Seminars in Immunology最新文献

{"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}

{"title":"Interferon regulatory factor 3 beyond innate immunity: Regulation in obesity and metabolic disorders","authors":"Heng Li ,&nbsp;Yongliang Zhang ,&nbsp;Hong Yong Peh","doi":"10.1016/j.smim.2025.101948","DOIUrl":"10.1016/j.smim.2025.101948","url":null,"abstract":"<div><div>Interferon regulatory factor 3 (IRF3) is a transcription factor known primarily for its role in antiviral immunity via regulation of type I interferons (IFNs). Recent research has broadened its significance to encompass metabolic disorders, particularly obesity and diabetes. Obesity is characterized by chronic low-grade inflammation, insulin resistance, and metabolic dysfunction, all of which are increasingly found to be associated with immune signaling pathways. IRF3 has emerged as an important regulator in the development of obesity and type 2 diabetes (T2D), predominantly through its regulation of inflammatory cytokines production in various cells in adipose tissue. In obese individuals, IRF3 is activated in the adipocytes and adipose tissue macrophages, to promote the expression of inflammatory cytokines, thereby contributing to chronic inflammation and exacerbating insulin resistance. Moreover, IRF3 has been linked to mitochondrial dysfunction in hepatic disorders, further amplifying metabolic stress and imbalances associated with obesity. The growing evidence suggests that IRF3 is an important mediator in both immune and metabolic pathways, highlighting its potential as a target for the development of therapeutic interventions for obesity-related inflammation and metabolic dysfunction.</div></div>","PeriodicalId":49546,"journal":{"name":"Seminars in Immunology","volume":"78 ","pages":"Article 101948"},"PeriodicalIF":7.4,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143715135","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 immunological processes behind aquaporin 4-antibody seropositive neuromyelitis optica spectrum disorders","authors":"Monika Bradl ,&nbsp;Qian Yu ,&nbsp;Yoshiki Takai","doi":"10.1016/j.smim.2025.101945","DOIUrl":"10.1016/j.smim.2025.101945","url":null,"abstract":"<div><div>Ever since the discovery of pathogenic aquaporin 4-specific antibodies in the serum of patients with neuromyelitis optica spectrum disorders current knowledge about clinical observations and diagnosis, and about the underlying pathology and resulting therapies have been put forward in excellent reviews and primary publications. However, in order to further develop novel strategies for the treatment of this disease, there is an urgent need to understand the immunological processes associated with the formation of the pathogenic antibodies, and with aberrant immune responses observed in affected patients. In this review, we will highlight and evaluate important studies on these processes.</div></div>","PeriodicalId":49546,"journal":{"name":"Seminars in Immunology","volume":"78 ","pages":"Article 101945"},"PeriodicalIF":7.4,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143705964","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":"Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD): Insights into pathogenesis and biomarkers of prognosis","authors":"Jane Andersen ,&nbsp;Fabienne Brilot","doi":"10.1016/j.smim.2025.101944","DOIUrl":"10.1016/j.smim.2025.101944","url":null,"abstract":"<div><div>MOG antibody-associated disease (MOGAD), an inflammatory demyelinating pathology, is typically associated with the clinical phenotypes acute disseminated encephalomyelitis (ADEM), optic neuritis (ON), or transverse myelitis (TM). The mainstay of diagnosis is detection of antibodies targeting oligodendrocyte-expressed MOG (MOG-IgG). MOG-IgG-mediated demyelination occurs via complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), enhanced cognate T-cell CNS infiltration and activation, and oligodendrocyte cytoskeleton disruption, but the exact role of the immune system in MOGAD is still poorly understood. The disease course is either monophasic or relapsing, with relapsing course affecting approximately two-thirds of individuals. Neurological disability accumulates with relapse and may manifest as visual, motor, sensory, and cognitive deficits. Thus, accurate disease course prediction is of paramount importance. Prognostic biomarkers, implemented at a global scale, have the potential to guide timely therapeutic decisions to limit relapse-associated disability accrual while simultaneously avoiding unnecessary immunosuppression in monophasic individuals. This review explores recent insights in the understanding of MOGAD pathogenesis as well as advances in prognostic biomarkers of relapsing course and disease activity.</div></div>","PeriodicalId":49546,"journal":{"name":"Seminars in Immunology","volume":"78 ","pages":"Article 101944"},"PeriodicalIF":7.4,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143621427","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":"Differential immune responses behind different celiac disease manifestations","authors":"Esko Kemppainen,&nbsp;Olga Albó,&nbsp;Helka Kaunisto,&nbsp;Emilia Siukola,&nbsp;Katri Lindfors","doi":"10.1016/j.smim.2025.101941","DOIUrl":"10.1016/j.smim.2025.101941","url":null,"abstract":"<div><div>In celiac disease (CeD), dietary gluten serves as the driver for a comparatively well characterized small bowel mucosal immune response that generally results in small bowel mucosal villous atrophy and crypt hyperplasia along with a disease-specific transglutaminase 2 (TG2) targeting autoantibody response. Individuals with positive TG2 autoantibodies but normal small intestinal mucosal morphology are regarded at increased risk of developing CeD and represent patients with potential CeD. The removal of gluten from the diet leads to disappearance of the autoantibodies and normalization of the mucosal architecture in most cases. However, refractory CeD patients deviate from this dogma as they present with abnormal T cell compartment, persistent symptoms and villous atrophy despite a strict gluten-free diet. The heterogeneity of CeD presentation is further diversified by varying symptomatology. Gastrointestinal symptoms are the most canonical signs of CeD, and they include for instance diarrhea, vomiting, constipation and abdominal pain. Yet, a great portion of the patients manifest the disease at extraintestinal sites such as skin, musculoskeletal system or neuronal tissues. Beyond the involvement of various transglutaminase autoantibodies, the detailed immune mechanisms contributing to the development of these manifestations remains elusive, though. This review highlights the current understanding of the immunological differences in various manifestations of CeD. As the immunological basis of the different CeD phenotypes is at present insufficiently understood, more research on the subject is warranted before such data could be maximally applied to clinical practice.</div></div>","PeriodicalId":49546,"journal":{"name":"Seminars in Immunology","volume":"78 ","pages":"Article 101941"},"PeriodicalIF":7.4,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143621426","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":"Neuroimmune interactions between itch neurons and skin microbes","authors":"Sharan Kumar Balaji ,&nbsp;Waris Muhammad Khuwaja ,&nbsp;Md Liakat Hossain ,&nbsp;Luchiano Giovanni Benjamin Fernando,&nbsp;Xintong Dong","doi":"10.1016/j.smim.2025.101933","DOIUrl":"10.1016/j.smim.2025.101933","url":null,"abstract":"<div><div>Itch is an unpleasant sensation that is encoded by specific sensory neurons called pruriceptors. Itch is associated with almost all skin diseases. Recent studies revealed that many itchy skin diseases are associated with microbiome dysbiosis. Pathogenic microbes secrete proteases and toxins to invade skin cells. Some microbial products can directly activate sensory neurons, while others activate the mammalian immune system and indirectly cause itch. In this review, we summarize the current knowledge on microbe-immune-neuron crosstalks and discuss their relevance in itchy skin diseases.</div></div>","PeriodicalId":49546,"journal":{"name":"Seminars in Immunology","volume":"78 ","pages":"Article 101933"},"PeriodicalIF":7.4,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143580292","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}