Immunological Reviews最新文献

{"title":"Chronic Inflammation in Asthma: Looking Beyond the Th2 Cell","authors":"Simone E. M. Olsthoorn,&nbsp;Anneloes van Krimpen,&nbsp;Rudi W. Hendriks,&nbsp;Ralph Stadhouders","doi":"10.1111/imr.70010","DOIUrl":"https://doi.org/10.1111/imr.70010","url":null,"abstract":"<p>Asthma is a common chronic inflammatory disease of the airways. A substantial number of patients present with severe and therapy-resistant asthma, for which the underlying biological mechanisms remain poorly understood. In most asthma patients, airway inflammation is characterized by chronic activation of type 2 immunity. CD4⁺ T helper 2 (Th2) cells are the canonical producers of the cytokines that fuel type 2 inflammation: interleukin (IL)-4, IL-5, IL-9, and IL-13. However, more recent findings have shown that other lymphocyte subsets, in particular group 2 innate lymphoid cells (ILC2s) and type 2 CD8⁺ cytotoxic T (Tc2) cells, can also produce large amounts of type 2 cytokines. Importantly, a substantial number of severe therapy-resistant asthma patients present with chronic type 2 inflammation, despite the high sensitivity of Th2 cells for suppression by corticosteroids—the mainstay drugs for asthma. Emerging evidence indicates that ILC2s and Tc2 cells are more abundant in severe asthma patients and can adopt corticosteroid-resistance states. Moreover, many severe asthma patients do not present with overt type 2 airway inflammation, implicating non-type 2 immunity as a driver of disease. In this review, we will discuss asthma pathophysiology and focus on the roles played by ILC2s, Tc2 cells, and non-type 2 lymphocytes, placing special emphasis on severe disease forms.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"330 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imr.70010","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143513660","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":"Location, Location, Location: Spatial Immune-Stroma Crosstalk Drives Pathogenesis in Asthma","authors":"Régis Joulia,&nbsp;Clare M. Lloyd","doi":"10.1111/imr.70013","DOIUrl":"https://doi.org/10.1111/imr.70013","url":null,"abstract":"<p>Chronic lung diseases including asthma are characterized by an abnormal immune response and active tissue remodeling. These changes in the architecture of the tissue are a fundamental part of the pathology across the life course of patients suffering from asthma. Current treatments aim at dampening the immune system hyperactivation, but effective drugs targeting stromal or acellular structures are still lacking. This is mainly due to the lack of a detailed understanding of the composition of the large airways and the cellular interactions taking place in this niche. We and others have revealed multiple aspects of the spatial architecture of the airway wall in response to airborne insults. In this review, we discuss four elements that we believe should be the focus of future asthma research across the life course, to increase understanding and improve therapies: (i) specialized lung niches, (ii) the 3D architecture of the epithelium, (iii) the extracellular matrix, and (iv) the vasculature. These components comprise the main stromal structures at the airway wall, each playing a key role in the development of asthma and directing the immune response. We summarize promising future directions that will enhance lung research, ultimately benefiting patients with asthma.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"330 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imr.70013","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143475778","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":"T1-T2 Interplay in the Complex Immune Landscape of Severe Asthma","authors":"Marc Gauthier,&nbsp;Sagar L. Kale,&nbsp;Anuradha Ray","doi":"10.1111/imr.70011","DOIUrl":"https://doi.org/10.1111/imr.70011","url":null,"abstract":"<p>Asthma is orchestrated by an aberrant immune response involving a complex interplay between multiple inflammatory cell types. An increase in Th2 cells in the asthmatic airway is a hallmark of asthma, and biologics blocking their effector functions have been life-changing for many severe asthma patients who poorly respond to immunosuppression by corticosteroids. However, studies in the past decade have highlighted not only other cell types that also produce Th2 cytokines boosting the Type 2/T2 phenotype but also a heightened IFN-γ response, primarily from T cells, referred to as a Type 1/T1 immune response. Data derived from studies of immune cells in the airways and mouse models of severe asthma suggest a role of IFN-γ in corticosteroid resistance, airway hyperreactivity, and also airway remodeling via effects on other cell types including mast cells, eosinophils, airway epithelial cells, and airway smooth muscle cells. The simultaneous presence of T1 and T2 immune responses is detectable in the sickest of asthma patients in whom corticosteroids suppress the T2 but not the T1 response. This article has reviewed our current understanding of the complex T1–T2 interplay in severe asthma highlighting mediators that impact both arms which may be targeted alone or in combination for disease alleviation.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"330 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imr.70011","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143475777","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":"Integrative Roles of Pro-Inflammatory Cytokines on Airway Smooth Muscle Structure and Function in Asthma","authors":"Maria L. Ford,&nbsp;Mohammad Irshad Reza,&nbsp;Anushka Ruwanpathirana,&nbsp;Venkatachalem Sathish,&nbsp;Rodney D. Britt Jr","doi":"10.1111/imr.70007","DOIUrl":"https://doi.org/10.1111/imr.70007","url":null,"abstract":"<p>Asthma has become more appreciated for its heterogeneity with studies identifying type 2 and non-type 2 phenotypes/endotypes that ultimately lead to airflow obstruction, airway hyperresponsiveness, and remodeling. The pro-inflammatory environment in asthma influences airway smooth muscle (ASM) structure and function. ASM has a vast repertoire of inflammatory receptors that, upon activation, contribute to prominent features in asthma, notably immune cell recruitment and activation, hypercontractility, proliferation, migration, and extracellular matrix protein deposition. These pro-inflammatory responses in ASM can be mediated by both type 2 (e.g., IL-4, IL-13, and TSLP) and non-type 2 (e.g., TNFα, IFNγ, IL-17A, and TGFβ) cytokines, highlighting roles for ASM in type 2 and non-type 2 asthma phenotypes/endotypes. In recent years, there has been considerable advances in understanding how pro-inflammatory cytokines promote ASM dysfunction and impair responsiveness to asthma therapy, corticosteroids and long-acting β2-adrenergic receptor agonists (LABAs). Transcriptomic analyses on human ASM cells and tissues have expanded our knowledge in this area but have also raised new questions regarding ASM and its role in asthma. In this review, we discuss how pro-inflammatory cytokines, corticosteroids, and LABAs affect ASM structure and function, with particular focus on changes in gene expression and transcriptional programs in type 2 and non-type 2 asthma.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"330 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imr.70007","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143475779","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":"Tissue-Resident Th2 Cells in Type 2 Immunity and Allergic Diseases","authors":"Jenny M. Mannion,&nbsp;Rod A. Rahimi","doi":"10.1111/imr.70006","DOIUrl":"https://doi.org/10.1111/imr.70006","url":null,"abstract":"<div>\u0000 \u0000 <p>Type 2 immunity represents a unique immune module that provides host protection against macro-parasites and noxious agents such as venoms and toxins. In contrast, maladaptive type 2 immune responses cause allergic diseases. While multiple cell types play important roles in type 2 immunity, recent studies in humans and murine models of chronic allergic diseases have shown that a distinct population of tissue-resident, CD4+ T helper type 2 (Th2) cells play a critical role in chronic allergic inflammation. The rules regulating Th2 cell differentiation have remained less well defined than other T cell subsets, but recent studies have shed new light into the specific mechanisms controlling Th2 cell biology in vivo. Here, we review our current understanding of the checkpoints regulating the development and function of tissue-resident Th2 cells with a focus on chronic allergic diseases. We discuss evidence for a barrier tissue checkpoint in initial Th2 cell priming, including the role of neuropeptides, damage-associated molecular patterns, and dendritic cell macro-clusters. Furthermore, we review the evidence for a second barrier tissue checkpoint that instructs the development of multi-cytokine producing, tissue-resident Th2 cells that orchestrate allergic inflammation. Lastly, we discuss potential approaches to therapeutically target tissue-resident Th2 cells in chronic allergic diseases.</p>\u0000 </div>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"330 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143455864","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 Cystic Fibrosis Transmembrane Conductance Receptor Brakes Allergic Airway Inflammation","authors":"Daniel P. Cook,&nbsp;R. Stokes Peebles Jr.","doi":"10.1111/imr.70009","DOIUrl":"https://doi.org/10.1111/imr.70009","url":null,"abstract":"<p>Cystic fibrosis (CF) is a common autosomal recessive disease resulting from mutations of the gene that encodes the cystic fibrosis transmembrane conductance regulator (CFTR). Although severe pulmonary neutrophilic inflammation is a primary pathologic feature of CF, more recent studies reveal a role for type 2 inflammation that is characterized by eosinophilia directed by both the innate and adaptive immune systems through ILC2 and CD4⁺ Th2 cells, respectively. We have published that a clear type endotype exists within CF subjects stratified by Th2 inflammation, defined by increased obstructive pulmonary disease and a distinct phenotypic signature of increased allergic disease, infections, and burden of CF complications. Further, we showed an increased risk of death among CF subjects with type 2 inflammatory signatures compared to CF subjects lacking significant type 2 inflammation. The mechanisms of this heightened type 2 inflammatory signature in CF are still being defined, but it is clear that airway epithelial cells from CFTR-deficient mice have increased expression and release of IL-33, a key activator of ILC2 and Th2 cells, compared to persons with normal CFTR function. Further, there is strong evidence that CF regulates CD4⁺ Th2 function in a cell-intrinsic fashion. These concepts are explored in this review article.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"330 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imr.70009","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143455865","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":"Innate Immune Sensors in Health and Disease","authors":"Prajwal Gurung","doi":"10.1111/imr.70008","DOIUrl":"https://doi.org/10.1111/imr.70008","url":null,"abstract":"&lt;p&gt;The immune system constantly patrols the body, identifying and responding to deviations from homeostasis. These deviations can include pathogens, foreign substances (such as inert particles or allergens), or signs of host tissue damage (e.g., from trauma or radiation). A robust host response is essential to resolve these challenges. Both immune and nonimmune cells work together to initiate these critical responses. All cells express a variety of pattern recognition receptors (PRRs) that detect potential threats. These PRRs recognize molecular patterns associated with pathogens, known as pathogen-associated molecular patterns (PAMPs), or molecular patterns derived from damaged host tissue, known as damage-associated molecular patterns (DAMPs) (Figure 1).&lt;/p&gt;&lt;p&gt;One of the major classes of pattern recognition receptors (PRRs) includes membrane-bound Toll-like receptors (TLRs). As membrane-bound receptors, TLRs recognize extracellular threats, including PAMPs and DAMPs present in the extracellular milieu or within endosomes. Humans possess 10 functional TLRs, designated TLR1 to TLR10 [&lt;span&gt;1&lt;/span&gt;]. In contrast, mice—the most used model system in research—have twelve functional TLRs, including TLR1 to TLR9 and then TLR11 to TLR13 [&lt;span&gt;1&lt;/span&gt;]. Similarly, C-type lectin receptors (CLRs) [&lt;span&gt;2&lt;/span&gt;] and formyl peptide receptors (FPRs) [&lt;span&gt;3&lt;/span&gt;] are membrane-bound PRRs that recognize distinct extracellular PAMPs and DAMPs. Collectively, these membrane-bound PRRs initiate signaling pathways, including nuclear factor kappa B (NFκB), mitogen-activated protein kinases (MAPK) and interferon (IFN) signaling. This activation ultimately leads to the production of pro-inflammatory cytokines and promotes a protective immune response.&lt;/p&gt;&lt;p&gt;While membrane-bound PRRs effectively detect extracellular PAMPs and DAMPs, they are less suited for sensing intracellular threats. Many pathogens—including viruses, bacteria, and protozoa—have evolved to survive within intracellular niches. Additionally, cellular damage within the intracellular milieu (i.e., damage of organelles) must also be detected, a task that membrane-bound PRRs cannot perform. Fortunately, immune cells are equipped with a diverse array of cytoplasmic PRRs to detect intracellular PAMPs and DAMPs. These cytoplasmic sensors can be broadly classified into three major groups: Nod-like receptors (NLRs), AIM2-like receptors (ALRs) and RIG-I-like receptors (RLRs). Additionally, broad classes of RNA and DNA sensors—including DEAD/H-box helicases and ZBP1—play crucial roles in intracellular immune surveillance. These have been reviewed in this issue and will be discussed in brief below.&lt;/p&gt;&lt;p&gt;The innate immune response is a double-edged sword. An insufficient immune response can result in uncontrolled infections and impaired tissue repair, whereas an overactive or dysregulated immune response can lead to autoinflammation and immunopathology. Our understanding of the roles of cytoplasmic PRRs in","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"330 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imr.70008","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143431604","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":"Innate Immune Receptors as Dynamic Modulators of Extrafollicular Autoimmune B Cell Response","authors":"Danni Yi-Dan Zhu,&nbsp;Carlos Castrillon,&nbsp;Michael C. Carroll","doi":"10.1111/imr.70005","DOIUrl":"https://doi.org/10.1111/imr.70005","url":null,"abstract":"<div>\u0000 \u0000 <p>The immune system relies on carefully calibrated cellular machineries to enable distinction between endogenous and foreign molecules, with autoimmunity arising when this balance is disrupted. As potent autoantibody factories, B cells are major drivers of many autoimmune diseases. A significant fraction of patients affected by chronic autoimmune diseases such as systemic lupus erythematosus (SLE) exhibit pathogenic accumulation of B-cell subsets that are believed to be derived from the extrafollicular (EF) differentiation pathway. These B-cell subsets, although variously named and exhibiting intrinsic heterogeneity, are all poised producers of autoantibodies that correlate with patient pathophysiology. In addition, they are often characterized by biomarkers known to drive the innate immune response, including toll-like receptors and complement receptors. Although many innate receptors have well-established functions in myeloid cells and other immune cell types, their B cell-specific functions are still under active investigation and are crucial for understanding the molecular pathways that drive B-cell breaks of tolerance. In this review, we summarize studies on innate immune receptors that serve prominent roles in regulating EF B-cell activation in health and autoimmunity. By discussing independent and collaborative functions of these receptors, we hope to provide new perspectives in autoimmune disease signature research.</p>\u0000 </div>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"330 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143362576","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":"Signaling Activation and Modulation in Extrafollicular B Cell Responses","authors":"Julian Staniek,&nbsp;Marta Rizzi","doi":"10.1111/imr.70004","DOIUrl":"https://doi.org/10.1111/imr.70004","url":null,"abstract":"<p>The differentiation of naive follicular B cells into either the germinal center (GC) or extrafollicular (EF) pathway plays a critical role in shaping the type, affinity, and longevity of effector B cells. This choice also governs the selection and survival of autoreactive B cells, influencing their potential to enter the memory compartment. During the first 2–3 days following antigen encounter, initially activated B cells integrate activating signals from T cells, Toll-like receptors (TLRs), and cytokines, alongside inhibitory signals mediated by inhibitory receptors. This integration modulates the intensity of signaling, particularly of the PI3K/AKT/mTOR pathway, which plays a central role in guiding developmental decisions. These early signaling events determine whether B cells undergo GC maturation or differentiate rapidly into antibody-secreting cells (ASCs) via the EF pathway. Dysregulation of these signaling pathways—whether through excessive activation or defective regulatory mechanisms—can disrupt the balance between GC and EF fates, predisposing individuals to autoimmunity. Accordingly, aberrant PI3K/AKT/mTOR signaling has been implicated in the defective selection of autoreactive B cells, increasing the risk of autoimmune disease. This review focuses on the signaling events in newly activated B cells, with an emphasis on the induction and regulation of the PI3K/AKT/mTOR pathway. It also highlights gaps in our understanding of how alternative B cell fates are regulated. Both the physiological context and the implications of inborn errors of immunity (IEIs) and complex autoimmune conditions will be discussed in this regard.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"330 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imr.70004","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143362575","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":"A Structural Voyage Toward the Landscape of Humoral and Cellular Immune Escapes of SARS-CoV-2","authors":"Jun Liu,&nbsp;Yan Wu,&nbsp;George F. Gao","doi":"10.1111/imr.70000","DOIUrl":"10.1111/imr.70000","url":null,"abstract":"<div>\u0000 \u0000 <p>The genome-based surveillance of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the past nearly 5 years since its emergence has refreshed our understanding of virus evolution, especially on convergent co-evolution with the host. SARS-CoV-2 evolution has been characterized by the emergence of sets of mutations that affect the functional properties of the virus by altering its infectivity, virulence, transmissibility, and interactions with host immunity. This poses a huge challenge to global prevention and control measures based on drug treatment and vaccine application. As one of the key evasion strategies in response to the immune profile of the human population, there are overwhelming amounts of evidence for the reduced antibody neutralization of SARS-CoV-2 variants. Additionally, data also suggest that the levels of CD4⁺ and CD8⁺ T-cell responses against variants or sub-variants decrease in the populations, although non-negligible cross-T-cell responses are maintained. Herein, from the perspectives of structural immunology, we outline the characteristics and mechanisms of the T cell and antibody responses to SARS-CoV and its variants/sub-variants. The molecular bases for the impact of the immune escaping variants on the interaction of the epitopes with the key receptors in adaptive immunity, that is, major histocompatibility complex (MHC), T-cell receptor (TCR), and antibody are summarized and discussed, the knowledge of which will widen our understanding of this pandemic-threatening virus and assist the preparedness for Pathogen X in the future.</p>\u0000 </div>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"330 1","pages":""},"PeriodicalIF":7.5,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143187806","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}