Advances in Immunology最新文献

{"title":"iPSC-derived neurospheres: A cellular platform for Tau and Alzheimer's disease immunotherapy.","authors":"Subashchandrabose Chinnathambi, Anusree Adityan, Madhura Chandrashekar, Gowshika Velmurugan","doi":"10.1016/bs.ai.2025.11.001","DOIUrl":"https://doi.org/10.1016/bs.ai.2025.11.001","url":null,"abstract":"<p><p>Alzheimer's disease is the most prevalent type of dementia, which is characterized by a progressive loss of memory and cognitive impairment. The internalization of extracellular Tau and Amyloid-β-induced pluripotent stem cells plays a crucial role in understanding the AD pathology. iPSC-derived neuron, microglia, and astrocyte are used as models to study the spreading of pathological proteins and their contribution in the disease progression. iPSC-derived neurons serve as an essential model for studying AD, particularly in relation to Tau aggregation, prion-like propagation, and the toxic effects of oligomeric amyloid beta. Extracellular Tau, along with oligomeric amyloid beta, enters neurons via endocytosis and macropinocytosis, leading to cellular abnormalities, oxidative stress, and dysfunction in neurons. Additionally, iPSC-derived microglia provide insights into neuroinflammatory responses and neurotoxic effects of Tau aggregation and Amyloid-β, highlighting their combined role in Alzheimer's pathology. Extracellular Tau internalization by microglia involves phagocytosis and exhibits activation response to Tau aggregates, releasing cytokines and undergoing calcium homeostasis. iPSC-derived astrocytes demonstrated a reactive state and disruption in calcium homeostasis upon the exposure of the pathological proteins, contributing to neurodegeneration. Further, the mechanisms of Tau and Amyloid-β internalization in iPSC-derived cells provide insights into disease progression and highlights potential therapeutic targets for neurodegenerative disease.</p>","PeriodicalId":50862,"journal":{"name":"Advances in Immunology","volume":"171 ","pages":"175-203"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148800759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chemokine receptor CX3CR1 modulates microglial activity through Tau and amyloid-β interactions in Alzheimer's disease.","authors":"Vaishnavi Ananathanarayana, Riddhi Upadhyay, Gouri H Illanad, Deena Krishnan, Neha P Bochageri, Murugan Sevanan, Zabin Bagewadi, R Sivasamy, Subashchandrabose Chinnathambi","doi":"10.1016/bs.ai.2025.11.002","DOIUrl":"https://doi.org/10.1016/bs.ai.2025.11.002","url":null,"abstract":"<p><p>Alzheimer's disease is one of the most prevalent forms of dementia characterized by neurocognitive decline. Key proteins involved in the progression of disease is amyloid-β and Tau. Abnormal accumulation of amyloid-β senile plaques and Tau neurofibrillary tangles are characteristic features of AD which drives synaptic dysfunction and leads to cognitive decline. Recent studies emphasizes the importance of G-protein coupled receptors in regulating microglial cells and has diverse functions in modulating AD, particularly in the clearance of these pathological proteins. Among these GPCRs, the chemokine receptor CX3CR1 has a critical role at the intersection of pathological proteins and microglial signalling. CX3CR1 receptor mediated signalling influences interaction between microglia and neuron mediating microglial uptake and processing of Aβ and Tau. Aging is also one of the risk factors of AD which alters CX3CR1 signalling, thereby exacerbating disease progression. This review highlights the multifaceted role of CX3CR1 in Tau and Aβ pathology and outlines its signalling mechanisms. Importantly, this review emphasizes the therapeutic potential of targeting the CX3CL1-CX3CR1 axis and involved in protein clearance and reduces neuroinflammation preserving synaptic function, offering a promising way to prevent AD.</p>","PeriodicalId":50862,"journal":{"name":"Advances in Immunology","volume":"171 ","pages":"83-108"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148800829","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microglial polarisation imbalance and receptor-targeted therapeutics in Parkinson's disease.","authors":"Riddhi Upadhyay, Murugan Sevanan","doi":"10.1016/bs.ai.2024.10.003","DOIUrl":"https://doi.org/10.1016/bs.ai.2024.10.003","url":null,"abstract":"<p><p>Parkinson's Disease (PD) is a progressive neurodegenerative disease, which is mainly characterised by the selective depletion of dopaminergic neurons in the substantia nigra and deposition of misfolded aggregates of α-synuclein. It is increasingly being observed that neuroinflammation, mitochondrial dysfunction, and lost neurotrophic support are interacting factors that drive disease progression. The aggregated 1-synuclein triggers an anti-inflammatory phenotype and pro-inflammatory phenotypes in activated microglia, which produce cytokines and reactive oxygen species, aggravating stress in neurons. At the same time, mitochondrial dynamic dysfunction increases oxidative injury, which makes neurons sensitive to degeneration. The low concentration of neurotrophic factors, especially the brain-derived neurotrophic factor (BDNF), impairs the innate ability of the brain to repair itself and maintain its synapses. These pathological processes gradually create a loop of self-feeding, which results in prolonged inflammation, loss of proteostasis, and gradual loss of dopaminergic neurons. This network is interconnected, and understanding it is crucial in the creation of therapies that attempt to restore proteostasis, inhibit inflammation, and increase neurotrophic signalling to delay or prevent PD progression.</p>","PeriodicalId":50862,"journal":{"name":"Advances in Immunology","volume":"171 ","pages":"343-369"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148801067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The microbiome of the head and neck region.","authors":"Akhilanand Chaurasia, Kalyana Ponangi","doi":"10.1016/bs.ai.2026.03.002","DOIUrl":"https://doi.org/10.1016/bs.ai.2026.03.002","url":null,"abstract":"<p><p>The head and neck region is a host to a diverse and complex microbiome, comprising of very specific microbial communities across different anatomical niches such as the oral cavity, nasal sinuses, pharynx, larynx, salivary glands, and middle ear. The existence of these communities is determined by various factors such as physicochemical conditions, local environment and host genetics playing a critical role in maintaining mucosal integrity, immune modulation, colonization resistance, and thereby achieving metabolic homeostasis. As the human ages, the microbiome constantly evolves, influenced by diet, hormonal changes, and lifestyle even causing disruptions such as dysbiosis linked to diseases like head and neck squamous cell carcinoma (HNSCC). This chapter attempts to explore the anatomical and ecological diversity, site-specific microbial compositions, functional roles, developmental trajectories, and the challenges in understanding these microbial communities. Even though there were significant advances in sequencing technologies helping in identifying the microbial protective and pathogenic potential, hurdles like sampling difficulties and low biomass contamination tend to complicate the research process. Therefore it is of utmost importance to understand the baseline microbiome thereby helping in laying a foundation for studying its role in HNSCC, creating a pathway for microbial diagnostics and curative therapies.</p>","PeriodicalId":50862,"journal":{"name":"Advances in Immunology","volume":"169 ","pages":"25-51"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148413570","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microbial biomarkers for OPMD progression.","authors":"Jing-Wen Li, Yujue Wang, Akhilanand Chaurasia","doi":"10.1016/bs.ai.2026.03.001","DOIUrl":"https://doi.org/10.1016/bs.ai.2026.03.001","url":null,"abstract":"<p><p>Oral potentially malignant disorders (OPMDs) present a heterogeneous risk of progression to oral squamous cell carcinoma (OSCC), underscoring the need for reliable, non-invasive biomarkers to aid in clinical stratification. This chapter evaluates the utility of the oral microbiome as a source of predictive biomarkers for OPMD progression. Current evidence indicates that OPMDs and OSCC are frequently associated with microbial dysbiosis, characterized by a shift toward anaerobic, periodontal-associated taxa, such as Fusobacterium and Porphyromonas, and a concomitant depletion of health-associated Streptococcus. However, translating these taxonomic signatures into clinical practice is hindered by overlapping community structures across healthy, premalignant, and malignant mucosal states, alongside significant confounding from periodontal inflammation and lifestyle exposures. Furthermore, the field remains divided on whether this dysbiosis acts as an upstream driver of carcinogenesis or a downstream consequence of tumor-associated microenvironmental selection. To overcome these methodological and biological limitations, this chapter advocates for an ecology-driven, multi-omics approach. By integrating taxonomic profiling with functional readouts like metabolomics and metaproteomics, and contextualizing these signals within host microenvironmental strata (e.g., hypoxia and inflammation), researchers can achieve greater mechanistic interpretability and robustness. Ultimately, microbiome-informed tools are best positioned not as standalone diagnostic tests, but as adjunctive instruments for clinical triage and risk enrichment, provided they are rigorously validated in prospective, longitudinal converter/non-converter cohorts.</p>","PeriodicalId":50862,"journal":{"name":"Advances in Immunology","volume":"169 ","pages":"193-212"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148413599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glial control of extracellular α-synuclein propagation in LRRK2 Parkinson's disease.","authors":"Indrani Datta, Dibyam Debasish Sahu","doi":"10.1016/bs.ai.2026.04.005","DOIUrl":"https://doi.org/10.1016/bs.ai.2026.04.005","url":null,"abstract":"<p><p>Parkinson's disease (PD) pathology extends well beyond dopaminergic neuronal loss, with glial cells-microglia and astrocytes-emerging as active architects of α-synuclein spread rather than passive bystanders. This review synthesises current evidence on how mutations in Leucine-Rich Repeat Kinase 2 (LRRK2), the most common genetic cause of familial PD, fundamentally corrupt glial handling of extracellular α-synuclein. We first outline the biology of extracellular α-synuclein-its cellular sources, conformational spectrum, prion-like propagation mechanisms, and principal glial clearance routes-before examining LRRK2 domain architecture, its downstream Rab GTPase signalling cascade, and the cellular processes it governs in glia. We then detail how LRRK2 mutations reconfigure microglial responses: driving constitutive NLRP3 inflammasome priming, impairing phagolysosomal degradation of α-synuclein aggregates, and redirecting phagocytosed cargo into pathogenic exosomal release via the LRRK2-Rab10-LYTL axis. In astrocytes, LRRK2 mutations disrupt annexin A2-mediated phagocytosis, impair chaperone-mediated autophagy and lysosomal acidification, deplete membrane cholesterol through Rab8A/Rab10 hyperphosphorylation, compromise glutamate transporter surface expression, and promote the secretion of phospho-α-synuclein-enriched extracellular vesicles that are neurotoxic to co-cultured dopaminergic neurons. Crucially, dysfunctional microglia and astrocytes do not operate independently-they form a self-amplifying feed-forward circuit in which microglial cytokines (IL-1α, TNF-α, C1q) drive A1 astrocyte conversion, tunnelling nanotube-mediated aggregate exchange propagates rather than resolves α-synuclein burden, and successive waves of neuronal death perpetuate the cycle. We highlight that these mechanisms are mutation-specific: the GTPase-domain variant I1371V, characterised through our group's patient-derived iPSC platform, drives qualitatively distinct membrane and metabolic dysfunction compared with the kinase-domain variant G2019S, underscoring the need for variant-tailored therapeutic strategies. We review human iPSC-based models-including microglia-like cells, midbrain-patterned astrocytes, and 3D midbrain organoids-that have proven indispensable for resolving cell-autonomous from non-cell-autonomous contributions of LRRK2 mutations. Finally, we evaluate emerging therapeutic strategies targeting LRRK2 kinase activity, NLRP3 inflammasome activation, extracellular α-synuclein immunotherapy, and glial lysosomal enhancement, including intranasal mesenchymal stromal cell-derived small extracellular vesicles. We conclude by identifying key unanswered questions regarding the relative dominance of microglial versus astrocytic clearance at different disease stages, the full pathogenic landscape of understudied LRRK2 variants, and the tractability of glial biomarkers as pharmacodynamic endpoints in clinical trials.</p>","PeriodicalId":50862,"journal":{"name":"Advances in Immunology","volume":"171 ","pages":"215-246"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148800781","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microglia-centered cellular crosstalk in neurodegeneration.","authors":"Hao Huang, Elvira Mass","doi":"10.1016/bs.ai.2026.06.001","DOIUrl":"https://doi.org/10.1016/bs.ai.2026.06.001","url":null,"abstract":"<p><p>Neuroinflammation shaped by aberrant cellular interactions represents a hallmark of neurodegenerative diseases of the central nervous system (CNS). Microglia are specialized tissue-resident macrophages that reside in the CNS parenchyma and have emerged as central regulators of this aberrant cellular crosstalk. They integrate local signals and orchestrate the cellular interaction networks that underlie disease progression. Recent advances in single-cell and single-nucleus omics, in combination with spatially resolved approaches, have substantially advanced our understanding of microglial dynamics in neurodegeneration. These technological and conceptual advances have revealed an unexpected diversity of disease-associated microglial states and highlighted microglia as central organizers of multicellular interaction networks within diseased CNS tissue. In this chapter, we discuss how these advances have reshaped our understanding of microglia-centered cellular crosstalk in neurodegeneration. We focus on the diversification of neurodegenerative CNS microglial states, the interaction of microglia with neurons, glial cells, adaptive immune cells, and the vasculature. We further discuss how this framework provides a basis for therapeutic strategies aimed at modulating, replacing, or reprogramming microglia in neurodegenerative disease.</p>","PeriodicalId":50862,"journal":{"name":"Advances in Immunology","volume":"171 ","pages":"437-462"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148800851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Brain macrophages in neurodegeneration.","authors":"Rachel J Johnston, Nicole A Pagán Torres, Yangchen Li, Claudia Z Han","doi":"10.1016/bs.ai.2026.06.005","DOIUrl":"https://doi.org/10.1016/bs.ai.2026.06.005","url":null,"abstract":"<p><p>Brain macrophages are not uniform responders to neurodegeneration, but anatomically specialized populations whose functions depend on niche, developmental history, and regulatory state. The goal of this chapter is to discuss how parenchymal microglia and brain border associated macrophages as components of a distributed macrophage network that operates across the central nervous system. Microglia are embedded within the parenchyma and are central to surveillance, synaptic remodeling, myelin maintenance and tissue repair, whereas BAMs occupy vascular, meningeal, and choroid plexus interfaces where they regulate barrier function, immune surveillance, fluid dynamics and solute clearance. Across disease settings, these populations repeatedly converge and diverge on pathological programs, including inflammatory activation, lysosomal stress, lipid handling and maladaptive crosstalk with neighboring cells. Future studies on how these populations are alike and different and development of technology to allow precise targeting of these populations will be essential towards enhancing macrophage protection of the brain.</p>","PeriodicalId":50862,"journal":{"name":"Advances in Immunology","volume":"171 ","pages":"33-81"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148800826","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microglial advances in Parkinson's disease.","authors":"Manuel Debasa-Mouce, Alberto Ouro, Joshua De Leon, Shelly Gulkarov, Allison B Reiss, Anastasia Bougea","doi":"10.1016/bs.ai.2026.06.003","DOIUrl":"https://doi.org/10.1016/bs.ai.2026.06.003","url":null,"abstract":"<p><p>Microglia perform the function of CNS macrophages and act as the primary immune cells in the brain. They surveil the environment, phagocytose cellular debris, maintain homeostasis and respond to tissue damage. While under physiological conditions they play a role in supporting neurons, activated microglia participate directly in the degeneration of neurons in the substantia nigra, as the hallmark of the Parkinsons disease (PD). Their detrimental effects result from direct phagocytosis of dopaminergic neurons as well as via neuroinflammation and release of toxic reactive oxygen and nitrogen species. This pathological shift is driven by a complex interplay of genetic predispositions, such as LRRK2 and GBA mutations, and environmental triggers like toxins and gut dysbiosis.A central mechanism of this neurodegeneration involves extracellular α-synuclein acting as a danger signal (DAMP), which activates microglial Toll-like receptors (e.g., TLR2) to initiate a severe inflammatory cascade. Furthermore, the extreme biophysical stability of aggregated α-synuclein overwhelms the microglial endolysosomal network, leading to lysosomal failure, \"frustrated phagocytosis,\" and the active propagation of the disease via exosomal shedding. Relieving this maladaptive chronic neuroinflammation is a primary therapeutic goal. Modern strategies aim to break this vicious cycle through precise interventions like NLRP3 inflammasome inhibition and autophagy enhancement. Concurrently, advanced fluid biomarkers, such as seed amplification assays (SAA), alongside multidimensional neuroimaging techniques (PET, SPECT, MRI), are proving crucial for detecting these early microglial and pathological changes to guide personalized, disease-modifying therapies of PD.</p>","PeriodicalId":50862,"journal":{"name":"Advances in Immunology","volume":"171 ","pages":"247-281"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148800891","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microglial advances in psychiatric disorders.","authors":"Jemmyson R de Jesus, Iare S Ribeiro, Marcos V S Pereira, Wesley C P Aquino, Lucas H M Alfredo","doi":"10.1016/bs.ai.2026.04.007","DOIUrl":"https://doi.org/10.1016/bs.ai.2026.04.007","url":null,"abstract":"<p><p>Psychiatric disorders constitute a major global challenge to public health, characterized by complex and multifactorial etiologies involving genetic, environmental, and neurobiological factors. In recent years, growing evidence has highlighted the central role of microglia, the resident immune cells of the central nervous system, in regulating brain homeostasis and in the pathophysiology of neuropsychiatric conditions. Beyond their classic immune functions, microglia actively participate in synaptic pruning, neurogenesis, and the modulation of neural circuits. Dysregulation of microglial activity, particularly chronic pro-inflammatory activation, has been strongly associated with disorders such as major depression, schizophrenia, bipolar disorder, and neurodegenerative diseases, contributing to impaired synaptic plasticity, neuroinflammation, and behavioral dysfunction. This chapter discusses recent advances in microglial biology, emphasizing its functional heterogeneity and dynamic phenotypic states. This chapter explores the main molecular pathways involved in microglia-mediated synaptic remodeling and their implications for the progression of neuropsychiatric disorders. Furthermore, emerging therapeutic strategies targeting microglia were discussed, including anti-inflammatory approaches, functional reprogramming, neuromodulation techniques, and microglial replacement or niche engineering. These advances support a paradigm shift from indiscriminate microglia inhibition to the precise modulation of specific functional states. Understanding and targeting microglia dynamics may provide innovative and more effective therapeutic pathways for the treatment of psychiatric disorders.</p>","PeriodicalId":50862,"journal":{"name":"Advances in Immunology","volume":"171 ","pages":"371-400"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148800969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}