Seminars in Immunology最新文献

{"title":"From immunobiology to intervention: Pathophysiology of autoimmune encephalitis","authors":"Marie A. Homeyer ,&nbsp;Alice Falck ,&nbsp;Lucie Y. Li ,&nbsp;Harald Prüss","doi":"10.1016/j.smim.2025.101955","DOIUrl":"10.1016/j.smim.2025.101955","url":null,"abstract":"<div><div>Autoimmune encephalitides (AEs) are neurological disorders caused by autoantibodies against neuronal and glial surface proteins. Nearly 20 years after their discovery, AE have evolved from being frequently misdiagnosed and untreated to a growing group of increasingly well-characterized conditions where patients benefit from targeted therapeutic strategies. This narrative review provides an immunological perspective on AE, focusing on NMDAR, CASPR2 and LGI1 encephalitis as the three most common forms of AE associated with anti-neuronal surface autoantibodies. We examine the autoreactive B cell subsets, the tolerance checkpoints that may fail, and the known triggers and predispositions contributing to disease. In addition, we discuss the roles of other immune cells, including T cells and microglia, in the pathogenesis of AE. By analyzing therapeutic strategies and treatment responses we draw insights into AE pathophysiology. Written at a time of transformative therapeutic advancements through cell therapies this work underscores the synergy between detailed immunological research and the development of innovative therapies.</div></div>","PeriodicalId":49546,"journal":{"name":"Seminars in Immunology","volume":"78 ","pages":"Article 101955"},"PeriodicalIF":7.4,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143855085","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":"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":"2025-04-22","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 spatial and single-cell landscape of skin: Charting the multiscale regulation of skin immune function","authors":"Abiha Kazmi ,&nbsp;Raman Gill ,&nbsp;Paula Restrepo ,&nbsp;Andrew L. Ji","doi":"10.1016/j.smim.2025.101958","DOIUrl":"10.1016/j.smim.2025.101958","url":null,"abstract":"<div><div>Immune regulation is a key function of the skin, a barrier tissue that exhibits spatial compartmentalization of innate and adaptive immune cells. Recent advances in single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) have facilitated systems-based investigations into the molecular and cellular features of skin immunity at single-cell resolution, identifying cell types that maintain homeostasis in a coordinated manner, and those that exhibit dysfunctional cell-cell interactions in disease. Here, we review how technological innovation is uncovering the multiple scales of heterogeneity in the immune landscape of the skin. The microanatomic scale encompasses the skin’s diverse cellular components and multicellular spatial organization, which govern the functional cell interactions and behaviors necessary to protect the host. On the macroanatomic scale, understanding heterogeneity in cutaneous tissue architecture across anatomical sites promises to unearth additional functional immune variation and resulting disease consequences. We focus on how single-cell and spatial dissection of the immune system in experimental models and in humans has led to a deeper understanding of how each cell type in the skin contributes to overall immune function in a context-dependent manner. Finally, we highlight translational opportunities for adopting these technologies, and insights gleaned from them, into the clinic.</div></div>","PeriodicalId":49546,"journal":{"name":"Seminars in Immunology","volume":"78 ","pages":"Article 101958"},"PeriodicalIF":7.4,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143858985","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":"Cellular stress and macrophage activation","authors":"Jing Yu,&nbsp;Bin-Zhi Qian","doi":"10.1016/j.smim.2025.101953","DOIUrl":"10.1016/j.smim.2025.101953","url":null,"abstract":"<div><div>Cellular stress responses are pivotal in maintaining tissue homeostasis and intricately linked with various diseases. Macrophages, a key player of innate immune system, exhibit remarkable plasticity and responsiveness to environmental cues. In response to various cellular stresses, macrophages contribute to tissue homeostasis and disease progression via specialized activation/polarization associated with distinctive phenotypes and functions. This review provides an overview of the intricate interplay between cellular stress responses and macrophage activation, summarizing recent advancements and offering insights into potential therapeutic strategies.</div></div>","PeriodicalId":49546,"journal":{"name":"Seminars in Immunology","volume":"78 ","pages":""},"PeriodicalIF":7.4,"publicationDate":"2025-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143820677","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":"2025-04-12","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":"Interplay between the complement system and other immune pathways in the tumor microenvironment","authors":"Cecilia Garlanda ,&nbsp;Monica Dambra ,&nbsp;Elena Magrini","doi":"10.1016/j.smim.2025.101951","DOIUrl":"10.1016/j.smim.2025.101951","url":null,"abstract":"<div><div>Tumor growth and spread are sustained by the tumor microenvironment. Inflammatory cells and pathways have a fundamental role in the tumor microenvironment, driving or conditioning the functional activation of other leukocyte subsets and favoring evasion of anti-tumor immunity. One of the inflammatory pathways contributing to cancer-related inflammation is the complement system. Complement has long been considered an immune mechanism associated with immunosurveillance. More recently it emerged as a tumor promoting pathway, due to direct effects on cancer cells or indirect effects via immunosuppression driven by myeloid cells. The role of complement in cancer is complex and ambiguous, and depends on the tumor type and stage, as well as other factors including oncogenic drivers, leukocyte infiltration, interactions with other tumor microenvironment components or tumor cells. Other factors of complexity include the source of complement molecules, its canonical or non-canonical extracellular functions, its potential intracellular activation, and the interaction with other systems, such as the coagulation or the microbiome. Preclinical studies generally demonstrate the involvement of complement activation in smouldering inflammation in cancer and promotion of an immunosuppressive environment. These studies paved the way for clinical trials aimed at enhancing the potential of immunotherapy, in particular by targeting complement-dependent myeloid-sustained immunosuppression. However, the complex role of complement in cancer and the multiplicity of complement players may represent stumbling blocks and account for failures of clinical trials, and suggest that further studies are required to identify patient subsets who may benefit from specific complement molecule targeting in combination with conventional therapies or immunotherapy. Here, we will discuss the anti- or pro-tumor role of complement activation in cancer, focusing on the interactions of complement with immune cells within the tumor microenvironment, in particular the myeloid compartment. Furthermore, we will examine the potential of complement targeting in cancer treatment, particularly in the context of macrophage reprogramming.</div></div>","PeriodicalId":49546,"journal":{"name":"Seminars in Immunology","volume":"78 ","pages":"Article 101951"},"PeriodicalIF":7.4,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143799164","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":"Endogenous glucocorticoids and human immunity: Time to revisit old dogmas","authors":"Brinda Bhatt ,&nbsp;Luis M. Franco","doi":"10.1016/j.smim.2025.101949","DOIUrl":"10.1016/j.smim.2025.101949","url":null,"abstract":"<div><div>Glucocorticoids (GCs) are steroid hormones with diverse and important roles in the physiologic response to stress. These include permissive and suppressive effects on immunity, which help prepare the organism for future infectious stressors and control the immunological response to a recent stressor, preventing autoimmune damage. The ability of GCs to rapidly suppress an overactive immune system has been harnessed pharmacologically and synthetic GCs have played a central role in the treatment of inflammatory and autoimmune diseases for the past eight decades. Given their importance in clinical medicine, an emphasis on the anti-inflammatory and immunosuppressive effects of synthetic GCs has overshadowed the study of the physiologic roles of endogenous GCs in human immunity. The rising interest in the intersection between neurobiology and immunity, and the development of technologies that facilitate direct experimentation with human cells and tissues, make this an ideal time to critically review existing knowledge on this subject. In this review of the past 100 years of biomedical literature on the effects of endogenous glucocorticoids on human immunity, we summarize existing experimental evidence, reveal key knowledge gaps and misconceptions, and highlight specific areas of opportunity for new research.</div></div>","PeriodicalId":49546,"journal":{"name":"Seminars in Immunology","volume":"78 ","pages":"Article 101949"},"PeriodicalIF":7.4,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143791907","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 role of the adaptive immune system in the initiation and persistence of multiple sclerosis","authors":"Ali Maisam Afzali ,&nbsp;Thomas Korn","doi":"10.1016/j.smim.2025.101947","DOIUrl":"10.1016/j.smim.2025.101947","url":null,"abstract":"<div><div>Multiple sclerosis (MS) is an inflammatory, demyelinating disease of the central nervous system (CNS) in which complex networks of interacting immune cells initiate and sustain the disease. The pathogenesis of relapsing MS is driven by adaptive immune cells that become activated outside the CNS compartment and then migrate into the CNS to initiate a presumably autoimmune inflammatory process. Recent technological advances, particularly single-cell analyses, have revealed substantial heterogeneity in T and B cells involved in this stage of the disease. Disease progression involves different mechanisms, with compartmentalized inflammation and chronic activation of CNS-resident cells becoming predominant features. The contribution of tissue-resident adaptive immune cells to the pathology of progressive MS, including tissue-resident CD8⁺ T cells and B cells in the meningeal compart, is increasingly debated. Here, we will discuss concepts of how adaptive immune cells might initiate and maintain autoimmune inflammation in the CNS, while the responses to autoimmune inflammation of CNS intrinsic cells, including astrocytes, oligodendrocytes, and neurons, are described elsewhere <span><span>[1]</span></span>, <span><span>[2]</span></span>, <span><span>[3]</span></span>, <span><span>[4]</span></span>, <span><span>[5]</span></span> and will not be a particular focus of this overview. Finally, it is the aim of this review to conceptualize the grounds for efficient therapeutic interventions targeting players of the adaptive immune system in relapsing but also in progressive MS.</div></div>","PeriodicalId":49546,"journal":{"name":"Seminars in Immunology","volume":"78 ","pages":"Article 101947"},"PeriodicalIF":7.4,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143760277","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":"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":"2025-04-02","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":"Variable domain glycosylation as a marker and modulator of immune responses: Insights into autoimmunity and B-cell malignancies","authors":"Roxane Biersteker ,&nbsp;Oliver F. Larsen ,&nbsp;Manfred Wuhrer ,&nbsp;Tom W.J. Huizinga ,&nbsp;René E.M. Toes ,&nbsp;Lise Hafkenscheid","doi":"10.1016/j.smim.2025.101946","DOIUrl":"10.1016/j.smim.2025.101946","url":null,"abstract":"<div><div>Glycosylation of antibodies is essential for shaping immune responses, as it contributes significantly to antibody function and diversity. While immunoglobulin G (IgG) Fc glycosylation is well-characterized, variable domain glycosylation (VDG) introduces an additional and less understood layer of complexity. Notably, VDG is associated with rheumatoid arthritis, where disease-specific IgG autoantibodies abundantly express this modification. Moreover, its presence on these antibodies correlates with disease progression in at-risk individuals and therapeutic outcomes. Emerging evidence links increased VDG levels to other autoimmune diseases and B-cell malignancies, highlighting its potential as both a marker and modulator in disease onset and progression. Importantly, VDG on IgG is now recognized to influence antigen binding, enhance antibody stability, and modulate interactions with the human neonatal Fc receptor. In addition, glycans in the antigen-binding domains of autoreactive B-cell receptors (BCRs) can significantly impact B cell activation. In follicular lymphoma and other B-cell malignancies, the presence of <em>N-</em>glycosylation sites in the immunoglobulin variable domains leads to the introduction of oligomannose glycans, which are postulated to bind to mannose-specific lectins. This interaction might promote antigen-independent activation of BCRs, thereby supporting malignant B cell survival and proliferation. Here, we explore the regulatory pathways of VDG and its functional roles across both physiological and pathological conditions, underscoring its prevalence and significance in various autoimmune diseases and B-cell malignancies. Ultimately, advancing our understanding of the regulatory factors influencing VDG and its functional implications could be highly rewarding for identifying potential therapeutic targets and strategies to prevent and treat autoimmune diseases and B-cell malignancies.</div></div>","PeriodicalId":49546,"journal":{"name":"Seminars in Immunology","volume":"78 ","pages":"Article 101946"},"PeriodicalIF":7.4,"publicationDate":"2025-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143724882","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}