Seminars in Immunology最新文献

{"title":"Endoplasmic reticulum stress: A key player in immune cell regulation and autoimmune disorders","authors":"Marion Moreews,&nbsp;Mikael C.I. Karlsson","doi":"10.1016/j.smim.2025.101954","DOIUrl":"10.1016/j.smim.2025.101954","url":null,"abstract":"<div><div>The endoplasmic reticulum (ER) is a large organelle, found in all eukaryotes, that is essential for normal cellular function. This function encompasses protein folding and quality control, post-translational modifications, lipid regulation, and the storage of intracellular calcium, among others. These diverse processes are essential for maintaining proteome stability. Therefore, a robust surveillance system is established under stress to ensure cell homeostasis. Sources of stress can originate from the cellular environment, including nutrient deprivation, hypoxia, and low pH, as well as from endogenous signals within the cell, such as metabolic challenges and increased demands for protein production. When cellular homeostasis is altered by one of these triggers, ER primary functions are altered which leads to the accumulation of misfolded proteins. These impaired proteins trigger the activation of the Unfolded Protein Response (UPR) pathway. This response aims at reducing ER stress by implementing the induction of complex programs to restore cell homeostasis. However, extended ER stress can modify the UPR response, shifting its signals from promoting survival to triggering pathways that reprogram or eliminate affected cells.</div></div>","PeriodicalId":49546,"journal":{"name":"Seminars in Immunology","volume":"78 ","pages":"Article 101954"},"PeriodicalIF":7.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143855101","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The stress and the alarmin-like cytokine interleukin-37 mediated extracellular and intracellular signal pathways","authors":"Yan Li ,&nbsp;Nuo Chen ,&nbsp;Yaxin Guo ,&nbsp;Lining Zhang","doi":"10.1016/j.smim.2025.101952","DOIUrl":"10.1016/j.smim.2025.101952","url":null,"abstract":"<div><div>IL-37, as a member of the IL-1 cytokine family, has been extensively characterized as a critical immunoregulatory molecule that suppresses both innate and adaptive immune responses. This cytokine demonstrates constitutive and inducible expression patterns across various immune and non-immune cells in response to diverse extracellular stimuli. Among its five identified isoforms (a, b, c, d, and e), IL-37b remains the most comprehensively studied variant. Compelling experimental evidence from murine models demonstrates that IL-37b exerts protective effects across a spectrum of pathological conditions, including inflammatory disorders, autoimmune diseases, neoplastic processes, and Alzheimer's disease (AD). In human, IL-37 serves as a natural modulator of inflammatory cascades with clinical studies frequently documenting dysregulated expression levels in patients with chronic inflammatory and autoimmune conditions. The anti-inflammatory mechanisms of IL-37b are primarily mediated through dual pathways: 1) extracellular signaling via the IL-18Rα receptor complex, and 2) intracellular modulation through direct interaction with signaling molecules such as Smad3. Recent advancements from our research group and others have elucidated novel biological functions for IL-37d and IL-37a isoforms and identified previously unrecognized intracellular targets of IL-37 including RAC1, C/EBPβ, and Rheb. This comprehensive review systematically examines current advancements in understanding IL-37's biological functions, with particular emphasis on emerging insights into its intracellular mechanisms of action in stress-associated pathologies.</div></div>","PeriodicalId":49546,"journal":{"name":"Seminars in Immunology","volume":"78 ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143820598","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Complement and the hallmarks of cancer","authors":"Mikel Rezola Artero ,&nbsp;Andrea Minery ,&nbsp;Leon Nedelcev ,&nbsp;Maria Radanova ,&nbsp;Lubka T. Roumenina","doi":"10.1016/j.smim.2025.101950","DOIUrl":"10.1016/j.smim.2025.101950","url":null,"abstract":"<div><div>The hallmarks of cancer are a set of traits that normal cells acquire during their transformation into malignancy. Among the biological processes influencing these hallmarks, the innate immune complement system plays a critical role. It can operate canonically—in blood and tissues—via phagocytosis, inflammation, and complement-dependent cytotoxicity, similar to its roles against invading pathogens. Additionally, it functions non-canonically by modulating the behavior of cells within the tumor microenvironment and their intracellular landscape which regulates cell fate. These mechanisms contribute to the complex and context-dependent roles of complement in both tumor growth and antitumor immunity, shaped by the characteristics of the dynamic tumor microenvironment. This review analyses the multifaceted interplay between complement proteins and cancer hallmarks, positioning this system as a target to cancer therapy.</div></div>","PeriodicalId":49546,"journal":{"name":"Seminars in Immunology","volume":"78 ","pages":"Article 101950"},"PeriodicalIF":7.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143747662","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Harnessing complement biomarkers for precision cancer care","authors":"Houcine Hamidi ,&nbsp;Idris Boudhabhay ,&nbsp;Marie-Agnes Dragon-Durey","doi":"10.1016/j.smim.2025.101963","DOIUrl":"10.1016/j.smim.2025.101963","url":null,"abstract":"<div><div>The tumor microenvironment (TME) consists of various immune and non-immune cells, along with proteins from different origins, and plays a crucial role in tumor development, treatment response, and patient prognosis. Complement system is a key player in the TME. It is a proteolytic cascade that generates cleavage fragments capable to activate cells through specific receptors or deposit on cells and tissues. This review summarizes current data on the complement system as a potential biomarker in cancer. Transcriptomic analyses have classified tumors based on the impact of complement gene expression on prognosis. Immunostaining provides insights into the expression and deposition of complement proteins and fragments in tumors and TME cells. In body fluids such as blood, measuring complement activation fragments and detecting anti-complement autoantibodies have identified non-invasive biomarkers relevant to certain cancer types. With the rise of complement-targeting therapies and new tools for analyzing the complement system in tumors and body fluids, it is time to define its role in cancer management. This includes its potential for cancer detection, staging, and potentially for treatment monitoring.</div></div>","PeriodicalId":49546,"journal":{"name":"Seminars in Immunology","volume":"78 ","pages":"Article 101963"},"PeriodicalIF":7.4,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144070699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neurogenic inflammation and itch in barrier tissues","authors":"Rebecca Liu ,&nbsp;Dean R. Buttaci ,&nbsp;Caroline L. Sokol","doi":"10.1016/j.smim.2024.101928","DOIUrl":"10.1016/j.smim.2024.101928","url":null,"abstract":"<div><div>Once regarded as distinct systems, the nervous system and the immune system are now recognized for their complex interactions within the barrier tissues. The neuroimmune circuitry comprises a dual-network system that detects external and internal disturbances, providing critical information to tailor a context-specific response to various threats to tissue integrity, such as wounding or exposure to noxious and harmful stimuli like pathogens, toxins, or allergens. Using the skin as an example of a barrier tissue with the polarized sensory neuronal responses of itch and pain, we explore the molecular pathways driving neuronal activation and the effects of this activation on the immune response. We then apply these findings to other barrier tissues, to find common pathways controlling neuroimmune responses in the barriers.</div></div>","PeriodicalId":49546,"journal":{"name":"Seminars in Immunology","volume":"77 ","pages":"Article 101928"},"PeriodicalIF":7.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142972902","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Decoding the multifaceted roles of galectins in self-defense","authors":"Sachiko Sato ,&nbsp;Jun Iwaki ,&nbsp;Jun Hirabayashi","doi":"10.1016/j.smim.2024.101926","DOIUrl":"10.1016/j.smim.2024.101926","url":null,"abstract":"<div><div>In this review, we aim to explore the multifaceted roles of galectins in host defense from a broader perspective, particularly regarding their functions when host integrity is compromised. Numerous comprehensive reviews on galectin functions in immunity have already been published. For researchers new to the field, this wealth of information may create an impression of galectins as proteins involved in a wide array of biological processes. Furthermore, due to the heterogeneity of galectin ligands, glycans, there is a risk of perceiving galectin-specific functions as ambiguous, potentially obscuring their core biological significance. To address this, we revisit foundational aspects, focusing on the significance of the recognition of galactose, a “late-comer” monosaccharide in evolutionary terms, provide an overview of galectin glycan binding specificity, with emphasis on the potential biological importance of each carbohydrate-recognition domain. We also discuss the biological implications of the galectin location paradox wherein these cytosolic lectins function in host defense despite their glycan ligands being synthesized in the secretory pathway. Additionally, we examine the role of galectins in liquid-liquid phase separation on membranes, which may facilitate their diverse functions in cellular responses. Through this approach, we aim to re-evaluate the complex and diverse biological roles of galectins in host defense.</div></div>","PeriodicalId":49546,"journal":{"name":"Seminars in Immunology","volume":"77 ","pages":"Article 101926"},"PeriodicalIF":7.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142899814","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Celiac disease, non-celiac wheat sensitivity, wheat allergy – clinical and diagnostic aspects","authors":"Ketil Størdal ,&nbsp;Kalle Kurppa","doi":"10.1016/j.smim.2025.101930","DOIUrl":"10.1016/j.smim.2025.101930","url":null,"abstract":"<div><div>In recent years, wheat- and gluten-free diets have increased in demand due to reported increases in various conditions reported to be driven by ingredients of these food products. Celiac disease, wheat allergy and non-celiac wheat sensitivity constitute the three main categories of wheat-related disorders. Celiac disease is a well-characterized immune-mediated disease caused by immune reaction against specific gliadin epitopes, the main protein in wheat. Screening studies of samples collected over time bring evidence that there is a true increase in prevalence not only driven by increased testing activity. Clinical presentation of CeD is diverse and there is an increased risk of autoimmune co-morbidities. Wheat allergy consists of IgE- and non-IgE-mediated reactions, driven by Th2-cells directing eosinophil and basophil responses. Rapid IgE-mediated reactions are characterized by specific IgE antibodies in conjunction with symptoms originating especially from the respiratory and gastrointestinal tract. There is an increased risk of other allergies and the majority recover during adolescence. Non-IgE-mediated wheat allergy is a less-well defined condition, which is often diagnostically challenging due to a longer interval between exposure and symptoms and lack of non-invasive biomarkers. In this condition, wheat as a trigger needs to be established by exclusion followed by dietary challenge. Non-celiac wheat sensitivity, despite being the most recently recognized, has the highest reported prevalence among the three wheat-related entities. It remains, however, particularly poorly characterized due to unclear pathophysiology and lack of diagnostic markers. This narrative review will scrutinize the shared and distinct clinical features of the three wheat-related conditions, focusing on epidemiology, clinical presentation, co-morbidities, diagnosis, treatment and prognosis.</div></div>","PeriodicalId":49546,"journal":{"name":"Seminars in Immunology","volume":"77 ","pages":"Article 101930"},"PeriodicalIF":7.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142967102","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhancing complement activation by therapeutic anti-tumor antibodies: Mechanisms, strategies, and engineering approaches","authors":"Vitalijs Ovcinnikovs ,&nbsp;Karin Dijkman ,&nbsp;Gijs G. Zom ,&nbsp;Frank J. Beurskens ,&nbsp;Leendert A. Trouw","doi":"10.1016/j.smim.2024.101922","DOIUrl":"10.1016/j.smim.2024.101922","url":null,"abstract":"<div><div>The complement system plays an integral role in both innate and adaptive immune responses. Beyond its protective function against infections, complement is also known to influence tumor immunity, where its activation can either promote tumor progression or mediate tumor cell destruction, depending on the context. One such context can be provided by antibodies, with their inherent capacity to activate the classical complement pathway. In recent years, our understanding of the mechanisms governing complement activation by IgG and IgM antibodies has expanded significantly. At the same time, preclinical and clinical studies on antibodies such as rituximab, ofatumumab, and daratumumab have provided evidence for the role of complement in therapeutic success, encouraging strategies to further enhance its activity. In this review we examine the main determinants of antibody-mediated complement activation, highlighting the importance of antibody subclass, affinity, valency, and geometry of antigen engagement. We summarize the evidence for complement involvement in anti-tumor activity and challenges of accurately estimating the extent of its contribution to therapeutic efficacy. Furthermore, we explore several engineering approaches designed to enhance complement activation, including increased Fc oligomerization and C1q affinity, bispecific C1q-recruiting antibodies, IgG subclass chimeras, as well as antibody and paratope combinations. Strategies targeting membrane-bound complement regulatory proteins to overcome tumor-associated complement inhibition are also discussed as a method to boost therapeutic efficacy. Finally, we highlight the potential of complement-dependent cellular cytotoxicity (CDCC) and complement-dependent cellular phagocytosis (CDCP) as effector mechanisms that warrant deeper investigation.</div><div>By integrating advances in antibody and complement biology with insights from efforts to enhance complement activation in therapeutic antibodies, this review aims to provide a comprehensive framework of antibody design and engineering strategies that optimize complement activity for improved anti-tumor efficacy.</div></div>","PeriodicalId":49546,"journal":{"name":"Seminars in Immunology","volume":"77 ","pages":"Article 101922"},"PeriodicalIF":7.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142916122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Roles for Siglec-glycan interactions in regulating immune cells","authors":"Sung-Yao Lin ,&nbsp;Edward N. Schmidt ,&nbsp;Kei Takahashi-Yamashiro ,&nbsp;Matthew S. Macauley","doi":"10.1016/j.smim.2024.101925","DOIUrl":"10.1016/j.smim.2024.101925","url":null,"abstract":"<div><div>Cell surface complex carbohydrates, known as glycans, are positioned to be the first point of contact between two cells. Indeed, interactions between glycans with glycan-binding can modulate cell-cell interactions. This concept is particularly relevant for immune cells, which use an array of glycan-binding proteins to help in the process of differentiating ‘self’ from ‘non-self’. This is exemplified by the sialic acid-binding immunoglobulin-type lectins (Siglecs), which recognize sialic acid. Given that sialic acid is relatively unique to vertebrates, immune cells leverage Siglecs to recognize sialic acid as a marker of ‘self’. Siglecs serve many biological roles, with most of these functions regulated through interactions with their sialoglycan ligands. In this review, we provide a comprehensive update on the ligands of Siglecs and how Siglec-sialoglycan interactions help regulate immune cells in the adaptive and innate immune system.</div></div>","PeriodicalId":49546,"journal":{"name":"Seminars in Immunology","volume":"77 ","pages":"Article 101925"},"PeriodicalIF":7.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142873311","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The complement system in clinical oncology: Applications, limitations and challenges","authors":"Daniel Ajona ,&nbsp;Mark S. Cragg ,&nbsp;Ruben Pio","doi":"10.1016/j.smim.2024.101921","DOIUrl":"10.1016/j.smim.2024.101921","url":null,"abstract":"<div><div>The complement system, a key component of innate immunity, is involved in seemingly contradictory aspects of tumor progression and cancer therapy. It can act as an immune effector against cancer and modulate the antitumor activity of certain therapeutic antibodies, but it can also contribute to a tumor-promoting microenvironment. Understanding this dual role should lead to the development of better therapeutic tools, strategies for cancer treatment and biomarkers for the clinical management of cancer patients. Here, we review recent advances in the understanding of the role of complement in cancer, focusing on how these findings are being translated into the clinic. We highlight the activity of therapeutic agents that modulate the complement system, as well as combination therapies that integrate complement modulation with existing therapies. We conclude that the role of complement activation in cancer is a rapidly evolving field with the potential to translate findings into new therapeutic strategies and clinically useful biomarkers</div></div>","PeriodicalId":49546,"journal":{"name":"Seminars in Immunology","volume":"77 ","pages":"Article 101921"},"PeriodicalIF":7.4,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142866001","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}