Journal of Immunology Research最新文献

Background: Host immune responses, including cytokine production, shape the severity of viral epidemics. Epigenetic mechanisms such as DNA methylation regulate cytokine gene expression and may contribute to immune dysregulation in severe disease.

Methods: This study analyzed interleukin-7 (IL-7), IL-8, and IL-10 promoter methylation in 145 COVID-19 patients (91 wards, 54 intensive care units (ICUs)), excluding 12 patients receiving epigenetically active drugs. Peripheral blood DNA underwent bisulfite conversion, followed by PCR and gel electrophoresis. Gene-specific methylation levels were quantified using beta values.

Results: IL-7 was significantly hypermethylated overall (β = 0.835, p < 0.001), especially in ICU patients (β = 0.863, p = 0.001), independent of age, mortality, and malignancy. An interaction between age and ICU status indicated group-specific effects. IL-10 showed significant hypomethylation (β = 0.243, p < 0.001), while IL-8 methylation did not differ significantly (p = 0.373). ICU patients had higher mortality (26% vs 5.5%, p < 0.001).

Conclusion: IL-7 hypermethylation may impair T-cell-mediated immunity in severe cases, while IL-10 hypomethylation may reflect enhanced immunosuppression. These findings suggest a role for epigenetic cytokine regulation in disease progression and may guide future immunomodulatory strategies.

Neutrophil extracellular traps (NETs) are web-like formations consisting of DNA-histone complexes and associated proteins released from activated neutrophils. While NET formation plays an important role in innate immunity, it is also associated with the pathogenesis of autoimmune disorders such as rheumatoid arthritis, psoriasis and systemic lupus erythematosus. Research suggests that NETosis (the process of NET formation) may contribute to the progression of cancer and the spread of malignant tumours. A clear link exists between the accumulation of neutrophils in the tumour microenvironment (TME), known as tumour-associated neutrophils (TANs) and NETosis activation in both primary and metastatic tumours. Furthermore, the literature highlights the role of NETs in modulating immune surveillance within the TME. This review aims to analyse the interplay between NETosis and the TME, emphasising its implications for tumour progression, immune evasion and resistance to therapy.

β₂-microglobulin (β2M) is a small protein playing a critical role in stabilizing major histocompatibility complex class I (MHC-I) molecules on nucleated cells. Elevated levels of β2M have been observed in several cancers, inflammatory and autoimmune conditions, and renal failures. High concentrations of β2M were reported to inhibit in vitro generation of functional dendritic cells (DCs). However, our findings showed that β2M exerts a negative effect on DCs only when contaminated with endotoxins. We found that β2M preparations with a high level of endotoxin impurities matured DCs, but that this effect was not seen with functional β2M preparations with low levels of endotoxin impurities, thus showing the maturation effect was due to endotoxin stimulation. We confirmed that the high-level endotoxin β2M compromised the in vitro differentiation of monocytes into DCs. In contrast, a low-level endotoxin β2M had no negative impact on DC differentiation nor prevented their maturation and functionality. Moreover, regardless of the levels of endotoxin impurities, β2M stabilized the expression of MHC-I molecules, confirming its functionality in the experimental settings. Our results show that β2M does not compromise the differentiation of DCs and indicate that elevated levels of β2M are unlikely to negatively regulate the immune system. These results have significant implications for understanding the functions of high β2M concentrations in clinical contexts and in vitro applications.

Multiple myeloma (MM) is the second most common hematological malignancy, characterized by a clonal expansion of malignant plasma cells in bone marrow. Monoclonal gammopathy of undetermined significance (MGUS) is the premalignant condition of MM. The tumor microenvironment is thought to influence the progression from premalignant conditions. Myeloid-derived suppressor cells (MDSCs) are a heterogenous group of different cellular subsets with myeloid origin, characterized by their ability to inhibit T-cell responses. MDSC are thought to play an important immunoregulatory role in different diseases, and in many cancers their levels seem to correlate with a poor prognosis. There are three different subsets, the neutrophil-like polymorphonuclear (PMN)-MDSC, the monocyte-like (M)-MDSC, and the immature early (e)MDSC. In this study, we investigate the levels and functions of all MDSC subsets in the bone marrow of both MGUS and MM patients and compare it to blood MDSC. We found that MDSC levels are not increased in neither the blood nor bone marrow of MGUS or MM patients, and they lack strong T-cell suppressive abilities. Blood PMN-MDSC seems to have a small inhibitory effect, but mature neutrophils were more suppressive. Interestingly, eMDSC levels were decreased in the blood of MM patients. Our data indicate that MDSC are not key players in the pathogenesis of MM, but that mature neutrophils may be more important as they have a stronger immunoregulatory effect.

The effective trafficking of dendritic cells (DCs) to the lymph nodes (LNs), orchestrated by CC-chemokine receptor 7 (CCR7) and its ligand CCL21, is essential for the success of DC-based immunotherapies. This study explores the potential of C21TP, a naturally occurring basic peptide derived from the C-terminal of CCL21, to enhance DC homing to the draining LNs in a murine model of DC migration. C21TP, containing three clusters of basic residues, significantly boosts CCL21-mediated signaling and chemotaxis of DCs in vitro. In vivo, DCs formulated with C21TP prior to injection migrated more efficiently to the draining LNs than DCs alone or DCs formulated with a mutated version of C21TP, harboring substitutions in key basic residues. Further studies are needed to evaluate the impact of C21TP on T-cell priming efficacy in the context of DC-based immunotherapies. Nonetheless, C21TP's ability to enhance lymph node homing of adoptively transferred cells without additional cellular modifications could offer a practical and scalable approach for advancing future DC-based vaccines.

Blood transfusion safety depends on swift blood compatibility testing. Alloantibodies recognizing these blood group antigens determine blood compatibility, and the transfusion of incompatible blood can lead to life-threatening hemolytic transfusion reactions. Recently, the landscape of blood compatibility testing has been complicated due to the interference caused by therapeutic antibodies targeting CD38, a key target in cancer immunotherapy that is also expressed on red blood cells. The presence of anti-CD38 antibodies in blood samples has been found to bind to test or donor red blood cells, resulting in false positive tests. This interference poses a serious risk as it can potentially mask immunogenic alloantibodies and cause delays in supplying safe blood products. We present the development and application of fragment crystallizable (Fc)-fusion constructs, referred to as "baitbodies", designed to neutralize anti-CD38 antibodies and mitigate false positive test outcomes. The extracellular domain of CD38 was fused to the Fc domain of a murine immunoglobulin G. These baitbody constructs were thoroughly characterized and applied in both serological microcolumn agglutination and automated solid-phase red cell adherence assays. The CD38-mFc baitbody successfully prevented agglutination reactions induced by three clinically relevant anti-CD38 monoclonal antibodies-daratumumab, felzartamab and isatuximab-in spiked samples. This allowed the detection of alloantibodies of the Rhesus, Kell and Duffy blood groups without interference. The CD38-mFc construct also demonstrated potential in a head-to-head comparison with commercial mitigation reagents, DaraEx and Grifols sCD38. Finally, the CD38-mFc baitbody effectively neutralized daratumumab in patient samples, preventing false positive test outcomes.

Liver fibrosis, characterized by the excessive deposition of extracellular matrix (ECM) driven by hepatic stellate cells (HSCs) activation, remains a critical challenge due to its progression to cirrhosis and hepatocellular carcinoma (HCC). This review clarifies the complex crosstalk between the immune system and HSCs, highlighting key cellular players including macrophages, natural killer (NK) cells, regulatory T cells (Tregs), and their cytokine-mediated signaling pathways that regulate fibrogenesis and fibrosis resolution. We describe pivotal molecular mechanisms such as transforming growth factor (TGF)-β, platelet-derived growth factor (PDGF), Wnt/β-catenin, and NF-κB signaling in HSCs modulation, emphasizing their interplay with immune responses. Novel therapeutic strategies targeting this complex immune-HSCs interaction, ranging from immunomodulatory agents, macrophage polarization, and NK cell-based therapies, to stem cell-derived exosomes, offer promising opportunities for preventing and reversing fibrosis. We further discuss innovative combination therapies integrating immunotherapies with antifibrotic agents, personalized strategies based on immune profiling, and the challenges of immune heterogeneity in fibrosis management. This review discusses recent advances in molecular interplay of immune system and HSCs, highlighting novel therapeutic targets, and future perspectives for managing chronic liver diseases.

Asthma is a chronic inflammatory respiratory disease with a distinct circadian rhythm. Common symptoms like cough, wheezing, and dyspnea, are worse at night and in the early morning (around 4 a.m.). The circadian pattern of asthma is intrinsically connected to the body's internal clock, which regulates a wide range of biological processes via transcription-translation feedback loop (TTFL). BMAL1 and CLOCK play a central role in the regulatory networks that control metabolism and immune function. When circadian rhythms are disrupted, it can result in metabolic disorders, immune dysfunction, and a worsening of asthma symptoms. A deeper understanding of the mechanisms underlying circadian rhythms may pave the way for innovative asthma treatments. Furthermore, the exploration and application of natural drugs and targeted therapies focusing on circadian rhythm genes show potential as a key approach for future precision treatment of asthma.

It has been known for about 50 years that a proportion of human basophils does not release histamine or leukotrienes or upregulates activation markers in response to IgE-dependent stimuli. This group of so-called nonresponders with unresponsive basophils is found in up to 20% of tests conducted. There seems to be no relation to clinical symptoms. The nonresponder status is not defined in a standardized manner, but basophils are often considered nonresponsive if they release less than 5% to 10% of their histamine content or show activation of less than or equal to 10% CD63+ basophils after FcεRI cross-linking. Results from nonresponder patients should be regarded as false negatives. Different genetic factors between reactive and anergic basophils appear to play a minor role because various other factors allow a conversion from the nonresponder status to the responder status in one individual (IL-3, low-Na⁺ medium, natural changes over time, etc.). In most studies reduced levels of Lyn and Syk proteins in nonreleasers were observed. Therefore, it was assumed that translational or posttranslational regulatory mechanisms (proteasomal degradation), especially specific to the Lyn and Syk levels, are responsible for the nonresponder status. Further biochemical studies, along with mechanistic experiments and multiomics approaches, should be conducted to clarify IgE unresponsiveness.

[This corrects the article DOI: 10.1155/2018/6529681.].