Clinical and experimental immunology最新文献

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.

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.

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.

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.

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.

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.

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.

Radiation-induced lymphopenia following brain irradiation may influence tumor response to cancer treatment. Interactions between the immune system, tumor, and radiotherapy manifest as global lymphopenia and result in changes in B-lymphocyte and T-lymphocyte levels. We assessed the longitudinal effects of brain irradiation on B-lymphocyte and T-lymphocyte concentrations in mice with and without glioblastoma. C57BL/6 mice were either tumor-free or tumor-bearing with GL-261 glioma cells and underwent brain irradiation with 2.5 Gy fractions in an 8-fraction irradiation regimen. We employed a tree-based model to analyze the acute impact of radiation and tumor volume on B-lymphocyte and T-lymphocyte reduction (total N = 130). Next, we developed semimechanistic models to describe the recovery patterns of B-lymphocyte and T-lymphocyte postdepletion after brain irradiation in tumor-free rodents (N = 40). Finally, we applied these models to predict B- and T-lymphocyte kinetics in tumor-bearing rodents. Brain irradiation induced a 50% reduction in B-lymphocyte and T-lymphocyte. Tumor volumes exceeding 59 mm³ caused B-lymphopenia but not T-lymphopenia during brain irradiation. Radiation exposure of lymph nodes resulted in both B- and T-lymphopenia. Our models successfully described the recovery of B/T-lymphocytes following their depletion induced by irradiation. Simulations revealed that all mice experienced B-lymphopenia, with recovery occurring within 8 days. 80% of mice experienced T-lymphopenia, with an average recovery time of 3.6 days. When tumor volumes exceeded 59 mm³, mice suffered prolonged B-lymphopenia. In conclusion, this study highlights the impact of lymph node radiation exposure and tumor volume on lymphocyte reduction and the utility of modeling in predicting long-term lymphocyte levels following brain irradiation.

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.

In recent years, research on innate lymphoid cells (ILCs) in pericardial adipose tissue has advanced significantly. These studies have revealed their dual role in maintaining cardiovascular homeostasis and mediating disease progression. Although the contribution of ILCs to cardiovascular diseases (CVDs) has garnered increasing attention, their heterogeneous nature complicates the analysis of their phenotypic and developmental characteristics. Furthermore, substantial differences in their composition, distribution, and function exist between murine and human hearts, highlighting the need for further investigation into how the high plasticity of ILCs influences disease processes. In this review, we examine the subpopulations, distribution patterns, and multifaceted roles of ILCs in the heart during CVDs, and discuss potential strategies to modulate ILC plasticity. We anticipate that, in the future, more precise immune modulation of ILCs will emerge as a promising therapeutic approach for CVDs, ultimately benefiting public health.