Immunologic Research最新文献

Clusters of Differentiation (CD) molecules are cell surface molecules that exhibit dynamic expression on immune cells. This plasticity characteristic of CD molecules is the basis for the high abundance and diversity of immune cell phenotypes. However, phenotypic associations of immune cells due to co-expression and mutual exclusion expression lead to some extent to a narrowing of the size of the immunophenotype repertoire. Therefore, a systematic exploration of the expression correlation including co-expression and mutual exclusion expression between CD molecules can help to reveal the co-phenotype and lost phenotypes during immunophenotyping analysis. In this study, using bioinformatics methods, we first confirmed that the conventional widely used Pearson and Spearman correlations are only suitable for co-expression but not for mutual exclusion expression analysis. Using bulk and single-cell RNA sequencing data, we systematically investigated the expression correlation and anti-correlation or mutual exclusion of 386 protein-encoding CD molecules in human CD4⁺ T cells, CD8⁺ T cells, B cells, NK cells, and monocytes. Highly correlated co-expression networks were identified in these cell types. Using flow cytometry, three CD molecules including CD58, CD63, and CD147 were experimentally validated to be significantly co-expressed in T cells. In particular, CD58 and CD147 showed a high correlation in either CD4⁺ or CD8⁺ T cells. Co-expression was also observed in T cells from patients with primary Sjögren's syndrome (pSS) and was found to be positively correlated with the increased cytotoxic potential of T cells. In addition, the combination of CD58 and CD147 provided a more precise definition of the T-cell phenotype, which would be beneficial for improving the diagnostic efficiency of pSS.

It has been reported that anlotinib exhibits antitumor efficacy in various cancers. However, the potential mechanisms by which anlotinib affects the immunosuppressive characteristics observed in tumor angiogenesis have not been fully elucidated. Therefore, we aimed to determine the potential of anlotinib in improving the effectiveness of PD-1/PD-L1 blockade therapy in lung cancer. An LLC mouse model was established by xenograft tumor model to evaluate the synergistic effects of anlotinib and anti-PD-1. Furthermore, changes in tumor vascular structure and T-cell infiltration were assessed using immunohistochemistry and flow cytometry. Clinical information from 198 lung cancer patients was collected to further analyze the relationship between Ki67 expression and patient survival as well as the synergistic effects. The study demonstrated that anlotinib successfully inhibited LLC cell growth. Additionally, anlotinib reduced related protein expressions in JAK2/STAT3 pathway. Mice in the anlotinib group exhibited lower expression levels of PD-L1 and VEGF-A and decreased intratumoral microvascular density. Moreover, PD-1/PD-L1 blockade combined with anlotinib promoted CD4 + T-cell infiltration into tumors, ultimately enhancing antitumor activity. Clinically, lung cancer patients treated with anlotinib and anti-PD-1 showed reduced Ki67 expression and improved survival rates. In conclusion, anlotinib improves tumor vascular structure and CD4 + T-cell infiltration by downregulating JAK2/STAT3 signaling, thereby enhancing the efficacy of PD-1 blockade in lung cancer.

Common Variable Immunodeficiency (CVID) is the most frequently encountered symptomatic primary immunodeficiency in clinical practice, presenting with heterogeneous clinical and genetic features. While traditionally considered polygenic, recent advances in genomic technologies have revealed monogenic causes in a significant subset of patients. This study aimed to investigate the genetic background of adult patients diagnosed with CVID or CVID-like phenotypes, using clinical exome sequencing (CES), focusing on atypical and syndromic presentations. Thirty adult patients fulfilling the ESID/PAGID criteria for CVID underwent CES. Genetic analysis targeted 451 immune-related genes, with variants interpreted according to ACMG guidelines. Pathogenicity was confirmed with Sanger sequencing. We detected potentially disease-related variants (TNFRSF13B, BTK, RAG1, SAMD9, NFKB2, PRKDC, CFTR, FCN3, IFIH1, ITGA3, and TNFRSF1A) in 12 of the 30 patients (40%). TNFRSF13B was the most frequently mutated gene among these patients. Deep phenotyping analyses revealed atypical findings included a hemizygous BTK variant mimicking CVID, a homozygous RAG1 variant consistent with leaky SCID, and a heterozygous SAMD9 variant not presenting with MIRAGE phenotype, and a homozygous ITGA3 insertion region variant that suggested a mild form of ILNED syndrome. Variants in CFTR, FCN3, and TNFRSF1A further expand the phenotypic spectrum, highlighting overlap between immunodeficiency and immune dysregulation syndromes in adulthood. A substantial proportion of adult patients with CVID-like phenotypes harbor variants in genes beyond the classical CVID-associated loci. Our findings support the utility of broad genetic screening in adult-onset antibody deficiency, particularly when non-infectious complications are present. Molecular diagnosis facilitates accurate classification, guides personalized treatment, and aids in genetic counseling.

This review explores the complex interplay between viral infections and psoriasis. It emphasizes how viruses like HIV, hepatitis, herpes, human papillomavirus, and SARS-CoV-2 can provoke and worsen psoriatic inflammation by disturbing immune balance. A key focus of the discussion is the IL-23/Th-17 pathway, which drives the production of proinflammatory cytokines that promote keratinocyte overgrowth and perpetuate chronic skin inflammation. Our article further investigates how disrupted intracellular pathways-such as those involving PI3K, Wnt signaling, and caveolin-affect the severity of the disease. This review supports the idea that viral infections can not only trigger psoriatic lesions but may also increase the risk of additional viral reactivation, thereby complicating the clinical picture of psoriasis. This thorough evaluation highlights the necessity for focused research to create innovative therapeutic strategies aimed at these viral triggers.

Sepsis, a life-threatening systemic infection, has long been recognized for its immediate risks, but its long-term consequences on health are increasingly evident, particularly in predisposing survivors to chronic cardiometabolic disorders (CMDs) such as atherosclerosis, insulin resistance, and dyslipidemia. Central to this process is trained immunity, where innate immune cells like monocytes, macrophages, and neutrophils undergo long-lasting epigenetic reprogramming after sepsis. This reprogramming, sustained by molecular pathways such as NF-κB, mTOR, and altered lipid metabolism, drives chronic inflammation, oxidative stress, and metabolic dysfunction, contributing to long-term cardiovascular diseases (CVDs) and metabolic disorders post-sepsis. This review explores the key mechanisms through which trained immunity bridges sepsis and CMDs, particularly focusing on epigenetic modifications such as histone acetylation, DNA methylation, and mitochondrial alterations. We discuss how trained immunity enhances immune cell activation, leading to persistent low-grade inflammation, lipid dysregulation, and impaired insulin sensitivity, all of which predispose sepsis survivors to CVDs. Additionally, we highlight potential therapeutic approaches targeting trained immunity, including statins, which reduce inflammation and immune reprogramming; metformin, which restores metabolic balance by activating AMPK and reducing oxidative stress; dimethyl fumarate (DMF), a potent Nrf2 activator that counteracts inflammation; and probiotics, which help restore gut microbiota balance and limit endotoxin-driven inflammation. These therapies offer promising strategies to mitigate long-term metabolic dysfunction and reduce the incidence of CMDs following sepsis. Understanding these mechanisms and developing targeted interventions may ultimately help prevent chronic cardiovascular and metabolic diseases in sepsis survivors and improve long-term outcomes.

In this paper, the study focuses on Type 1 Diabetes Mellitus (T1D), a chronic condition that affects the insulin-producing cells of the pancreas, requiring individuals to depend on external insulin for survival. We introduce a novel method for analyzing protein sequences by treating them as rigid bodies with mass and moment of inertia to assess sequence similarity. This method transforms the protein sequences into vectors using the moment of inertia tensor, with similarity calculated using Euclidean distance. Using this technique, we identified 24 genes linked to T1D, showing significant similarities to known T1D-related genes and highlighting their potential importance in the disease. Further, we conduct functional enrichment analysis for better understanding, which is very helpful for investigating their roles in various biological processes and molecular functions. The Gene Ontology (GO)analysis is crucial for prioritizing the identified genes and providing insights into their contributions to T1D pathophysiology. To combine the concepts from physics with computational biology, our research not only increases the understanding of T1D disease but also introduces an innovative approach for gene discovery and functional analysis in autoimmune diseases.

Autoimmune hepatitis (AIH) is an immune-mediated liver disease that currently lacks viable drug treatment methods. This study is to explore the role of piceatannol (PIC) in ConA-induced AIH and the related mechanisms. A mouse model of AIH was established by injecting ConA (i.v.), and PIC was administered as an intervention. The protective effect of PIC was evaluated by the liver function, liver pathology, and serum levels of inflammatory factors. Subsequently, network pharmacology was used to predict the pathways and targets of PIC in the treatment of AIH, and the predicted results were validated using flow cytometry, molecular docking, surface plasmon resonance (SPR) and so on. Finally, the immunosuppressive effect of PIC was further validated in a mouse heart transplantation model. PIC can improve liver function decline and reduce pathological liver damage, as well as inhibit the increase of serum inflammatory factor levels in mice with AIH induced by ConA. The protective effect is achieved by suppressing the immune activity of T cells and macrophages through binding to c-Jun. PIC can also extend the survival of cardiac allografts and inhibit acute rejection reactions. These results indicated that PIC can significantly improve ConA-induced AIH in mice by inhibiting the immune activity of T cells and macrophages through binding to c-Jun. PIC can also extend the survival of cardiac allografts in mice and inhibit acute rejection responses. The above results indicated that PIC may serve as a promising immunosuppressant and be effective for AIH.

Chimeric antigen receptor T (CAR-T) cell therapy has revolutionized the treatment of hematologic malignancies, yet its efficacy in solid tumors remains limited due to antigen heterogeneity, immunosuppressive tumor microenvironments, and therapy-associated toxicities. This review highlights advances across CAR-T generations, emphasizing co-stimulatory domains and cytokine-armed TRUCKs to enhance persistence and function. Viral (lentiviral, gamma-retroviral) and non-viral (CRISPR, transposons, mRNA electroporation) delivery systems are compared for efficiency, safety, and scalability, with CRISPR enabling multiplex edits for improved specificity. Dual-targeting CARs counter antigen heterogeneity, while hypoxia-inducible and SynNotch CARs restrict activity to tumor sites. Chemokine receptor engineering enhances infiltration, and armored CARs secreting IL-12 or checkpoint inhibitors remodel the TME. Nanobody-based CAR-T cells further expand design versatility, offering improved stability, tumor penetration, and reduced immunogenicity compared with single-chain variable fragment constructs. Safety innovations include iCasp9 Suicide switches, dasatinib-controlled activation, and cytokine blockade. Clinical trials of bispecific CAR-Ts show promise, yet challenges Like manufacturing complexity and off-target effects persist. Integrating AI-driven design and Personalized neoantigen targeting may unlock CAR-T 2.0 for solid tumors, pending scalable production and regulatory harmonization.

Human herpesvirus 8 (HHV-8), also known as Kaposi's sarcoma-associated herpesvirus (KSHV), is the etiological agent of Kaposi's Sarcoma (KS) and other lymphoproliferative disorders. Over three decades after its discovery, many aspects of its biology, latency, immune evasion, and oncogenic mechanisms remain poorly understood. This review provides an integrative and up-to-date analysis of KSHV, from its molecular architecture and gene regulation to its complex host interactions and transmission dynamics. We highlight key viral proteins-LANA, RTA, vFLIP, vCyc, kaposins, and viral miRNAs-that orchestrate latency maintenance, lytic reactivation, immune modulation, and tumor development. The review maps how KSHV establishes persistent infection, exploits host signaling pathways, and induces hallmarks of cancer, such as angiogenesis and uncontrolled proliferation. We also discuss glycoprotein-receptor interactions involved in viral entry and the structural mechanisms facilitating KSHV-cell fusion. Clinically, we present updated epidemiological data and analyze the diversity of KS forms-classic, endemic, iatrogenic, epidemic, and anaplastic-highlighting regional disparities, diagnostic challenges, and treatment gaps. The article emphasizes the virus's role in aggressive neoplasms in immunocompromised individuals and underscores the lack of antiviral strategies specifically targeting KSHV. By combining molecular virology, oncogenesis, immunology, and epidemiology, this review advances the current understanding of KSHV and reinforces the urgent need for effective diagnostic tools, preventive strategies, and targeted therapies. Our findings contribute to bridging knowledge gaps and promoting translational approaches to mitigate the global impact of KSHV-related diseases.

Phosphoinositide 3-kinases (PI3Ks), particularly the PI3Kδ pathway, play a crucial role in regulating immune functions. Alterations in this pathway, either as hyperactivation, such as in activated PI3Kδ syndrome (APDS), or rarely described hypoactivation, profoundly influence immune function and are linked to a spectrum of immunodeficiencies and autoimmune conditions. This report describes two cases of late-onset immunodeficiencies associated with PI3Kδ pathway dysregulation, each presenting with unique mutations and clinical manifestations. The first case involves a heterozygous mutation in PI3KR1 (c.5A > T, p.Tyr2Phe) indicative of PI3Kδ hyperactivation, effectively managed with sirolimus. The second case is characterized by a homozygous mutation in PIK3CD (c.2608C > T, p.Arg870Ter), suggesting PI3Kδ hypoactivation, with clinical features including psoriatic arthritis and ulcerative colitis. These cases underscore the heterogeneous clinical features and the challenges in managing such rare genetic variants. These cases underscore the importance of considering primary immunodeficiency in individuals exhibiting signs of both infectious and non-infectious autoimmune or immune dysregulation complications. Prompt genetic screening and strategic therapeutic approaches are crucial for effectively managing these conditions and mitigating the risks associated with immunosuppressive treatments. These insights emphasize the need for a deeper understanding of genetic factors in immunodeficiencies to devise personalized treatment strategies that substantially improve patients' quality of life.