Intestinal immunity is coordinated by the spatial organization and temporal regulation of immune cells within a complex, antigen-rich environment. In this review, we discuss the latest advances in our understanding of how these two fundamental dimensions together shape intestinal immune homeostasis. We first examine the temporal dynamics of intestinal immunity, ranging from prenatal immune development, early-life immune education, and differentiation established by maternal factors and dietary changes. We discuss recent discoveries identifying RORγt-expressing antigen-presenting cells as key regulators of oral tolerance, providing a mechanism for how transient developmental windows establish long-lasting immune homeostasis. We then explore the spatial organization of intestinal immune cells, from regional specialization along the length of the gastrointestinal tract to compartment-specific immune populations, as well as micro-niches revealed by emerging spatial technologies. We review specialized chemokine networks, cellular interactions, and the microenvironments that coordinate immune responses in distinct intestinal regions. As we face increasingly detailed spatiotemporal maps, the next challenge will be to translate all this information into mechanisms underpinning how immune niches are established and maintained to promote intestinal health.
Multimodal artificial intelligence (AI) is an emerging domain comprising a set of tools with potential clinical relevance in paediatric rheumatology, a field characterised by rare, heterogeneous diseases and diagnostic delays. This narrative review synthesises current evidence on how multimodal and fair AI could reshape diagnosis, monitoring, and treatment for children with rheumatic diseases, while examining the risks of exacerbating existing inequities. Complex architectures fuse clinical data, laboratory parameters, imaging, omics profiles, and wearable signals into dynamic ‘digital phenotypes’ capable of predicting flares, treatment response, and long-term outcomes. Explainable AI approaches render high-capacity models more actionable and trustworthy. Large language models can translate complex clinical information into family-centred plain language; however, a human-in-the-loop approach remains essential to limit hallucinations, omissions, and confidentiality breaches. Bias accumulation across the AI lifecycle demands equity-centred design. Emerging ethical, methodological, and regulatory frameworks should guide responsible adoption, outlining a roadmap toward a more equitable future for children with rheumatic diseases worldwide.
Real-world data (RWD) from nonrandomized clinical settings, such as registries and observational cohorts, can be used to address research questions for which randomized controlled trials (RCTs) are not feasible or appropriate. However, these data are susceptible to important sources of bias, including confounding by indication and immortal time bias. Target trial emulation (TTE) has emerged as a framework to improve the quality, credibility, and reproducibility of observational causal inference by aligning the design and analysis of observational studies with the structure of a hypothetical RCT. Appropriate application of the TTE framework requires careful specification of key design elements. Recent methodological guidance documents and reporting guidelines now provide practical support for researchers seeking to specify, conduct, and report TTE studies. Although TTE is increasingly used in rheumatology, its application in pediatric rheumatology remains limited despite the expanding availability of RWD. This review details the most recent methodological developments and guidelines, outlining the core concepts needed to apply the framework appropriately. The aim of this review is also to summarize recent applications in adult and pediatric immune-mediated diseases, and to explore the opportunities and limitations of this approach with a specific focus on pediatric rheumatology.
Recurrent pericarditis complicates approximately one-third of initial pericarditis episodes in children. Once considered a postinfectious sequel, it is now understood as an autoinflammatory disorder sustained by dysregulated interleukin-1 signaling and inflammasome hyperactivation. This review evaluates therapeutic strategies for idiopathic recurrent pericarditis in patients younger than 18 years using the PICO framework. First-line management with nonsteroidal anti-inflammatory drugs and colchicine remains the therapeutic backbone, with colchicine conferring a roughly 50% reduction in relapse risk. Glucocorticoids, although acutely effective, predispose to steroid-dependence and rebound flares, and should be reserved for refractory disease at low doses. IL-1 receptor antagonism, principally anakinra, has emerged as a transformative steroid-sparing option for colchicine-resistant or steroid-dependent cases, achieving rapid symptom control and durable remission in most treated children. Nonetheless, pediatric evidence remains limited to retrospective cohorts and small case series, highlighting the need for prospective controlled trials, standardized outcome definitions, and long-term safety surveillance of biologic agents.
Over the last two years, inflammatory dermatology has undergone a transition from morphology-based classification toward pathway-driven immune endotyping. Atopic dermatitis, psoriatic disease, and hidradenitis suppurativa have emerged as paradigmatic models of this transition, illustrating how epithelial dysfunction, involving autoinflammation and adaptive immunity, may lead to systemic inflammatory crosstalks, connecting cutaneous and musculoskeletal manifestations. Recent studies have refined the understanding of progressive immune maturation in atopic dermatitis, while psoriasis and juvenile psoriatic arthritis support skin-to-joint inflammatory models involving IL-23/IL-17 signaling. Hidradenitis suppurativa is increasingly recognized as a systemic autoinflammatory disease within a broader neutrophilic inflammatory spectrum. Parallel therapeutic advances involving IL-17, IL-23, TNF, and JAK inhibition reinforced the translational importance of these discoveries and accelerated the development of precision dermatology strategies.
Once considered incurable, psoriasis is now being re-evaluated in light of sustained, drug-free remissions, prompting a redefinition of ‘cure’ as long-term/drug-free remission. Psoriatic disease is primarily driven by dysregulation of the interleukin-23 (IL-23)/IL-17 axis, and the survival of tissue-resident memory T cells (TRM), key mediators of lesion recurrence and chronicity. Targeting this axis early with high-dose IL-23 inhibitors has shown promise, as exemplified by the KNOCKOUT trial, where intensified induction dosing of risankizumab resulted in marked TRM cell depletion and durable remission. Early intervention appears crucial, with studies such as the GUIDE trial demonstrating that patients with early disease duration respond more to IL-23 inhibition with guselkumab, achieving higher rates of complete skin clearance. Beyond biologics, curative strategies encompass stem cell therapy, with case reports of long-lasting remission supporting their potential role in immune reprogramming. Cutting-edge interventions such as gene editing, chimeric antigen receptor-T cell therapy, and microRNA modulation are also under exploration.
Microglia are the resident innate immune cells of the brain that play essential roles in immune surveillance, phagocytosis, and neuroinflammatory responses. A central regulator of these diverse functions is intracellular Ca2+ signaling, which connects extracellular cues to transcriptional and metabolic programs that shape microglial activation states. Recent advances have expanded understanding of the ‘Ca2+ toolkit’ in microglia, which includes P2X and P2Y receptors, Orai Ca2+ channels, transient receptor potential channels, inositol triphosphate receptors, and organellar Ca2+ handling systems. These pathways generate dynamic and spatially localized Ca2+ signals that regulate numerous effector functions, including process motility, cytokine production, phagocytosis, metabolism, and communication with other brain cells. Emerging evidence further identifies dysregulated Ca2+ signaling as a key driver of chronic neuroinflammation in brain disorders. Here, we review the major components of the microglial Ca2+ signaling toolkit, discuss their molecular mechanisms and physiological functions, and highlight contributions to neuroinflammatory diseases.
The development of clinical trials is limited by high costs and methodological complexities. In this context, artificial intelligence (AI) is emerging as a key instrument for their optimization. In the early phases of study design and recruiting, generative AI systems may help refine eligibility criteria and boost enrollment; in parallel, the integration of digital biomarkers and patient-reported outcomes may allow continuous remote monitoring and improved safety data collection. Moreover, machine learning models may be applied to effectively analyze longitudinal multimodal trial data. However, AI implementation in real-world settings must overcome significant challenges; regulatory authorities are updating guidance, and a successful integration of AI-based interventions will depend on the rigorous application of quality standards while preserving the central role of medical judgment. In this review, we provide a comprehensive overview of the clinical applications, ethical considerations, and regulatory aspects of implementing AI in clinical trials in adult and pediatric rheumatology.
Germline mutations in GATA2 cause a syndromic inborn error of immunity characterized by cytopenia, infections, immune dysregulation, and a marked predisposition to myelodysplastic syndrome and acute myeloid leukemia. Initially defined by the DCML phenotype-dendritic cell, monocyte, B- and NK-cell deficiency-GATA2 deficiency is now recognized as a disorder of global immune-hematopoietic homeostasis. Recent multi-omics and experimental models reveal enhancer-driven inflammatory rewiring, IRF8-dependent lineage imbalance, and premature hematopoietic aging. In parallel, adaptive immune defects, including impaired B- and T-cell development and function, contribute to defective immune surveillance. These alterations not only explain susceptibility to infection but also shape clonal evolution and malignant transformation. Clinically, improved risk stratification and transplant outcomes underscore the importance of early recognition and monitoring of immune dysfunction. GATA2 deficiency thus represents a paradigm linking immune dysregulation, inflammatory stress, and cancer predisposition.
Antibodies are fundamental to human health but can also drive pathology. Each antibody has a molecular specificity, encoded by their clonally heritable B cell receptor (BCR). Recent advances in spatial transcriptomics coupled with repertoire sequencing have enabled capturing antibody-secreting cells (ASCs) and their clonal BCR within their tissue microenvironment. However, our understanding of antibody production niches remains limited. Furthermore, where antibodies are produced can be distinct from where antibodies exert their effector function. Here, we propose a conceptual spatial framework to distinguish between ‘antibody production niches’, defined by the ASC, BCR, and niche composition, versus ‘antibody functional niches’, composed of the antibody, antigen, and effector landscape. We then examine the possibilities and challenges to map and link antibody-encoding sequences and antibody effector functions using current and emerging technologies. Combined, we argue that integrating spatial sequence data with the antibody functional context is essential to decode the architecture of antibody-mediated immunity.
Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease characterized by sicca symptoms, fatigue, multiorgan involvement, and an increased risk of B-cell lymphoma. Accumulating evidence over the past decades indicates that epithelial cells are not passive targets but active drivers of disease. Histopathologic and immunologic studies show lymphocytic infiltration around epithelial structures and aberrant epithelial expression of HLA-DR, co-stimulatory molecules, cytokines, chemokines, and autoantigens. Notably, patient-derived epithelial cells maintain these activated features in vitro, supporting intrinsic dysregulation. Functionally, epithelial cells can act as non-professional antigen-presenting cells, contributing to T-cell activation and local immune responses. Mechanistic pathways, including viral triggers, type I interferon signaling, autophagy, mitochondrial dysfunction, and innate immune activation, further support an epithelial-centered model. This review summarizes evidence for ‘autoimmune epithelitis’, examines related autoimmune paradigms, and discusses therapeutic strategies targeting both immune pathways and epithelial homeostasis.
Ion channels are classically regarded as regulators of electrical excitability, but their role in immune activation and barrier homeostasis extends far beyond global transmembrane ion flux. This functional diversity is, among other things, the result of noncanonical signaling pathways. In this review, we examine the neurovascular endothelium as a paradigm for barrier-associated neuroimmune pathology and discuss three mechanistic principles: (1) permeation-independent scaffolding via cytoplasmic interaction domains, (2) spatio-temporally restricted ion flux within signaling microdomains, and (3) compartmentalized or cargo-mediated signaling. These mechanisms shape endothelial barrier integrity, inflammatory junctional remodeling, and the diapedesis of immune cells across the blood-brain barrier. A deeper understanding of such noncanonical channel functions opens new therapeutic perspectives beyond conventional pore blockade, including the targeted modulation of signaling domains, protein interactions, and subcellular channel localization.
The fate of T cells is determined through the expression of a unique T cell receptor (TCR). TCR epitope specificity drives spatial localization, phenotypic and metabolic plasticity, effector function, as well as the evolution of complex repertoires of T cell clones. However, human immunology is often restricted to the peripheral blood compartment and neglects 'professional' lymphoid organs. Furthermore, despite the generation of single-cell 'atlases', our knowledge of the epitopes that are recognized by human T cells is largely limited to only a handful of antigenic specificities from conventionally studied viruses. So far, this has prevented a holistic understanding of T cell clonotypes that link location-dependent cellular qualities to specific antigen exposures or disease entities. Novel methodologies for high-throughput annotation of T cell epitope specificity and high-resolution mapping of histological context bear the potential to enhance our understanding of basic human T cell biology, to provide a large-scale data resource for the connected field of computational T cell biology, and to facilitate the development of novel or improved vaccines and other immunotherapies.
In this review, we detail the features of barrier germinal centers (GC) that form in tertiary lymphoid structures (TLSs) within non-immune organs that host a local microbiome, and posit a framework of immunity where TLS-GCs created at barrier sites are a key part of normal humoral immunity, and that they form the first layer of an intended multi-layered and increasingly defensive adaptive immune system, providing complementary tissue-specific responses, alongside the local secondary lymphoid organ network and systemic immune responses.
Ocular sarcoidosis is a frequent manifestation of sarcoidosis and may occur most commonly affecting adults between 30 and 60 years old. Uveitis may be anterior, intermediate, posterior, or present as panuveitis, with marked heterogeneity in severity and clinical course. Diagnosis relies on a combination of compatible ocular findings and systemic investigations, including serum biomarkers, thoracic imaging, and histological evidence of noncaseating granulomas while carefully excluding infectious and neoplastic mimickers, particularly in atypical or corticosteroid-resistant cases. Bilateral, intermediate, posterior, and panuveitis often require systemic corticosteroids. Because of the unfavorable long-term safety profile of systemic corticosteroids, early introduction of steroid-sparing therapy is recommended in chronic, severe, or recurrent disease. Emerging therapies such as interleukin-6 receptor antagonists, Janus kinase inhibitors, and mTOR inhibitors represent promising options on top of methotrexate and TNF inhibitors for refractory sarcoid uveitis, although their use requires careful risk-benefit assessment and further validation in controlled trials.
The SARS-CoV-2 pandemic has renewed interest in mucosal vaccines, yet these approaches have long struggled to generate durable protection against airway pathogens. A key limitation is the incomplete understanding of how upper airway antigens are handled to shape immune response quality and durability. Antigens located within the airspace or on the mucosal surface can be directly sampled by mucosal-associated lymphoid tissues (MALTs), such as Nasal-associated lymphoid tissue (NALT) in mice, or tonsils in humans. Because MALTs lack afferent lymphatics, antigen entry occurs primarily across a specialized epithelium. In contrast, antigens that arise within the mucosa following barrier breach are captured by immune cells and lymphatics for delivery to draining lymph nodes. This framework suggests that 'on the mucosa' antigens preferentially engage MALTs, whereas 'within the mucosa' antigens are handled by lymph nodes. However, the rules governing antigen handling within the nasal cavity remain poorly defined, limiting rational mucosal vaccine design.
The intestine integrates nutrient digestion and absorption with immune surveillance, being continuously challenged by dietary antigens, commensal microbiota, and pathogens. Its highly regionalized structure requires the immune system to balance tolerance to food and commensal organisms with protective responses against pathogens, generating substantial heterogeneity and complexity across multiple spatial scales that make it inherently difficult to study. Conventional techniques such as flow cytometry, immunohistochemistry, and RNA-sequencing can characterize immune cell location, composition, and transcriptional state, but do not enable simultaneous and unbiased interrogation of cellular state and spatial context. Over the last decade, spatial transcriptomics has allowed researchers to unbiasedly profile gene expression in situ for the first time. In this review, we discuss the suitability of spatial transcriptomics for profiling the intestinal immune system, key discoveries made using this technology, complementary techniques, current challenges, and future opportunities for its application in gut immunology research and beyond.
Solid‑phase assays for the detection of antiphospholipid antibodies (aPL) are central to the laboratory evaluation of antiphospholipid syndrome (APS). Growing insights into the molecular immunology underlying these assays challenge traditional interpretations. It is now evident that the antigenic drivers are phospholipids (PL)‑binding proteins - primarily β2-glycoprotein I (β2GPI) and prothrombin (PT). β2-glycoprotein I‑dependent aPL represent the dominant subset, recognizing discontinuous conformational epitopes spanning domains I-II (DI-DII). Solid matrices coated with anionic PL or partially oxidized polystyrene amplify DV anchoring through its lysine‑rich cationic loop, thereby increasing local antigen density and molecule orientation, ultimately enhancing functional avidity of intrinsically low‑affinity aPL. These antibodies contribute to reactivity across all three APS laboratory criteria assays: lupus anticoagulant (LA), anticardiolipin, and anti‑β2GPI. Beyond β2GPI, PT‑reactive aPL, detected by phosphatidylserine/prothrombin (aPS/PT) ELISAs, bind epitopes unveiled only when PT engages anionic PL in a Ca²⁺‑dependent conformational transition. Distinct antigenic specificities - type I (open‑conformation fragment‑1 epitope) and type II (C‑terminal Gla domain) - exhibit divergent affinities, matrix‑dependent binding behaviors, and heterogeneous LA activity. Antibodies detected through aPS/PT assays are associated with APS manifestations and often with LA (range 54.8-82.0%). Conversely, a smaller population of 'pure' lipid‑binding aPL, independent of β2GPI or PT, appears to target lysobisphosphatidic acid (LBPA) within the endothelial protein C receptor/LBPA complex, activating pro‑inflammatory/pro‑coagulant pathways. Although these antibodies may contribute to APS pathogenesis in a minority of patients, their detection remains technically challenging and is currently confined to research settings. Understanding the immunological characteristics of aPL subsets is essential for interpreting solid‑phase assays and improving APS management.
The synovium is a critical site for the initiation and persistence of inflammatory joint diseases, including rheumatoid arthritis (RA), osteoarthritis (OA), and gout. Conventional 2D cultures and animal models fail to recapitulate the multicellular organization, mechanical regulation, and inter-tissue communication that shape human joint pathology. Synovial organoids and related microphysiological systems address these gaps by reconstructing stromal, macrophage, vascular, and immune components within controllable human 3D environments. Here, we review advances in synovial organoid engineering, focusing on multicellular integration, mechanically active modeling, and modular coupling with joint tissues. We discuss how these systems reveal disease-relevant stromal-immune-vascular circuits, mechanobiological regulation, and synovium-tissue crosstalk across RA, OA, and gout. We further highlight their translational value for therapeutic testing and target prioritization, while outlining challenges in durable vascularization, complete immune organization, multiaxial mechanical control, and functional benchmarking. Together, these advances are transforming synovial models into tractable joint microecosystems for mechanistic and translational rheumatology.
