Clinical and experimental immunology最新文献

Introduction: Despite its interest for the development of personalised 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 hypothesised that, in tissues, the humoral response differs between ileal and colonic CD.

Methods: 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.

Results: 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.

Conclusion: 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.

Introduction: 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.

Methods: 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 tuberculosis disease.

Results: Using an integrative approach combining next-generation sequencing (NGS), 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: 1,117 vs. 3,328 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.

Conclusion: 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.

Introduction: 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).

Method: RASFs were cultured in the presence of dopamine. Pharmacological modulation of D3R by D3R agonist (7-OH-DPAT) and antagonist (NGB2904) was used to investigate the regulatory role of D3R in dopamine-induced activation and glycolysis in RASFs.

Results: 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 inα-SMA expression and inflammatory response in RASFs, whereas NGB2904 treatment resulted in the enhancedeffects 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.

Conclusion: 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.

Introduction: 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.

Methods: The review summarizes recent studies on the functions of lncRNAs in OSCC, particularly their role in neuroimmune interactions.

Results: 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.

Conclusion: 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.

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.

Systemic autoimmune diseases have been traditionally studied with a special focus on the immune system and less attention was paid to the roles of target tissues that are being exposed to the immune assault. For many common autoimmune diseases accumulating data unravel and highlight the potential role of the target tissues as orchestrators of the autoimmune responses. In this selective review, using Sjögren's disease (SjD) as a paradigm, we discuss the role of salivary gland epithelial cells (SGEC) not as innocent bystander targets of autoimmune responses, but rather as initiators and amplifiers of the inflammatory reactions. In fact, SGEC patients with Sjögren's disease are characterized by a unique phenotype which is capable of initiating and perpetuating both innate and adaptive immune responses in the glandular microenvironment. Aberrant expression and function of TLRs and IFN pathways, lymphocyte activating proteins as well as rewired cellular metabolism and antigen-presenting features, shape this distinct auto-antigenic phenotype of SGEC. These discoveries and ideas regarding the regulatory potential of the target SGEC in Sjögren's disease add a new dimension to our concept of regulatory circuits in autoimmunity.

In 2022, tuberculosis (TB) caused 1.3 million deaths worldwide, making it the second leading infectious cause of death. Diagnosing TB remains challenging because current immunological tests cannot distinguish between TB disease and TB infection (TBI). Research suggests that ratios such as monocyte-to-lymphocyte, neutrophil-to-lymphocyte, and platelet-to-lymphocyte, along with absolute counts of various blood cells, could help develop a low-cost and easy-to-use diagnostic tool to distinguish TB disease from TBI among IFN-γ release assay (IGRA)-positive subjects without relying on microbiological tests. We enrolled 112 TB-infected subjects and used blood cell count parameters and ratios to develop a TB score that can indicate TB status. We then validated the score in another cohort of IGRA-positive hospitalized patients. We developed a TB score based on 11 blood parameters to identify TB disease among IGRA-positive subjects, with 93% specificity and 71% sensitivity. This score can support physicians in making therapeutic decisions for IGRA-positive subjects, offering a practical approach to differentiate TB disease from TBI.

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.

Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) is a systemic autoimmune disease characterized by significant renal involvement, yet identifying novel biomarkers for renal complications remains a clinical priority. Metrnl is a recently identified immunomodulatory cytokine implicated in inflammation, but its specific role in AAV has historically been unknown. To address this, this study investigated serum Metrnl levels via ELISA in 37 patients with microscopic polyangiitis (MPA), 17 with granulomatosis with polyangiitis (GPA), and 30 healthy controls (HCs), analysing correlations with clinical parameters such as the Birmingham Vasculitis Activity Score (BVAS) and renal function indicators under false discovery rate (FDR) correction. The results demonstrated that serum Metrnl levels were significantly elevated in both MPA and GPA patients compared to HCs and exhibited a strong positive correlation with BVAS in both subgroups. Crucially, following FDR adjustment, Metrnl levels showed significant correlations with key markers of renal impairment, including creatinine, cystatin C, and estimated glomerular filtration rate (eGFR). Stratification of MPA patients based on renal function (eGFR cut-off: 60 ml/min/1.73 m²) further revealed substantially higher Metrnl levels in those with impaired renal function. Receiver operating characteristic curve analysis indicated superior diagnostic efficacy for Metrnl in identifying AAV with renal involvement [area under the curve (AUC) = 0.8150] compared to diagnosing AAV overall (AUC = 0.7214). Collectively, these findings provide the first evidence that serum Metrnl is elevated in AAV and associated with disease activity and renal dysfunction, suggesting that Metrnl warrants further investigation as a potential biomarker for renal involvement in AAV.

Neutralizing autoantibodies against type I interferons are a risk factor for multiple severe viral diseases. The timely detection of these autoantibodies remains an unmet need. We hypothesized that paradoxically low expression of type I IFN-induced CD169/SIGLEC1 expression analyzed by flow cytometry may allow rapid screening for the presence of these autoantibodies. In a prospective cohort study, we quantified monocytic CD169/SIGLEC1 expression and neutralizing autoantibodies against type I interferons in 808 patients who presented to the emergency room with signs of acute infections during the second wave of the SARS-CoV-2 pandemic in Germany in 2021. In patients, elevated CD169/SIGLEC1 (>2400 mAb/cell) demonstrated a negative predictive value of 100% for the detection of neutralizing autoantibodies against type I interferons. Low CD169/SIGLEC1 (<2400 mAb/cell) and a CRP >50 mg/L exhibited a positive predictive value of 70% for neutralizing autoantibodies against type I interferons. We further compared the adjusted odds ratio for mortality in patients with these autoantibodies to that in patients without autoantibodies against type I interferons. Neutralizing autoantibodies against type I interferons were associated with a worse clinical outcome, independent of SARS-CoV-2 infection, implying their presence is a risk factor for a worse general outcome.