediated ADCC induced by rituximab via NKG2A and killer cell immunoglobulin-like receptors (KIR). Moreover, B cells that have differentiated through the germinal centre have higher expression of HLA-E and total HLA compared with naive B cells and are more resistant to depletion by rituximab. In accordance with this, blockade of NKG2A and inhibitory KIRs by monalizumab and lirilumab, respectively, increased antibody-dependent cellular cytotoxicity against autologous B cells in vitro. Overall, this study identifies a novel mechanism of resistance of B cells to NK cell cytotoxicity and indicates that blockade of the HLA-E:NKG2A and HLA:KIR checkpoint axes could be beneficial for improving B-cell depletion in patients with autoimmune diseases.
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