Hair follicle immune privilege and its collapse in alopecia areata

Experimental Dermatology, Journal Year: 2020, Volume and Issue: 29(8), P. 703 - 725

Published: July 18, 2020

Anagen stage hair follicles (HFs) exhibit "immune privilege (IP)" from the level of bulge downwards to bulb. Both passive and active IP mechanisms protect HFs physiologically undesired immune responses limit surveillance. is relative, not absolute, primarily based on absent, or greatly reduced, intra-follicular antigen presentation via MHC class I II molecules, along with prominent expression "no danger" signals like CD200 creation an immunoinhibitory signalling milieu generated by secretory activities HFs. Perifollicular mast cells, Tregs other immunocytes may also contribute HF maintenance in healthy human skin. Collapse anagen bulb essential prerequisite for development alopecia areata (AA). In AA, lesional are rapidly infiltrated NKG2D + T cells natural killer (NK) while perifollicular acquire a profoundly pro-inflammatory phenotype interact autoreactive CD8+ cells. Using animal models, significant functional evidence has accumulated that demonstrates dominance system AA pathogenesis. Purified CD8+T-cell NK cell populations alone, which secrete fγ, suffice induce phenotype, CD4+T-cells aggravate it, iNKT provide relative protection against development. While collapse be induced exogenous agents, inherent deficiencies might confer increased susceptibility some individuals. Thus, key goal effective management re-establishment IP, will superior disease relapse.

Language: Английский

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Detrimental and protective action of microglial extracellular vesicles on myelin lesions: astrocyte involvement in remyelination failure

Acta Neuropathologica, Journal Year: 2019, Volume and Issue: 138(6), P. 987 - 1012

Published: July 30, 2019

Microglia are highly plastic immune cells which exist in a continuum of activation states. By shaping the function oligodendrocyte precursor (OPCs), brain differentiate to myelin-forming cells, microglia participate both myelin injury and remyelination during multiple sclerosis. However, mode(s) action supporting or inhibiting repair is still largely unclear. Here, we analysed effects extracellular vesicles (EVs) produced vitro by either pro-inflammatory pro-regenerative on OPCs at demyelinated lesions caused lysolecithin injection mouse corpus callosum. Immunolabelling for proteins electron microscopy showed that EVs released blocked remyelination, whereas co-cultured with immunosuppressive mesenchymal stem promoted OPC recruitment repair. The molecular mechanisms responsible harmful beneficial EV actions were dissected primary cultures. exposing OPCs, cultured alone astrocytes, inflammatory EVs, observed blockade maturation only presence implicating these failure. Biochemical fractionation revealed astrocytes may be converted into cargo, as indicated immunohistochemical qPCR analyses, surface lipid components promote migration and/or differentiation, linking lipids Although through species enhance remain fully defined, provide first demonstration vesicular sphingosine 1 phosphate stimulates migration, fundamental step From this study, microglial emerge multimodal multitarget signalling mediators able influence around lesions, exploited develop novel approaches not sclerosis, but also neurological neuropsychiatric diseases characterized demyelination.

Language: Английский

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Role of tumor necrosis factor-alpha in the central nervous system: a focus on autoimmune disorders

Frontiers in Immunology, Journal Year: 2023, Volume and Issue: 14

Published: July 7, 2023

Tumor necrosis factor-alpha (TNF-α) is a pleiotropic immune cytokine that belongs to the TNF superfamily of receptor ligands. The exists as either transmembrane or soluble molecule, and targets two distinct receptors, TNF-α 1 (TNFR1) 2 (TNFR2), which activate different signaling cascades downstream genes. cellular responses depend on its molecular form, targeted receptor, concentration levels. plays multifaceted role in normal physiology highly relevant human health disease. In central nervous system (CNS), this regulates homeostatic functions, such neurogenesis, myelination, blood-brain barrier permeability synaptic plasticity. However, it can also potentiate neuronal excitotoxicity CNS inflammation. pleiotropism various roles CNS, whether deleterious, only emphasizes functional complexity cytokine. Anti-TNF-α therapy has demonstrated effectiveness treating autoimmune inflammatory diseases emerged significant treatment option for diseases. Nevertheless, crucial recognize effects therapeutic target are diverse complex. Contrary initial expectations, anti-TNF-α been found have detrimental multiple sclerosis. This article focuses describing roles, both physiological pathological, CNS. Additionally, discusses specific disease processes dependent regulated by rationale use target.

Language: Английский

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Cross-reactive EBNA1 immunity targets alpha-crystallin B and is associated with multiple sclerosis

Science Advances, Journal Year: 2023, Volume and Issue: 9(20)

Published: May 17, 2023

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system, for which and Epstein-Barr virus (EBV) infection a likely prerequisite. Due to homology between nuclear antigen 1 (EBNA1) alpha-crystallin B (CRYAB), we examined antibody reactivity EBNA1 CRYAB peptide libraries in 713 persons with MS (pwMS) 722 matched controls (Con). Antibody response amino acids 7 16 was associated (OR = 2.0), combination high responses positivity markedly increased risk 9.0). Blocking experiments revealed cross-reactivity homologous epitopes. Evidence T cell obtained mice CRYAB, CD4

Language: Английский

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Multiple Sclerosis: Inflammatory and Neuroglial Aspects

Current Issues in Molecular Biology, Journal Year: 2023, Volume and Issue: 45(2), P. 1443 - 1470

Published: Feb. 8, 2023

Multiple sclerosis (MS) represents the most common acquired demyelinating disorder of central nervous system (CNS). Its pathogenesis, in parallel with well-established role mechanisms pertaining to autoimmunity, involves several key functions immune, glial and nerve cells. The disease’s natural history is complex, heterogeneous may evolve over a relapsing-remitting (RRMS) or progressive (PPMS/SPMS) course. Acute inflammation, driven by infiltration peripheral cells CNS, thought be relevant process during earliest phases RRMS, while disruption neural pathways energy metabolism, survival cascades, synaptic ionic homeostasis are mostly long-standing disease, such as forms. In this complex scenario, many originally distinctive neurodegenerative disorders being increasingly recognized crucial from beginning disease. present review aims at highlighting between MS, autoimmune diseases biology disorders. fact, there an unmet need explore new targets that might involved master regulators inflammation

Language: Английский

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The (neuro)inflammatory system in anxiety disorders and PTSD: Potential treatment targets

Pharmacology & Therapeutics, Journal Year: 2025, Volume and Issue: unknown, P. 108825 - 108825

Published: Feb. 1, 2025

Language: Английский

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Tumor necrosis factor receptor-2 (TNFR2): an overview of an emerging drug target

Expert Opinion on Therapeutic Targets, Journal Year: 2019, Volume and Issue: 23(4), P. 295 - 307

Published: March 11, 2019

Tumor necrosis factor (TNF) receptor 2 (TNFR2) is one of two receptors the cytokines, TNF and lymphotoxin-α. TNFR1 a strong inducer proinflammatory activities. TNFR2 has effects too, but it also elicits anti-inflammatory activities protective on oligodendrocytes, cardiomyocytes, keratinocytes. The may explain why inhibitors failed to be effective in diseases such as heart failure or multiple sclerosis, where been strongly implicated driving force. Stimulatory inhibitory targeting hence attracts considerable interest for treatment autoimmune cancer. Areas covered: Based brief description pathophysiological importance TNF-TNFR1/2 system, we discuss potential applications therapies. We debate activation way forward search TNFR2-specific agents. Expert opinion: use target regulatory T-cells attractive, this approach just amongst many suitable targets. With respect its preference Treg stimulation protection non-immune cells, more unique thus offers opportunities translational success.

Language: Английский

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Review article: managing the adverse events caused by anti‐TNF therapy in inflammatory bowel disease

Alimentary Pharmacology & Therapeutics, Journal Year: 2019, Volume and Issue: 49(6), P. 664 - 680

Published: Feb. 8, 2019

Biological therapy is currently widely used to treat IBD. Infliximab, adalimumab and golimumab are licensed anti-TNF therapies. Biosimilar monoclonal antibodies increasingly used. Anti-TNF therapies their adverse effects well characterised, may cause significant morbidity mortality in a small proportion of exposed patients. Gastroenterologists need understand the mechanisms for these effects, recognise swiftly manage such events appropriately.To cover range potential reactions as result biologic specifically management events.A Medline Pubmed search was undertaken. Search terms included were "anti-TNF," "infliximab" or "adalimumab" "golimumab" combined with keywords "ulcerative colitis" "Crohn's disease" "inflammatory bowel then narrowed articles containing "complications," "side effects" "adverse events" "safety profile." International guidelines also reviewed where relevant.Adverse discussed this review include infusion reactions, blood disorders infections (including bacterial, viral, fungal opportunistic infections) autoimmune, dermatological disorders, cardiac neurological conditions. Malignancies including solid organ, haematological those linked viral disease discussed.Anti-TNF has wide-ranging on immune system resulting spectrum Research advances improving understanding, recognition events.

Language: Английский

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Astrocyte and Oligodendrocyte Cross-Talk in the Central Nervous System

Cells, Journal Year: 2020, Volume and Issue: 9(3), P. 600 - 600

Published: March 3, 2020

Over the last decade knowledge of role astrocytes in central nervous system (CNS) neuroinflammatory diseases has changed dramatically. Rather than playing a merely passive response to damage it is clear that actively maintain CNS homeostasis by influencing pH, ion and water balance, plasticity neurotransmitters synapses, cerebral blood flow, are important immune cells. During disease become reactive hypertrophic, was long considered be pathogenic. However, recent studies reveal also have strong tissue regenerative role. Whilst most astrocyte research focuses on modulating neuronal function synaptic transmission little known about cross-talk between oligodendrocytes, myelinating cells CNS. This communication occurs via direct cell-cell contact as well secreted cytokines, chemokines, exosomes, signalling molecules. Additionally, this for glial development, triggering onset progression, stimulating regeneration repair. Its critical evident when fails. Here, we review emerging evidence astrocyte-oligodendrocyte health disease. Understanding pathways involved will insights into pathogenesis treatment diseases.

Language: Английский

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A New Venue of TNF Targeting

International Journal of Molecular Sciences, Journal Year: 2018, Volume and Issue: 19(5), P. 1442 - 1442

Published: May 11, 2018

The first Food and Drug Administration-(FDA)-approved drugs were small, chemically-manufactured highly active molecules with possible off-target effects, followed by protein-based medicines such as antibodies. Conventional antibodies bind a specific protein are becoming increasingly important in the therapeutic landscape. A very prominent class of biologicals anti-tumor necrosis factor (TNF) that applied several inflammatory diseases characterized dysregulated TNF levels. Marketing inhibitors revolutionized treatment Crohn’s disease. However, these also have undesired some them directly associated inherent nature this drug class, whereas others linked their mechanism action, being pan-TNF inhibition. effects can diverge at level format or receptor, we discuss consequences sepsis, autoimmunity neurodegeneration. Recently, researchers tried to design reduced side effects. These include more specificity targeting one neutralize cells. Alternatively, TNF-directed without typical antibody structure manufactured. Here, review complications related use conventional inhibitors, together anti-TNF alternatives benefits selective approaches different diseases.

Language: Английский

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