Immunological Reviews最新文献

{"title":"Posttranslational Modifications of Unconventional Autoantigens: Shaping Immunogenicity and Inflammatory Activity","authors":"Roberto Lande,&nbsp;Anna Mennella,&nbsp;Raffaella Palazzo,&nbsp;Loredana Frasca","doi":"10.1111/imr.70186","DOIUrl":"https://doi.org/10.1111/imr.70186","url":null,"abstract":"<div>\u0000 \u0000 <p>Posttranslational modifications (PTMs) of self-antigens precipitate autoimmunity by generating neo-epitopes that breach tolerance and activate autoreactive T and B cells. This review spotlights cathelicidin LL37 and chemokine CXCL4 (PF4) in psoriatic disease (psoriasis and psoriatic arthritis, PSO and PSA), systemic lupus erythematosus (SLE), and systemic sclerosis (SSc), drawing on key studies including our own. Uniquely, unlike most autoantigens, LL37 and CXCL4 exert a dual role: they are immunogenic targets for T and B cells while directly fueling innate inflammation. Through chaperone-like binding to self- and microbial DNA/RNA, they form complexes that potently stimulate plasmacytoid and myeloid dendritic cells (pDCs/mDCs) via DNA/RNA sensors, such as TLR7-9 and cGAS/STING, driving Type I interferon and cytokines storms. Strikingly, these complexes also induce B cells to become antibody-producing plasma cells, amplifying adaptive responses and likely suppressing regulation. Here, we detail the role of PTM-modified LL37 in PSO, PSA, and SLE—forming autoantigenic neutrophil extracellular traps—and CXCL4 in SSc, where it acts as biomarker and autoantibody target. Our work underscores how this dual functionality as “bifunctional autoantigens” exacerbates disease, and how PTMs modification influence these phenomena. These molecules and their PTM can be targeted to halt inflammatory cascades and restore tolerance.</p>\u0000 </div>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"344 1","pages":""},"PeriodicalIF":10.6,"publicationDate":"2026-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149311511","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":"B Cell Subpopulations and Their Functions","authors":"Andrew Getahun","doi":"10.1111/imr.70187","DOIUrl":"https://doi.org/10.1111/imr.70187","url":null,"abstract":"&lt;p&gt;B cells play a central role in both protective immunity and immune-driven pathology. Following activation, they can acquire several effector functions. In addition to differentiating into antibody-secreting cells, B cells can produce substantial amounts of pro- and anti-inflammatory cytokines and act as antigen presenting cells impacting T cell responses. B cells can be classified into subsets with distinct properties and differentiation potential. The subsets involved in a particular immune response depend on the stimulus, anatomical location, and timing of exposure. This classification provides a useful framework for describing and understanding B cell responses and is widely used in immunology textbooks.&lt;/p&gt;&lt;p&gt;The rise of high-dimensional flow cytometry and single-cell RNA sequencing has substantially blurred the boundaries between B cell subsets and has revealed unexpected complexity within populations once considered homogeneous. At the 2026 B cell Keystone Symposium, a panel discussion titled “Defining B Cell Subsets” reached one clear point of agreement: the issue is complicated. Although surface markers and transcription factors are practical tools, their expression levels alone have limited ability to define subsets. This is further complicated as expression may vary with tissue location and environmental exposure. How to best define a B cell subset remains an open question: Should it be based on function, anatomical location or developmental origin? And what distinguishes a subset from an activation or transitional state?&lt;/p&gt;&lt;p&gt;Much of our current understanding of B cell subsets, their behavior, and their potential comes from studies in mice. Reductionistic models remain indispensable for gaining mechanistic insight into B cell biology and the relationships among activation and differentiation states. However, findings from these models do not always translate directly to human B cell biology. This gap is becoming increasingly apparent as technologies such as single-cell RNA sequencing and spatial transcriptomics provide unprecedented insight into B cells under homeostatic conditions and during disease.&lt;/p&gt;&lt;p&gt;In this volume of &lt;i&gt;Immunological Reviews&lt;/i&gt;, 11 experts offer new insights into both classical and more recently defined B cell subsets, including age-associated B cells (ABC cells). These reviews often toggle between insights from murine models and observations in humans, touching on the broader question of what constitutes a B cell subset and whether definitions are useful or potentially restrictive.&lt;/p&gt;&lt;p&gt;Thomas Rothstein focuses on the biology of B-1 B cells, their protective functions, and their identification in humans, where it is clear that markers that define these cells in mice are not extrapolated to humans [&lt;span&gt;1&lt;/span&gt;]. Shiv Pillai and colleagues provide a thorough overview of human B cell subsets, including transitional B cells, ABC cells, memory B cells, and B cells involved in extrafollicular responses. The","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"344 1","pages":""},"PeriodicalIF":10.6,"publicationDate":"2026-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imr.70187","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149311001","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":"Hybrid Insulin Peptides in Type 1 Diabetes: How They Form and Why They Matter","authors":"Kelly Douglas,&nbsp;Thomas Delong","doi":"10.1111/imr.70185","DOIUrl":"10.1111/imr.70185","url":null,"abstract":"<div>\u0000 \u0000 <p>Type 1 diabetes is a T cell-mediated autoimmune disease that leads to the destruction of the insulin-producing beta cells of the pancreas, yet the antigens that drive this response have been difficult to define. This review traces the identification of hybrid insulin peptides (HIPs), posttranslationally modified autoantigens formed when a fragment of insulin is joined through a peptide bond to a fragment of a second beta cell granule protein, creating a sequence not encoded by any single gene. Beginning with the search for the antigen of the diabetogenic BDC-2.5 clone in the nonobese diabetic (NOD) mouse, we show that its natural ligand is a hybrid of an insulin C-peptide fragment and a peptide derived from chromogranin A, and that subsequent mass spectrometry analyses defined a set of disease-relevant HIPs supported by both T cell reactivity and detection of the endogenous peptide. We summarize the recognition of HIPs by CD4 T cells across several HLA class II alleles in human disease, the enzymatic and nonenzymatic routes of HIP formation within acidic secretory and crinophagic compartments, and genetic evidence that reducing HIP formation delays diabetes. Finally, we propose a multi-trigger model linking a species difference in HIP formation to the focal, episodic islet pathology of human type 1 diabetes.</p>\u0000 </div>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"343 1","pages":""},"PeriodicalIF":10.6,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149222871","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":"Oxidative Stress, Post-Translational Modifications, and Type 1 Diabetes Pathogenesis","authors":"Colleen J. Winstead,&nbsp;Miki Hodel,&nbsp;Hubert M. Tse","doi":"10.1111/imr.70182","DOIUrl":"10.1111/imr.70182","url":null,"abstract":"<p>Type 1 diabetes (T1D) is an organ-specific autoimmune disease that destroys insulin-producing beta-cells. Insulin is a vital hormone for regulating glycemia that often undergoes post-translational modifications during processing from pre-proinsulin to biologically active insulin. While necessary for proper glucose homeostasis, insulin is also an autoantigen recognized by autoreactive T cells in T1D. Cellular stress pathways including endoplasmic reticulum stress and oxidative stress mediated by an increase in reactive oxygen species (ROS) synthesis and/or a concomitant decrease in antioxidant function can further drive post-translational modifications of various autoantigens in T1D including insulin. Innate immune-derived ROS generation is an essential frontline defense against microbial infections, but ROS can also function as signaling intermediates to properly stimulate T cell responses. Oxidative stress-induced post-translational modifications are thought to trigger autoreactive T cells in T1D by generating novel neoepitopes, eliciting epitope spreading, or enhancing autoantigen interactions with antigen-presenting cells. With the current technology, detecting post-translationally modified proteins is challenging. In this review, we will explore the role of ROS and other post-translational modifications involved in T1D. We will also discuss islet transplantation strategies being used for patients with T1D including novel cell sources for beta-cell replacement and management of oxidative stress after transplantation.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"343 1","pages":""},"PeriodicalIF":10.6,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imr.70182","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149178229","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":"Entering the Age of Specificity in T Cell Immunity","authors":"Paul G. Thomas","doi":"10.1111/imr.70184","DOIUrl":"10.1111/imr.70184","url":null,"abstract":"<p>The discovery of MHC restriction, the resolution of peptide–MHC structure, and the identification of the T cell receptor gene quickly centered epitope-level specificity as a core concern of T cell biology. Epitope mapping culminated in functional peptide-based stimulation assays and tetramer staining, which together provide exquisite resolution of individual responses. Despite these tools, quantitative assessment of epitope-resolved responses in complex human infections and tumors has rarely been applied at scale. As a result, no epitope-aware correlates of protection or risk have been established for major infections, and most human T cell profiling still occurs at the level of representative epitopes or bulk assays. In this review, I propose that variation in specificity, defined as distinct epitope-level responses across individuals, represents a largely untested critical element in our assessment of anti-pathogen and antitumor immunity. Advances in TCR repertoire profiling and reverse epitope discovery now make formal tests of this hypothesis tractable, and I discuss approaches to determine the extent to which epitope variation underlies the noise and variation of human immune phenotypes.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"343 1","pages":""},"PeriodicalIF":10.6,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13643677/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149126368","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":"Beta Cell Stress to Epitope Diversification: Post-Translationally Modified Antigens in Type 1 Diabetes","authors":"Megan L. Proffer,&nbsp;Saptarshi Roy,&nbsp;Jon D. Piganelli","doi":"10.1111/imr.70183","DOIUrl":"10.1111/imr.70183","url":null,"abstract":"<p>Pancreatic beta cells are active participants in the loss of immune tolerance because their high secretory demand creates exceptional vulnerability to inflammatory exposure, endoplasmic reticulum (ER) stress, calcium dysregulation, and redox imbalance. These conditions can promote enzymatic and nonenzymatic changes in self-proteins, generating post-translationally modified (PTM) antigens and neoepitopes that were absent or poorly represented during immune tolerance. This review integrates the contributions with the broader type 1 diabetes (T1D) field to examine how beta cell stress, transglutaminase-2 dependent reactions, peptidyl-arginine deiminase mediated citrullination, oxidative modifications, and post-translational peptide fusion reshape the antigenic landscape. We consider how these products alter antigen presentation and recognition by autoreactive T cells and how an evolving neoepitope repertoire may promote antigenic diversification and epitope spreading. Importantly, clonal recruitment of new determinants must be distinguished from apparent broadening caused by T cell receptor (TCR) cross-reactivity, dual-TCR expression, bystander activation, or tissue redistribution. Defining when modified epitopes arise, which are naturally presented, and which responses contribute to pathogenesis could improve biomarker development, patient stratification, and therapeutic strategies designed to reduce beta cell stress, thus enhancing survival and identity maintenance, while restoring immune tolerance.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"343 1","pages":""},"PeriodicalIF":10.6,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13643625/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149126355","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":"Human IgD+IgM− Memory B Cells and Their Possible Impact on Mucosal Homeostasis and Tolerance","authors":"Xavi Marcos-Fa,&nbsp;Mauricio Guzmán,&nbsp;Celia Corral-Vazquez,&nbsp;Andrea Cerutti","doi":"10.1111/imr.70181","DOIUrl":"10.1111/imr.70181","url":null,"abstract":"<div>\u0000 \u0000 <p>This review discusses evidence indicating that the human nasopharyngeal mucosa includes a heterogeneous subset of memory B cells expressing IgD but not IgM. Such IgD⁺IgM⁻ memory (IgD-ME) B cells differentiate from germinal center B cell precursors that have undergone class switching from IgM to IgD in tonsillar lymphoid follicles. This DNA recombination process is associated with a mutation-intensive program aimed at generating broadly reactive IgD antibodies that target a vast array of microbial and non-microbial antigens. We review data indicating that many IgD-ME B cells express atypical-like B cell properties, accumulate polyreactivity and some autoreactivity in a somatic hypermutation-dependent manner, and include precursors of IgD-secreting IgD⁺IgM⁻ plasma cells (IgD-PCs). We further discuss the complex innate and adaptive signaling networks underlying the induction of IgD-ME B cells and their clonal differentiation into IgD-PCs. Furthermore, we consider the broad reactivity and functional effects of the IgD antibodies expressed by IgD-ME B cells and released by IgD-PCs. Moreover, we delve into the mechanisms whereby secreted IgD antibodies may contribute to mucosal tolerance and homeostasis. Lastly, we examine human disorders associated with abnormalities of the IgD response.</p>\u0000 </div>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"343 1","pages":""},"PeriodicalIF":10.6,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149101561","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":"Building an Interleukin-10-Producing Identity: How B Cells Acquire Interleukin-10 Competence and How Plasma Cell Differentiation Consolidates This Program","authors":"Bui Thi Cuc,&nbsp;Yanli Tong,&nbsp;Zhiguo Wu,&nbsp;Daniel Alvarez-Simon,&nbsp;Simon Fillatreau","doi":"10.1111/imr.70180","DOIUrl":"https://doi.org/10.1111/imr.70180","url":null,"abstract":"<p>Interleukin (IL)-10-producing B cells represent an archetype for the regulatory functions of B cells. Here, we review the cell-surface receptors and transcriptional regulators that control IL-10 expression in B cells and enable their regulatory function in vivo. To integrate available data, we propose a three-layer competence–execution–stabilization (CES) framework for IL-10-mediated B cell regulation. We propose that B cell receptor signaling during B cell development and at homeostasis contributes to establishing high IL-10 competence in selected B cell subsets at steady state. Execution of IL-10 expression and regulatory function then requires the integration of canonical B cell activation pathways with environmental signals and involves transcriptional programs that are largely intertwined with those controlling plasma cell differentiation. Notably, chemically induced IL-10-producing B cells progressively differentiate into IL-10-producing plasma cells and acquire homogeneous and stable IL-10 expression. Together with LAG-3⁺CD138^hi plasma cells, these cells represent the only B cell populations described so far in which IL-10 expression approaches population-wide penetrance. We therefore propose that plasma cell differentiation may constitute an attractor state for stabilizing IL-10-producing regulatory programs. The CES framework provides a conceptual basis for investigating the diversity and regulatory functions of IL-10-expressing B cell states in vivo.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"343 1","pages":""},"PeriodicalIF":10.6,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imr.70180","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149068591","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":"Discovery of Post-Translationally Modified Epitopes in Autoimmunity: Someone Has to Fish so Everyone Can Eat","authors":"Sanya Arshad,&nbsp;Benjamin M. Cameron,&nbsp;Alok V. Joglekar","doi":"10.1111/imr.70179","DOIUrl":"https://doi.org/10.1111/imr.70179","url":null,"abstract":"<p>Post-translational modifications (PTMs) chemically diversify the ~20,000 genomically encoded proteins into millions of functional variants, and this diversity has profound consequences for T cell-mediated immune responses. PTM-reactive T cells have been identified across numerous autoimmune diseases and, in several cases, implicated directly as pathogenic drivers. Mechanistically, PTMs promote autoimmunity through two intertwined routes: by altering peptide–MHC and TCR binding to favor recognition of self-epitopes, and by generating neoepitopes in peripheral and/or inflamed tissues that are absent from the thymus, allowing PTM-reactive T cells to escape central tolerance. This cascade is amplified by inflammatory cytokines, upregulated antigen-processing machinery, disease-associated HLA alleles, and, in some cases, exogenous triggers such as diet. We use three well-characterized examples—citrullination in multiple autoimmune disorders, hybrid insulin peptide (HIP) formation in type 1 diabetes, and gluten deamidation in celiac disease—to illustrate how distinct PTM biology, tissue specificity, and genetic encodability shape the antigenic landscape and dictate feasible discovery strategies. We then review four complementary approaches for identifying PTM-specific T cell responses: mass spectrometry-based proteomics and immunopeptidomics, computational MHC-binding prediction, antigen-directed methods, and high-throughput T cell receptor (TCR)-directed library screening methods. For each, we discuss underlying principles, strengths, and limitations, with particular attention to the challenge posed by non-canonical, PTM-bearing residues. By comparing citrullination, HIPs, and gluten deamidation across these methodologies, we highlight how biochemical alterations, tissue accessibility, and mouse-to-human conservation determine which discovery approach is most tractable. We conclude that while synthetic peptide-based methods remain the standard for validating known epitopes, emerging high-throughput, cell-based platforms are rapidly expanding the accessibility of the PTM antigenic landscape for both known and undiscovered autoimmune epitopes.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"343 1","pages":""},"PeriodicalIF":10.6,"publicationDate":"2026-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imr.70179","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149068511","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":"BAFF and APRIL Receptors in B Cell Immunity and Autoimmunity","authors":"Daisy H. Luff,&nbsp;Edina Schweighoffer,&nbsp;Victor L. J. Tybulewicz","doi":"10.1111/imr.70170","DOIUrl":"10.1111/imr.70170","url":null,"abstract":"<p>BAFF and APRIL are TNF superfamily proteins that bind to BAFFR, TACI and BCMA, members of the TNF receptor superfamily. These proteins have both unique and overlapping roles in B cell development and survival and are major therapeutic targets for antibody- and B-cell-driven pathologies. BAFF and BAFFR are required for development and survival of follicular and marginal zone (MZ) B cells, whereas BAFF and APRIL acting through TACI and BCMA support plasma cell survival. TACI and BCMA can both be cleaved to generate soluble decoy receptors binding to BAFF or APRIL, forming feedback circuits. Thus, loss of TACI leads to an increase in BAFF, resulting in B cell hyperplasia. Recent work showed that TACI is required for MZ B cell development, a finding that has implications for understanding immune dysfunction in humans. Both monoallelic and biallelic loss-of-function TACI mutations result in immunodeficiency, potentially due to impaired MZ B cell function. Paradoxically, monoallelic TACI mutations predispose to autoimmunity. We propose this may be due to increased BAFF levels which promote selection of self-reactive B cell clones into the mature B cell pool, particularly the MZ B cell compartment. A deeper understanding of this ligand-receptor system is essential for effective therapeutic targeting.</p>","PeriodicalId":178,"journal":{"name":"Immunological Reviews","volume":"342 1","pages":""},"PeriodicalIF":10.6,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/imr.70170","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148987341","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}