Pub Date : 2025-04-28DOI: 10.1016/j.smim.2025.101961
Samagra Agrawal, Govind K. Makharia
Celiac disease and food-allergy are both food-related chronic immune disorders with a common pathogenic link being breakdown in the gut tolerance to otherwise innocuous food antigens. Notwithstanding the similarities, there are significant differences in the pathogenesis of both disorders, which translates to variations in clinical presentations, diagnostic tools and disease epidemiology. The past few decades have witnessed a global increase in prevalence and incidence of both disorders, driven both by true rise due to epidemiological factors and unmasking of previously undiagnosed disease due to better diagnostics and health seeking behavior, related to economic factors. Worldwide as more cases are diagnosed, disparities in healthcare and resources available for disease management are increasingly becoming more relevant but are infrequently discussed. In this review we will discuss the global epidemiology of celiac disease and food allergy, their epidemiological risk factors and future directions for their improved diagnosis and management.
{"title":"Global aspects of celiac disease and food allergy","authors":"Samagra Agrawal, Govind K. Makharia","doi":"10.1016/j.smim.2025.101961","DOIUrl":"10.1016/j.smim.2025.101961","url":null,"abstract":"<div><div>Celiac disease and food-allergy are both food-related chronic immune disorders with a common pathogenic link being breakdown in the gut tolerance to otherwise innocuous food antigens. Notwithstanding the similarities, there are significant differences in the pathogenesis of both disorders, which translates to variations in clinical presentations, diagnostic tools and disease epidemiology. The past few decades have witnessed a global increase in prevalence and incidence of both disorders, driven both by true rise due to epidemiological factors and unmasking of previously undiagnosed disease due to better diagnostics and health seeking behavior, related to economic factors. Worldwide as more cases are diagnosed, disparities in healthcare and resources available for disease management are increasingly becoming more relevant but are infrequently discussed. In this review we will discuss the global epidemiology of celiac disease and food allergy, their epidemiological risk factors and future directions for their improved diagnosis and management.</div></div>","PeriodicalId":49546,"journal":{"name":"Seminars in Immunology","volume":"78 ","pages":"Article 101961"},"PeriodicalIF":7.4,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143879308","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}
Pub Date : 2025-04-27DOI: 10.1016/j.smim.2025.101956
Magdalena Lerch , Sudarshini Ramanathan
Cancer is a leading cause of morbidity and mortality worldwide. The development of immune checkpoint inhibitors (ICI) has revolutionised cancer therapy, and patients who were previously incurable can now have excellent responses. These therapies work by blocking inhibitory immune pathways, like cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed cell death-1 (PD-1), its ligand PD-L1, and lymphocyte activation gene 3 (LAG-3); which leads to increased anti-tumour immune responses. However, their use can lead to the development of immune-related adverse events (irAEs), which may result in severe disability, interruption of cancer therapy, and even death. Neurological autoimmune sequelae occur in 1–10 % of patients treated with ICIs and can be fatal. They encompass a broad spectrum of diseases, may affect the central and the peripheral nervous system, and include syndromes like encephalitis, cerebellitis, neuropathy, and myositis. In some cases, neurological irAEs can be associated with autoantibodies recognising neuronal or glial targets. In this review, we first describe the key targets in ICI therapy, followed by a formulation of irAEs and their clinical presentations, where we focus on neurological syndromes. We comprehensively formulate the current literature evaluating cell surface and intracellular autoantibodies, cytokines, chemokines, leukocyte patterns, other blood derived biomarkers, and immunogenetic profiles; and highlight their impact on our understanding of the pathogenesis of neurological irAEs. Finally, we describe therapeutic pathways and patient outcomes, and provide an overview on future aspects of ICI cancer therapy.
{"title":"The pathogenesis of neurological immune-related adverse events following immune checkpoint inhibitor therapy","authors":"Magdalena Lerch , Sudarshini Ramanathan","doi":"10.1016/j.smim.2025.101956","DOIUrl":"10.1016/j.smim.2025.101956","url":null,"abstract":"<div><div>Cancer is a leading cause of morbidity and mortality worldwide. The development of immune checkpoint inhibitors (ICI) has revolutionised cancer therapy, and patients who were previously incurable can now have excellent responses. These therapies work by blocking inhibitory immune pathways, like cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed cell death-1 (PD-1), its ligand PD-L1, and lymphocyte activation gene 3 (LAG-3); which leads to increased anti-tumour immune responses. However, their use can lead to the development of immune-related adverse events (irAEs), which may result in severe disability, interruption of cancer therapy, and even death. Neurological autoimmune sequelae occur in 1–10 % of patients treated with ICIs and can be fatal. They encompass a broad spectrum of diseases, may affect the central and the peripheral nervous system, and include syndromes like encephalitis, cerebellitis, neuropathy, and myositis. In some cases, neurological irAEs can be associated with autoantibodies recognising neuronal or glial targets. In this review, we first describe the key targets in ICI therapy, followed by a formulation of irAEs and their clinical presentations, where we focus on neurological syndromes. We comprehensively formulate the current literature evaluating cell surface and intracellular autoantibodies, cytokines, chemokines, leukocyte patterns, other blood derived biomarkers, and immunogenetic profiles; and highlight their impact on our understanding of the pathogenesis of neurological irAEs. Finally, we describe therapeutic pathways and patient outcomes, and provide an overview on future aspects of ICI cancer therapy.</div></div>","PeriodicalId":49546,"journal":{"name":"Seminars in Immunology","volume":"78 ","pages":"Article 101956"},"PeriodicalIF":7.4,"publicationDate":"2025-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143877450","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}
Pub Date : 2025-04-26DOI: 10.1016/j.smim.2025.101957
Lili Li , Yanqiong Zeng , Genhong Cheng , Heng Yang
In response to stress stimuli, cells have evolved various mechanisms to integrate internal and external signals to achieve dynamic homeostasis. Lysine acetyltransferase (KATs) and deacetyltransferase (KDACs) are the key modulators of epigenetic modifications, enabling cells to modulate cellular responses through the acetylation and deacetylation of both histone and nonhistone proteins. Understanding the signaling pathways involved in cellular stress response, along with the roles of KATs and KDACs may pave the way for the development of novel therapeutic strategies. This review discusses the molecular mechanisms of acetylation and deacetylation in stress responses related to tumorigenesis, viral and bacterial infections. In tumorigenesis section, we focused on the tumor cells’ intrinsic and external molecules and signaling pathways regulated by acetylation and deacetylation modification. In viral and bacterial infections, we summarized the update research on acetylation and deacetylation modification in viral and bacterial infections, which systematical introduction on this topic is not too much. Additionally, we provide an overview of current therapeutic interventions and clinical trials involving KAT and KDAC inhibitors in the treatment of cancer, as well as viral and bacterial infection-related diseases.
{"title":"Acetylation and deacetylation dynamics in stress response to cancer and infections","authors":"Lili Li , Yanqiong Zeng , Genhong Cheng , Heng Yang","doi":"10.1016/j.smim.2025.101957","DOIUrl":"10.1016/j.smim.2025.101957","url":null,"abstract":"<div><div>In response to stress stimuli, cells have evolved various mechanisms to integrate internal and external signals to achieve dynamic homeostasis. Lysine acetyltransferase (KATs) and deacetyltransferase (KDACs) are the key modulators of epigenetic modifications, enabling cells to modulate cellular responses through the acetylation and deacetylation of both histone and nonhistone proteins. Understanding the signaling pathways involved in cellular stress response, along with the roles of KATs and KDACs may pave the way for the development of novel therapeutic strategies. This review discusses the molecular mechanisms of acetylation and deacetylation in stress responses related to tumorigenesis, viral and bacterial infections. In tumorigenesis section, we focused on the tumor cells’ intrinsic and external molecules and signaling pathways regulated by acetylation and deacetylation modification. In viral and bacterial infections, we summarized the update research on acetylation and deacetylation modification in viral and bacterial infections, which systematical introduction on this topic is not too much. Additionally, we provide an overview of current therapeutic interventions and clinical trials involving KAT and KDAC inhibitors in the treatment of cancer, as well as viral and bacterial infection-related diseases.</div></div>","PeriodicalId":49546,"journal":{"name":"Seminars in Immunology","volume":"78 ","pages":"Article 101957"},"PeriodicalIF":7.4,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143877360","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}
Pub Date : 2025-04-23DOI: 10.1016/j.smim.2025.101960
Dianne E. Campbell , Sam Mehr , Olivia G. Moscatelli , Robert P. Anderson , Jason A. Tye-Din
Coeliac disease and food allergy management primarily relies on the strict avoidance of dietary antigens. This approach is challenging to maintain in real-world settings and in food allergy carries the risk of life-threatening anaphylaxis. Despite their distinct pathogenesis, both disorders are driven by maladaptive responses to dietary proteins, creating opportunities for shared treatment strategies. In food allergy, desensitisation therapies such as oral, sublingual, and epicutaneous immunotherapy are well-established, complemented by biologics like omalizumab and dupilumab. However, the induction of sustained tolerance remains challenging. In contrast, therapeutic advancements for coeliac disease are still in their early stages. Current efforts focus on gluten detoxification or modification, immune blockade or modulation, tolerogenic approaches, and barrier restoration. Emerging therapies, including JAK and BTK inhibitors and microbiome-targeted interventions, support further targeted treatment options for both conditions. Biomarkers tracking gluten-specific T cells have emerged as valuable tools for immunomonitoring and symptom assessment in coeliac disease, although standardisation of patient-reported outcome measures and gluten challenge protocols is still needed. Food allergy trials are reliant on double-blind placebo-controlled food challenges to measure allergen reactivity, but these are time-consuming, carry risks, and underscore the need for surrogate biomarkers. The successful development of immune-targeted therapies will require building an immune toolset to optimally assess systemic responses to antigens in both conditions. Clinically, this could lead to better outcomes for patients who might otherwise remain undiagnosed or untreated due to the absence of significant enteropathy or allergen-specific symptoms.
{"title":"Immune therapies in coeliac disease and food allergies: Advances, challenges, and opportunities","authors":"Dianne E. Campbell , Sam Mehr , Olivia G. Moscatelli , Robert P. Anderson , Jason A. Tye-Din","doi":"10.1016/j.smim.2025.101960","DOIUrl":"10.1016/j.smim.2025.101960","url":null,"abstract":"<div><div>Coeliac disease and food allergy management primarily relies on the strict avoidance of dietary antigens. This approach is challenging to maintain in real-world settings and in food allergy carries the risk of life-threatening anaphylaxis. Despite their distinct pathogenesis, both disorders are driven by maladaptive responses to dietary proteins, creating opportunities for shared treatment strategies. In food allergy, desensitisation therapies such as oral, sublingual, and epicutaneous immunotherapy are well-established, complemented by biologics like omalizumab and dupilumab. However, the induction of sustained tolerance remains challenging. In contrast, therapeutic advancements for coeliac disease are still in their early stages. Current efforts focus on gluten detoxification or modification, immune blockade or modulation, tolerogenic approaches, and barrier restoration. Emerging therapies, including JAK and BTK inhibitors and microbiome-targeted interventions, support further targeted treatment options for both conditions. Biomarkers tracking gluten-specific T cells have emerged as valuable tools for immunomonitoring and symptom assessment in coeliac disease, although standardisation of patient-reported outcome measures and gluten challenge protocols is still needed. Food allergy trials are reliant on double-blind placebo-controlled food challenges to measure allergen reactivity, but these are time-consuming, carry risks, and underscore the need for surrogate biomarkers. The successful development of immune-targeted therapies will require building an immune toolset to optimally assess systemic responses to antigens in both conditions. Clinically, this could lead to better outcomes for patients who might otherwise remain undiagnosed or untreated due to the absence of significant enteropathy or allergen-specific symptoms.</div></div>","PeriodicalId":49546,"journal":{"name":"Seminars in Immunology","volume":"78 ","pages":"Article 101960"},"PeriodicalIF":7.4,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143864235","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}
Pub Date : 2025-04-22DOI: 10.1016/j.smim.2025.101959
Pei Min Thong , Yi Hao Wong , Hardy Kornfeld , Delia Goletti , Catherine W.M. Ong
The rising prevalence of diabetes mellitus (DM) is undermining global efforts to eliminate tuberculosis (TB). Most studies found that patients with pulmonary TB and DM have more cavitary lung lesions, higher mycobacterial burden on the lungs, longer periods of infectiousness, and worse outcomes. Both human and animal studies indicate that TB-DM is associated with impaired innate and adaptive immune responses, resulting in delayed bacterial clearance. Similar observations have been noted in other infections, such as those caused by Klebsiella pneumoniae, where DM contributes to increased susceptibility and worse outcomes due to compromised immune functions including defective phagocytosis and impaired early immune cell recruitment. This review delves into the mechanisms of immune dysfunction in TB-DM, exploring how DM increases TB susceptibility and severity. By elucidating these complex interactions, this review aims to offer insights into more effective strategies for managing and improving outcomes for patients with this challenging comorbidity.
{"title":"Immune dysregulation of diabetes in tuberculosis","authors":"Pei Min Thong , Yi Hao Wong , Hardy Kornfeld , Delia Goletti , Catherine W.M. Ong","doi":"10.1016/j.smim.2025.101959","DOIUrl":"10.1016/j.smim.2025.101959","url":null,"abstract":"<div><div>The rising prevalence of diabetes mellitus (DM) is undermining global efforts to eliminate tuberculosis (TB). Most studies found that patients with pulmonary TB and DM have more cavitary lung lesions, higher mycobacterial burden on the lungs, longer periods of infectiousness, and worse outcomes. Both human and animal studies indicate that TB-DM is associated with impaired innate and adaptive immune responses, resulting in delayed bacterial clearance. Similar observations have been noted in other infections, such as those caused by <em>Klebsiella pneumoniae</em>, where DM contributes to increased susceptibility and worse outcomes due to compromised immune functions including defective phagocytosis and impaired early immune cell recruitment. This review delves into the mechanisms of immune dysfunction in TB-DM, exploring how DM increases TB susceptibility and severity. By elucidating these complex interactions, this review aims to offer insights into more effective strategies for managing and improving outcomes for patients with this challenging comorbidity.</div></div>","PeriodicalId":49546,"journal":{"name":"Seminars in Immunology","volume":"78 ","pages":"Article 101959"},"PeriodicalIF":7.4,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143855100","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}
Pub Date : 2025-04-22DOI: 10.1016/j.smim.2025.101955
Marie A. Homeyer , Alice Falck , Lucie Y. Li , Harald Prüss
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.
{"title":"From immunobiology to intervention: Pathophysiology of autoimmune encephalitis","authors":"Marie A. Homeyer , Alice Falck , Lucie Y. Li , 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}
Pub Date : 2025-04-22DOI: 10.1016/j.smim.2025.101954
Marion Moreews, Mikael C.I. Karlsson
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.
{"title":"Endoplasmic reticulum stress: A key player in immune cell regulation and autoimmune disorders","authors":"Marion Moreews, 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}
Pub Date : 2025-04-22DOI: 10.1016/j.smim.2025.101958
Abiha Kazmi , Raman Gill , Paula Restrepo , Andrew L. Ji
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.
{"title":"The spatial and single-cell landscape of skin: Charting the multiscale regulation of skin immune function","authors":"Abiha Kazmi , Raman Gill , Paula Restrepo , 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}
Pub Date : 2025-04-12DOI: 10.1016/j.smim.2025.101953
Jing Yu, Bin-Zhi Qian
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.
{"title":"Cellular stress and macrophage activation","authors":"Jing Yu, 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}
Pub Date : 2025-04-12DOI: 10.1016/j.smim.2025.101952
Yan Li , Nuo Chen , Yaxin Guo , Lining Zhang
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.
{"title":"The stress and the alarmin-like cytokine interleukin-37 mediated extracellular and intracellular signal pathways","authors":"Yan Li , Nuo Chen , Yaxin Guo , 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}
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