Trends in Immunology最新文献

An allelic variant of the autophagy gene ATG16L1 (T300A) is a genetic risk factor for Crohn's disease. However, over 50% of the global population carries at least one copy. Yao et al. have demonstrated a heterozygote advantage, where the pathogen-protective effect of one allele may outweigh the disease risk in homozygotes.

Chronic inflammation drives diseases like osteoarthritis and MASH, yet its molecular distinction from acute inflammation remains unclear. In a recent Nature study, Wang et al. revealed that chronic stress triggers WSTF degradation via nuclear autophagy, amplifying NF-κB responses. Blocking this pathway attenuates chronic inflammation while sparing acute immunity.

Mucocutaneous surfaces rely on IL-17-producing lymphocytes to preserve barrier integrity and prevent bacterial and fungal overgrowth. Accordingly, genetic or pharmacological IL-17 deficiencies lead to mucocutaneous infections. Interferon (IFN)-γ mediates host defense against intracellular pathogens, but excessive mucosal IFN-γ activity can paradoxically impair epithelial integrity and promote infection, as shown in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy-associated oral candidiasis, even with intact IL-17 responses. Further evidence for IFN-γ-driven pathology is emerging in bacterial, fungal, and protozoal infections at mucocutaneous tissues. Together, these findings support a model in which IL-17 promotes barrier resistance, whereas unchecked IFN-γ erodes it. Collectively, they advance the concept that although mucocutaneous infections are classically caused by immunodeficiency, epithelial disruption by immunopathology represents a novel and underappreciated mechanism of infection susceptibility at barrier sites.

Mosaic errors of immunity (MEI) encompass a group of immune disorders caused by somatic or gonosomal gene variants affecting hematopoiesis and immune function. Although the causal role of mosaicism in monogenic immune disorders has been recognized for over two decades, our understanding of their pathogenesis, genotype-phenotype correlation and clonal evolution remains poor. In this review, we synthesize shared and distinct molecular determinants from the currently recognized MEI and provide a mechanistic framework for future research. Exploring the implications of mosaic genetic variation in patients with unexplained immune disorders could uncover novel, actionable genetic disorders. Moreover, the study of these rare 'experiments of nature' may shed light on cell-specific immune pathways, non-malignant clonal dynamics, and mosaic disorders more broadly.

The immunological tolerance protecting the fetus from maternal rejection during pregnancy involves nonclassical human leukocyte antigen (HLA) class I molecules (HLA-G, HLA-E, HLA-F) interacting with maternal immune-inhibitory receptors. Cancers similarly exploit these molecules to evade immune detection and promote tumor progression. Pseudogenes within the major histocompatibility complex may modulate these pathways via noncoding RNA, gene conversion, or protein interactions, although their precise roles remain unclear. Furthermore, fetal-maternal microchimerism potentially reinforces maternal tolerance but could also influence susceptibility to autoimmune disorders or cancer. This review critically evaluates current experimental evidence, identifies knowledge gaps, and proposes therapeutic approaches targeting these pathways in oncology without compromising maternal-fetal tolerance.

FOXP3⁺ regulatory T cells (Tregs) are essential for maintaining immune tolerance, and their dysfunction is a hallmark of autoimmune diseases. Recent studies have identified key transcriptional, metabolic, and environmental drivers of Treg instability and loss of function. Understanding these mechanisms opens new avenues for therapeutic interventions aimed at restoring immune homeostasis in autoimmunity.

The border tissues of the brain harbor specialized immune cells known as border-associated macrophages (BAMs), which have vital roles at these interfaces. However, factors governing their development and maintenance remain elusive. In a recent study, Van Hove et al. elegantly demonstrated that interleukin (IL)-34 is critical for sustaining BAMs and enabling their regulation of vascular function.

Amyotrophic lateral sclerosis (ALS) is a life-threatening neurodegenerative disease caused by motor neuron loss. In a recent Phase 2b trial, Bensimon and colleagues report that the addition of low-dose interleukin 2 (LD-IL-2) immunotherapy to standard of care (SOC) shows promise in enhancing immune tolerance and improving survival in individuals with slower disease progression.

CD4 T cell tolerance is essential for immune homeostasis but its mechanisms remain unclear. Although regulatory T cells (Tregs) mediate T cell-extrinsic tolerance, this review emphasizes the CD4 T cell-intrinsic pathways - anergy and exhaustion - that are triggered by suboptimal or persistent antigen stimulation. These states share transcriptional and epigenomic features across contexts such as cancer, pregnancy, and transplantation. Instead of being distinct, they form a spectrum of tolerance with potential for therapeutic targeting. CD154 has re-emerged as a promising target, although memory T cell tolerization remains challenging. A deeper understanding of what sustains or reverses CD4 T cell tolerance is key to designing treatments that induce/maintain tolerance in autoimmunity and transplantation, or restore functionality in cancer and chronic infection.

Circadian rhythms are key regulators of immune functions. These endogenous oscillations help to maintain immune homeostasis, regulate responses to pathogens, and shape vaccine efficacy. Recent studies further indicate that they are of clinical relevance for cancer immunotherapies. While circadian immune rhythms are thus recognized to be important in adults, it is unknown at what developmental stage these rhythms begin to manifest. In this opinion article we review the development of circadian rhythms in the immune system in both rodents and humans, with a focus on their interactions during the perinatal period. Understanding their emergence in early life may help guide time-based clinical interventions for infants.