Seminars in Immunopathology最新文献

Inflammatory bowel disease (IBD) is a multifactorial and heterogeneous disorder that remains challenging to manage. Growing evidence implicates the gut microbiome as a key player in IBD pathogenesis, with many patients displaying intestinal dysbiosis that can drive aberrant immune responses. Traditional microbiome-targeted interventions, such as dietary modifications, probiotics, and fecal microbiota transplantation (FMT), have yielded mixed and often temporary benefits in IBD. This shortcoming of broad-spectrum approaches underscores the need for more precise, personalized strategies that account for each patient's unique microbiota and disease phenotype. Recent advances in omics and bioengineering have catalyzed the development of emerging microbiome-directed therapies that move beyond these broad approaches. This narrative review highlights emerging microbiome-directed therapies that aim to restore gut homeostasis and mitigate inflammation in IBD. We critically evaluate the rationale and therapeutic potential of rationally designed bacterial consortia and genetically engineered bacteria, which represent next-generation probiotics tailored to complement deficient microbial functions or deliver anti-inflammatory agents in situ. We also expand the discussion to underexplored microbiome constituents - archaea, protists, bacteriophages, and fungi - highlighting their roles in IBD and potential as therapeutic targets. Finally, we discuss the key advances and ongoing challenges of these innovative approaches, from ecological stability and engraftment to safety and regulatory considerations.

Necrotizing enterocolitis (NEC) is the most common surgical emergency in preterm infants; nonetheless, besides supportive measures, no treatment is available. NEC significantly increases length of hospitalization of preterm infants, causes severe morbidity and up to 70% mortality. Despite limited understanding of the underlying mechanisms, prematurity, dysbiosis and an underdeveloped immune system are known to increase the risks of developing NEC. The low weight of preterm infants (often < 2000 g) and unpredictable progression of NEC hinder clinical research; hence, most of our mechanistic understanding of NEC pathophysiology has arisen from animal models. Recent advances in bacterial genomic analyses highlighted the intestinal microbiome's key role in NEC, strengthening the concept that this disease results from an interaction between the patient's developing immune system and their microbiome. This notion is supported by the moderate effect of probiotics in preventing NEC. Here, we review the current knowledge on how the immune system interacts with the intestinal microbiome in early life, including in relation to NEC, describe the current evidence from cohort studies, clinical trials, in vivo and in vitro models used to study NEC, and methods to modulate the immune system and microbiome in early life. Knowledge on the early-life microbiome and immune system in health and diseases, including NEC, can be harnessed to develop novel and urgently needed immunomodulatory and microbiota-based therapeutics.

Systemic sclerosis (SSc) is a rare systemic autoimmune disease characterized by a triad of pathogenic mechanisms, including: a) microvascular hyperreactivity secondary to endothelial dysfunction, b) dysregulated immune activation of both innate and adaptive immunity, with the production of autoantibodies targeting nuclear antigens (e.g., anticentromere antibodies, anti-RNA polymerase III antibodies, and anti-topoisomerase I antibodies), and c) fibrosis of the skin and internal organs, such as the lungs, due to excessive extracellular matrix deposits produced by dysregulated myofibroblasts. Skin involvement plays a crucial role in the detrimental impact of SSc on quality of life. Skin fibrosis in SSc is characterized by the progressive accumulation of extracellular matrix components, including collagen, in the dermis, and is associated with adipocyte atrophy in the hypodermis. Visceral manifestations include fibrotic interstitial lung disease (ILD), myocardial involvement, pulmonary arterial hypertension, gastrointestinal manifestations, and scleroderma renal crisis. These manifestations are key determinants of prognosis and significant contributors to mortality in SSc. This review will explore the clinical features of SSc, the existing subtypes based on different classification approaches (such as skin-driven classifications, autoantibodies, or molecular subsets), epidemiology, identified etiologies, pathogenesis, current standards of care, and a selection of potential therapeutic perspectives. This review will emphasize SSc-related skin manifestations, including their pathogenesis and treatment, while also discussing other organ manifestations.

Pyoderma gangrenosum (PG) is a rare inflammatory skin disease belonging to the group of neutrophilic dermatoses. The pathogenesis of PG involves a predisposing genetic background that facilitates a dysregulated innate and adaptive immune response, with an imbalance between pro-inflammatory and anti-inflammatory mediators, leading to neutrophil-driven inflammatory damage. Several immunosuppressants and immunomodulatory drugs are currently available for the treatment of PG, in combination with topical therapies, wound management and pain control strategies. Systemic corticosteroids and cyclosporine remain the first-line treatment options with the best evidence. However, in recent years, the rise of knowledge about different pathogenic mechanisms has led to a significant increase in studies attesting the efficacy and safety of biologic therapies including, among others, antagonists of tumour necrosis factor (TNF)-α and interleukin (IL)-23, becoming the drug of choice in specific clinical setting. Similarly, different small molecules such as JAK-STAT (Janus kinase/signal transducer and activator of transcription) inhibitors are showing promising results for the treatment of PG. We review established and emerging pathogenesis-driven treatments, also providing a therapeutic algorithm and informing future directions in the management of PG.

Conventional dendritic cells (cDCs) play a pivotal role in orchestrating the delicate balance between immunity and tolerance within the gastrointestinal tract by interacting with other cell types, particularly T cells. Meanwhile, the microbiota is critical for the induction and modulation of the immune system in the gut and plays a key role in the function of cDCs. So far, the study of intestinal cDCs has been encumbered by their limited numbers and phenotypic overlap with other myeloid cells. Recent advancements in single-cell sequencing technology have helped define cDCs and their subsets, while also providing valuable insights into the contribution of cDCs to Inflammatory Bowel Disease (IBD). However, the exact role of cDCs in IBD remains unclear, particularly in terms of how the microbiota influences their function in this context. In this review, we summarize the functions of cDCs in the intestine and during IBD, and the role of the microbiota in cDC biology. We also describe the current limitations in the study of cDCs and the microbiota, as well as new methods for studying DC-T cell communications in vivo, which can help increase our understanding of the function of cDCs in the intestine and develop new therapeutic strategies against IBD.

Uterine disorders, such as thin endometrium and intrauterine adhesions, remain significant challenges in reproductive medicine, often leading to infertility and poor pregnancy outcomes. Recent advances in regenerative medicine and tissue engineering have led to the development of innovative therapeutic strategies aimed at restoring endometrial structure and function. Biomaterials play a central role in these advancements, serving not only as structural scaffolds and delivery vehicles for stem/progenitor cells and bioactive molecules but also as modulators of the tissue microenvironment by promoting angiogenesis and regulating immune responses. Mesenchymal stem cells from various sources, including female reproductive tissues, along with their extracellular vesicles, have demonstrated potential in promoting angiogenesis, reducing fibrosis, and modulating immune responses for endometrial repair. Additionally, platelet-rich plasma and a range of pharmacological agents-often with advanced drug delivery systems, such as nanocarriers-further contribute to endometrial regeneration. Engineered scaffolds, particularly those derived from decellularized extracellular matrix or fabricated using three-dimensional bioprinting technologies, closely mimic the biomechanical and biochemical properties of native endometrium. These scaffolds facilitate cellular engraftment and provide valuable platforms for in vitro modeling of endometrial physiology. The development of uterus-derived extracellular matrix scaffolds with immunologically compatible biomaterials and organoids marks a pivotal step toward reducing immune rejection and improving clinical applicability. This review highlights recent progress in biomaterial-based therapeutics for uterine regeneration and discusses the remaining challenges in shifting therapeutic paradigms of personalized and tissue-specific regenerative strategies.

Galectins, a family of β-galactoside-binding proteins, are critical in regulating feto-maternal interactions during pregnancy. Their evolutionary trajectory is reflected in their expression patterns and diverse functions in embryo implantation, trophoblast invasion, and maternal immune and vascular adaptation, contributing to healthy placentation and uncomplicated pregnancy. Galectin-1 (gal-1), one of the most ancient galectins, plays a pivotal role in feto-maternal immune regulation, acting predominantly from the maternal side to promote immune tolerance, a function integrated early in placental mammalian evolution. In contrast, anthropoid primates introduced a unique set of fetal (placental) galectins (gal-13, gal-14, and gal-16) through birth-and-death evolution, with these genes localized on human chromosome 19. Notably, these primate species have evolved varying degrees of deep placentation, with humans exhibiting the deepest, which facilitates enhanced nutrient delivery to the fetus, particularly for brain development. Placental galectins have been implicated in the evolution of immune tolerance mechanisms that support deep placentation. During pregnancy, reduced expression of maternal galectins (e.g., gal-1) and placental galectins (e.g., gal-13) has been associated with severe obstetric complications, signaling disruptions in feto-maternal tolerance. This review provides a comprehensive overview of gal-1, gal-13, gal-14, and gal-16, highlighting their shared and unique roles in maternal and placental immune regulation and placental development. Additionally, the review explores the potential of maternal versus placental galectins as biomarkers and therapeutic targets to improve diagnostic and treatment strategies for adverse pregnancy outcomes.

Anaphylaxis is a severe, potentially life-threatening allergic reaction that can occur through both IgE- and non-IgE-mediated pathways. The classic IgE-mediated pathway involves allergen-specific IgE binding to FcεRI on mast cells and basophils, triggering degranulation and the release of inflammatory mediators. Non-IgE-mediated mechanisms, which are commonly associated with drug-induced reactions, at least in mice, involve the activation of the G-protein-coupled receptor (MRGPRX2), triggering mast cell degranulation in an IgE independent manner. Anaphylaxis can also be mediated through IgG immune complex interaction with Fc gamma receptors on various cell types, leading to mediator release. This review will describe current understanding of the pathomechanisms of anaphylaxis. Understanding these diverse pathways is crucial for accurate diagnosis, effective treatment, and prevention of anaphylaxis.