International Reviews of Immunology最新文献

Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease characterized by excessive production of type I interferons (IFNs) and autoantibodies with limited effective clinical treatments. Solute carrier family 15 member 4 (SLC15A4), a proton-coupled oligopeptide transporter, facilitates the transmembrane transport of L-histidine and some di- and tripeptides from the lysosome to the cytosol. A growing body of evidence has elucidated the critical role of SLC15A4 in pathogenesis and disease progression of SLE. Genome-wide association studies have identified SLC15A4 as a new susceptibility locus of SLE. Further mechanistical studies have demonstrated that SLC15A4 involves in the production of type I IFNs in plasmacytoid dendritic cells (pDCs) and its necessity in B cells for autoantibody production in lupus models. These studies strongly support the potential of SLC15A4 as a promising therapeutic target for SLE. This review aims to summarize recent advances in understanding the role of SLC15A4 in disease progression of SLE and the development of SLC15A4-targeted inhibitors as well as discuss its potential as a target for SLE treatment.

Because of numerous stress signals, intracellular protein complexes are called inflammasomes. They function as catalysts for the proteolytic transformation of pro-interleukin into the active form of interleukin. Inflammasomes can promote a type of cell death process known as pyroptosis. The NLRP3 inflammasome, comprised of the NLRP3 protein, procaspase-1, and ASC, tightly regulates inflammation. The NLRP3 inflammasome is activated by a variety of stimuli, and several molecular and cellular events, such as ion influx, mitochondrial dysfunction, reactive oxygen species production, and lysosomal damage have been shown to trigger its activation. Inflammation plays a major role in almost all types of human diseases. The NLRP3 inflammasome has been the most widely studied and plays an important pathogenic role in various inflammatory pathologies. This review briefly presents the basic features of NLRP3 inflammasome and their mechanisms of activation and regulation. In addition, recent studies report the role of NLRP3 inflammasome in several diseases have been summarized.

Background: T cells play a crucial role in immune responses and are involved in chronic diseases such as Type 2 Diabetes Mellitus (T2DM) and its complications, including Diabetic Nephropathy (DN). Among these, regulatory T cells (Treg) act as key regulators, while T helper 9 (Th9) cells, which produce IL-9, are essential in maintaining immune balance.

Methods: The study included 145 participants divided into four groups: T2DM with nephropathy (35), T2DM without nephropathy (35), non-diabetic chronic kidney disease (ND-CKD) (35), and healthy controls (35). Various assessments were conducted, including anthropometric measurements, biochemical analyses, gene expression analysis was performed using RT-qPCR to profile mRNA and miRNA expression levels, flow cytometry (immune cell populations), and cytokine analysis by ELISA. Statistical analyses were carried out using SPSS, jamovi, Orange Data Mining, and Excel, ensuring robust evaluation and interpretation of the data.

Results: Th9 cells correlated with IL-9 (r = 0.72, p < 0.01), and Treg cells with IL-10 (r = 0.68, p < 0.01). The Th9/Treg ratio significantly increased across groups (χ² = 14.8, p < 0.001), with notable differences between HC and T2DM (p = 0.009) and HC and DN (p < 0.001). IL-9 (AUC = 0.880) and Th9/Treg ratio (AUC = 0.762) showed potential as DN diagnostic markers. PTEN levels were reduced in DN and ND-CKD (p < 0.001, p = 0.017), while MMP2, hsa-miR-21-5p, and hsa-miR-181b-5p were elevated in disease groups (all p < 0.001), correlating with renal markers. COL4A4 was higher in DN vs. HC (p = 0.004), with PTEN downregulation linked to immune imbalance and fibrosis.

Conclusion: Our study unveils immune cell and cytokine intricacies in DN. The high Th9/Treg ratio in T2DM and DN suggests immune tolerance loss, potentially influencing DN development. IL-9 and IL-10 display diagnostic potential. The Th9/Treg ratio and IL-9 serves as a discriminative diagnostic marker, particularly in DN. These insights offer avenues for early DN diagnosis and management.

In recent years, mostly spanning the past decade, the concept of immunometabolism has ushered with a novel perspective on carcinogenesis, tumor progression, and tumor response to therapy. It has become clear that the metabolic state of immune cells plays a significant role in shaping their antitumor or protumor activities within the cancer microenvironment. Consequently, the examination of tumor metabolic heterogeneity, including an exploration of immunometabolism, proves indispensable for enhancing prognostic tools and advancing the quest for personalized treatments. Here we have delved into how metabolic reprogramming profoundly influences the acquisition and maintenance of functional states, spanning from effector and cytotoxic profiles to regulatory and immunosuppressive phenotypes in both innate and adaptive immunity. These alterations wield considerable influence over tumor evolution and affect the outcome of cancer. Furthermore, we explore some of the cellular signaling mechanisms that underpin the metabolic and phenotypic flexibility of immune cells in response to external stimuli.

Atheroma formation is initiated by the activation of endothelial and smooth muscle cells, as well as immune cells, including neutrophils, lymphocytes, monocytes, macrophages, and dendritic cells. Monocytes, macrophages, and neutrophils are the innate immune cells that provide a rapid initial line of defence against vascular disease. These cells have a short lifespan and cannot retain memories, making them potential therapeutic targets for the inflammatory process associated with atherosclerosis. In addition, macrophages comprise the majority of vessel wall infiltrates and are, therefore, implicated in all stages of atherosclerosis progression. Neutrophils are the most common type of leukocyte found in circulation, and their high levels of matrix-degrading protease explain their significance in fibrous cap destabilization. However, the activation of immune cells becomes more complex by various microenvironmental stimuli and cytokines, which ultimately transform immune cells into their pro-inflammatory state. Different types of macrophage subsets with distinct functions in inflammation, such as M1 macrophages, cause an increase in pro-inflammatory cytokines and produce reactive oxygen species and nitric oxide, further worsening the disease. This review aims to shed light on immune-mediated inflammation in cardiovascular disease by focusing on the role of macrophage subsets in vascular inflammation and plaque stability, as well as the interaction between neutrophils and monocyte-macrophages.

This study aimed to explore the critical role of FUNDC1 on epithelial cells in model of asthma. Patients with asthma and normal healthy volunteers were obtained from our hospital. The serum of FUNDC1 mRNA expression was down-regulated in patients with asthma. Meanwhile, the serum of FUNDC1 mRNA expression was positive correlation with IgE and anti-HDM IgE protein. FUNDC1 expression in lung tissue of mice model was decreased in mice model of asthma. Sh-FUNDC1 enhanced asthma in mice model of asthma. FUNDC1 up-regulation reduced IL-4, IL-5, IL-10 and IL-13 activity levels in vitro model of asthma.FUNDC1 down-regulation promoted IL-4, IL-5, IL-10 and IL-13 activity levels in vitro model of asthma. FUNDC1 reduced ferroptosis of epithelial cells in model of asthma through the inhibition of mitochondrial damage. FUNDC1 induced FBXL2 and AR protein expression in model of asthma. FUNDC1 interlinked with FBXL2 is modified by SUMO1 at K136. FBXL2, ASN-205, GLN-204, ARG-235, and GLN-237 form hydrogen bonds with FUNDC1's ASP-15, ASP-16, GLU-25, and ARG-29, with lengths of 2.3, 3.1, 2.9, 2.3, and 2.9 Å, respectively. The induction of FBXL2 reduced the effects of Sh-FUNDC1 on asthma in mice model of asthma. The inhibition of AR reduced the effects of Sh-FUNDC1 on asthma in mice model of asthma Overall, FUNDC1 prevents ferroptosis of airway epithelial cells of asthma through FBXL2/AR/GPX4 signaling pathway of SUMO1 at K136. FUNDC1 might benefit the treatment of asthma or other pulmonary disease.

Objective: Heart failure (HF) causes structural and functional changes in the heart, with the pyroptosis-mediated inflammatory response as the core link in HF pathogenesis. E3 ubiquitin ligases participate in cardiovascular disease progression. Here, we explored the underlying molecular mechanisms of E3 ubiquitin ligase Smurf1 in governing HF.

Methods: HF rat/H9C2 cell models were established by doxorubicin intraperitoneal injections/hypoxia-reoxygenation (H/R), and treated with Smurf1 siRNA and oe-TRIB2 lentivirus plasmids or the NF-κB pathway inhibitor PDTC/si-smurf1, si-TRIB2, protease inhibitor MG132, or lysosomal inhibitor NH4Cl. The cardiac function/cardiac tissue pathological changes/fibrosis in HF rats were evaluated by echocardiography/H&E and Masson staining. GSDMD-N expression was determined by immunohistochemistry. Cell viability/lactate dehydrogenase (LDH) activity/IL-1β and IL-18 levels were measured by CCK-8/LDH kit/ELISA. The interaction between TRIB2 and Smurf1/TRIB2 ubiquitination levels was assessed by co-immunoprecipitation assay. The expression levels of Smurf1 and TRIB2 messenger RNA (mRNA) were determined by RT-qPCR. Levels of Smurf1/TRIB2/the NF-κB pathway-related factors/pyroptosis-related factors and TRIB2 mRNA were determined by Western blot/RT-qPCR.

Results: Smurf1 was highly expressed in H/R-induced H9C2 cells/HF rats, while its knockdown up-regulated TRIB2 and repressed the NF-κB pathway, reduced cardiomyocyte pyroptosis, and attenuated HF. Mechanistically, Smurf1 promoted TRIB2 degradation through an ubiquitin-dependent manner and activated the NF-κB pathway under H/R conditions. TRIB2 silencing annulled Smurf1 knockdown-regulated NF-κB pathway and cardiomyocyte pyroptosis. TRIB2 overexpression inactivated the NF-κB pathway and reduced cardiomyocyte pyroptosis, thus retarding HF.

Conclusion: Smurf1 was highly expressed in HF rats, which promoted TRIB2 ubiquitination degradation and activated the NF-κB pathway, thereby promoting cardiomyocyte pyroptosis in HF rats.

Background: Granulomatosis with polyangiitis (GPA) is an autoimmune condition. This study evaluated the relationship between CTLA4 gene polymorphisms, specifically rs231775, rs5742909, and rs3087243, and the risk of developing GPA.

Materials and methods: A case-control study was conducted with 217 participants, 102 individuals diagnosed with GPA, and 115 control subjects. The high-resolution melting (HRM) technique was used to genotype these polymorphisms.

Results: For the rs231775 polymorphism, the combined frequencies of AG and GG genotypes suggested an increased risk for GPA. Additionally, the GPA group had a higher frequency of the G allele. Also, patients with GG and AG genotypes displayed elevated levels of certain laboratory indices. Regarding rs5742909, the combined frequencies of TC and TT genotypes were linked to a lower risk of GPA. Moreover, a significant increase in the frequency of the T allele was noted in the control group. Those with the CC genotype exhibited a notably higher incidence of specific laboratory indices and some clinical manifestations. Our study found no significant association between the rs3087243 variant and the risk of developing GPA, nor with clinical or laboratory parameters.

Conclusion: The G allele of the rs231775 is associated with a heightened risk of developing GPA. Conversely, the T allele of the rs5742909 SNP offers a protective effect against GPA; however, the presence of the C allele positively correlates with some laboratory parameters and symptoms. Furthermore, the rs3087243 polymorphism does not seem to be linked to an increased risk of GPA.

Preventive vaccination is a crucial strategy for controlling and preventing infectious diseases, offering both effectiveness and cost-efficiency. However, despite the widespread success of vaccination programs, there are still certain population groups who struggle to mount adequate responses to immunization. These at-risk groups include but are not restricted to the elderly, overweight individuals, individuals with chronic infections and cancer patients. All of these groups are characterized by persistent chronic inflammation. Recent studies have demonstrated that one of the key players in immune regulation and the promotion of chronic inflammation are myeloid-derived suppressor cells (MDSCs). These cells possess a wide range of immunosuppressive mechanisms and are able to dampen immune responses in both antigen-specific and antigen-nonspecific manner, thus contributing to the establishment and maintenance of an inflammatory environment. Given their pivotal role in immune modulation, there is growing interest in understanding how MDSCs may influence the efficacy of vaccines, particularly in vulnerable populations. In this narrative review, we discuss whether MDSCs are able to regulate vaccine-induced immunity and whether their suppression can potentially enhance vaccine efficacy in vulnerable populations.

B-cells are vital immune cells that differentiate into plasma cells to produce antibodies targeting specific antigens. They also act as Antigen Presenting Cells, displaying processed antigens on Major Histocompatibility Complex class-II molecules to activate helper T-cells. This process triggers immune response and memory development. B-cells have surface antigens crucial for their function, which are often overexpressed in B cell cancers, making them targets for therapies like Chimeric Antigen Receptor (CAR) T-cell therapy. However, the choice of antigen is crucial. Tumor associated antigens are common but can cause off-target effects, while tumor specific antigens are more specific but less common. Furthermore, the precise epitope on the antigen recognized by the CAR-T cells significantly influences activation, which can also depend on the epitope's distance from the B-cell membrane. To facilitate the identification of extracellular regions of tumor antigens for CAR interactions, this review models tumor antigen structures embedded in the lipid bilayer, analyzing their roles and functions. Specifically, the characterization of B-cell surface antigens, encompassing their structural features and their potential as targets for CAR-T therapy are discussed. Each antigen is meticulously examined to gain insights into their specific roles within B cell biology and their potential as therapeutic targets. In conclusion, this review highlights the importance of understanding B cell antigens for the development of effective CAR-T cell therapies. The insights into antigen structures and functions presented here can guide the selection of optimal targets and the design of CAR-T cells to combat B cell malignancies effectively.