Advances in Genetics最新文献

Long non-coding RNAs (lncRNAs) have emerged as critical regulators of immune and inflammatory responses. Recent studies have highlighted the involvement of lncRNA in several inflammatory pathways such as NF-κB, MAPK, and JAK/STAT, where lncRNAs control processes like cytokine expression, transcription factor activation, nuclear translocation, and chromatin remodeling. They modulate the proliferation and differentiation of immune cells, including macrophages, dendritic cells, and T lymphocytes, by interacting with microRNAs, transcription factors, signaling proteins, and chromatin modifiers. They also affect the inflammatory response of non-immune cells, such as epithelial and endothelial cells. These multifaceted roles position lncRNAs as master regulators of inflammation, with their dysregulation contributing to the development and progression of various inflammatory diseases. Understanding their context-specific functions opens new avenues for therapeutic intervention and biomarker development.

The JAK-STAT signaling pathway is essential for regulating pro-inflammatory and immune responses across various cell types. Its involvement in inflammation has linked it to the pathogenesis of numerous autoimmune and inflammatory diseases. Genome-wide association studies have identified associations between JAK-STAT pathway genes and increased susceptibility to conditions such as type 1 diabetes, celiac disease, and multiple sclerosis. In recent years, this pathway has gained attention as a promising therapeutic target, leading to the development and clinical testing of several JAK-STAT inhibitors aimed at modulating immune-mediated inflammation. Despite notable progress in therapeutic modulation of the pathway, challenges remain in developing highly specific and effective drugs. Continued research is necessary to improve the precision and efficacy of treatments targeting the JAK-STAT pathway for autoimmune and inflammatory disorders.

Autoimmune diseases represent a complex class of disorders characterized by the immune system's aberrant attack on self-tissues, driven by intricate genetic and environmental factors. Long noncoding RNAs (lncRNAs), a diverse class of transcripts exceeding 200 nucleotides in length and lacking protein-coding capacity, have emerged as pivotal regulators of gene expression, chromatin architecture, and immune cell function. Here, we review literature in autoimmune disease pathogenesis and the role of lncRNAs, particularly in the immune system. We also provide a summary of recent advances elucidating the multifaceted roles of lncRNAs in autoimmune pathogenesis. This review underscores the expanding significance of lncRNAs in immunogenetics and autoimmune biology, offering new avenues for research and clinical intervention.

Interferons are key mediators of antiviral defense. They enable infected cells and specialized immune populations to mount rapid transcriptional responses that restrict viral replication and support immune activation. Type I and type III interferons share many antiviral properties, but their effects are determined by distinct receptor distributions, signaling dynamics, and tissue localization. While both families contribute to protection against infection, this chapter focuses primarily on the regulation and function of type I interferons. The induction of interferons depends on the activation of pattern recognition receptors that detect viral nucleic acids and trigger signaling cascades involving IRF and NF-κB transcription factors. These pathways control tightly regulated transcriptional and epigenetic programs that drive interferon gene expression and the induction of interferon-stimulated genes. Balanced regulation is essential, as excessive or persistent signaling can cause immunopathology and chronic inflammation. Genetic variation in interferon pathways influences susceptibility to viral infections, and defects in interferon regulation contribute to several monogenic interferonopathies. Plasmacytoid dendritic cells are a major source of type I interferons and illustrate the complexity of cellular specialization in antiviral defense. Understanding these mechanisms is essential for the development of therapies that enhance antiviral protection or limit pathogenic inflammation in chronic infections and autoimmune disease.

Leukocytes are typically migratory immune cells, and their migration is of critical immunological importance. In this context, chemokines and their receptors play a dynamic role in regulating the functions of leukocytes within the immune system, since they drive leukocytes into and out of blood and lymphatic vessels and direct their interstitial movement and positioning. Chemokines constitute a large family of cytokines that primarily regulate immune cell migration through the binding to chemokine receptors expressed on the surface of leukocytes. They are expressed by both immune and non-immune cells, and their activity is tightly regulated at several levels from transcription to secretion and distribution. Conventional chemokine receptors are G protein-coupled receptors (GPCR) found mainly in immune cells that can modulate the immune response activation by the initiation of a signaling cascade. On the contrary, atypical chemokine receptors act as decoy receptors and regulate chemokine levels in the blood. Together, chemokines and their receptors form the chemokine system, a complex network with high redundance and promiscuity. Dysregulation of this system can contribute to various disorders that have an immune or inflammatory component mediated by chemokine-directed leukocyte migration, such as chronic inflammatory and neurodegenerative disorders. Thus, in this chapter I focused on the role of chemokines and their receptors under physiological conditions and on their implication in disorders like multiple sclerosis, Parkinson's Disease and Alzheimer's Disease, in which neuroinflammation caused by the infiltration of these immune cells into the CNS and their activation plays a key role in the development of the pathologies.

Recent discoveries in the field of epigenetic regulation have shed light on the intricate processes of immune cell activation, differentiation, and function in response to threats. Epigenetics connects genetic and environmental factors and includes DNA methylation, histone post-translational modifications and the regulation of chromatin accessibility by non-coding RNAs controlling constitutive or inducible gene transcription. These mechanisms coordinate the activation or suppression of immune cells via specific transcriptional programmes. In particular, epigenetic marks at the sites of lineage-specific transcription factors, as well as the maintenance of cell-type-specific epigenetic modifications, dictate cell differentiation, cytokine production and functional ability following repeated exposure to antigens in memory T cells. Furthermore, the epigenetic and metabolic reprogramming that occurs during a primary innate immune response, results in enhanced responses to secondary challenges. A complete understanding of the epigenetic basis of immune cell differentiation and cellular stability will clarify pathological dysregulation and help delineate new therapeutic strategies for targeting immune disorders.

Genetics is a significant risk factor for developing type 2 diabetes, with a family history conferring a 1.5-3-fold increased risk. Intriguingly, this heritable risk is higher when the affected parent is the mother, suggesting a potential role of mitochondrial genetics -maternally inherited DNA - in diabetes pathogenesis, a hypothesis this chapter will explore. While obesity mediates some of the genetic risk of type 2 diabetes, the chapter and will focus on genetic influences on diabetes independent of obesity. Mechanistically, genetic variants directly or indirectly contribute to insulin resistance across key tissues, including liver, muscle and adipose tissue. This insulin resistance prevents the liver from efficiently suppressing glucose production in response to insulin and impairs glucose uptake in muscle during postprandial states. Insulin resistance is driven by complex interactions between the genome and environmental, which can, in turn, influence gene expression and contribute to worsening of metabolic dysfunction. This chapter examines how tissue-specific genetic changes drive insulin resistance in individual organs and how these localized dysfunctions contribute to the broader, multi-organ metabolic dysfunction that characterize type 2 diabetes.

Obesity is increasingly recognized not only for its systemic health impacts but also for its association with visual defects and eye diseases. This chapter explores the relationship between obesity and ocular health, highlighting the mechanisms by which metabolic dysregulation influences visual outcomes. Obesity exacerbates risk factors such as hypertension, dyslipidemia, and insulin resistance, which compromise retinal and optic nerve health. Conditions like diabetic retinopathy, age-related macular degeneration, and glaucoma are discussed in the context of obesity-related inflammation, oxidative stress, and altered vascular function, focusing on the retina as one of the body's most metabolically demanding tissues. Key pathways include adipose-derived cytokines that disrupt retinal homeostasis, and the effects of insulin resistance on retinal cells and vasculature. Furthermore, this chapter covers emerging evidence on the advances of genetic factors linking diabetic retinopathy to retinal impairments. By elucidating these interactions, we aim to provide insight into preventive and therapeutic strategies that could mitigate vision loss among individuals with obesity.

The intestinal epithelium serves as a critical mechanical barrier against potentially pathogenic bacteria and their antigens while maintaining immune homeostasis and facilitating nutrient and water absorption. In the gut, T cells undergo a multitude of highly specialized differentiation processes which are influenced by the unique microenvironment. Several studies reveal that intestinal epithelial cells (IECs) not only provide signals that shape T cell responses but also express a variety of factors that modulate T cell activity, such as cytokines, chemokines, and antigen-presenting molecules. The crosstalk between T cells and intestinal epithelium is necessary to grant a delicate immune balance to prevent excessive inflammation while assuring tolerance towards commensal microbial communities. Disruption of this line of communication can be deleterious since it could lead to immune-inflammatory disorders such as inflammatory bowel disease (IBD) and other disorders such as colorectal cancer. In recent years, advanced genomic and transcriptomic technologies have partially untangled the regulatory networks underlying this interaction. Understanding how the mechanisms governing the regulation of the interaction between T cells and IECs offers potential therapeutic hints for enhancing mucosal immunity and treating related diseases affecting gastrointestinal health. This chapter explores the key cellular players of mucosal immunity and the importance of epithelial-T cell interactions for immune regulation and potential therapeutic applications.

Coeliac disease (CD) is a chronic immune-mediated inflammatory disorder triggered by dietary gluten ingestion in genetically predisposed individuals. While gluten-specific T cells and HLA-DQ2/DQ8 alleles are critical to the disease onset, they account for less than half of the genetic heritability, underscoring the complexity of CD's genetic underpinnings. Genome-Wide Association Studies (GWAS) and next-generation sequencing have identified 42 non-HLA loci associated with CD risk, yet the molecular mechanisms underlying these associations remain largely unexplored. Notably, most disease-associated single nucleotide polymorphisms (SNPs) associated with CD are located in non-coding genomic regions, highlighting the regulatory potential of these variants. Emerging evidence demonstrates that non-coding RNAs (ncRNAs), particularly microRNAs and long non-coding RNAs, play crucial roles in gene regulation and disease development. Recent advances in transcriptomics have revealed new transcribed regions of the genome, shedding light on the functional significance of previously unannotated sequences. This review discusses the contribution of non-coding SNPs located in regulatory RNA regions to CD development, emphasizing the role of long non-coding RNAs and their potential as therapeutic targets.