Treatment of Multiple Sclerosis: A Review

The American Journal of Medicine, Journal Year: 2020, Volume and Issue: 133(12), P. 1380 - 1390.e2

Published: July 17, 2020

Language: Английский

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B cell depletion therapies in autoimmune disease: advances and mechanistic insights

Nature Reviews Drug Discovery, Journal Year: 2020, Volume and Issue: 20(3), P. 179 - 199

Published: Dec. 15, 2020

Language: Английский

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CD4 T cells mediate brain inflammation and neurodegeneration in a mouse model of Parkinson's disease

Brain, Journal Year: 2021, Volume and Issue: 144(7), P. 2047 - 2059

Published: March 8, 2021

α-Synuclein, a key pathological component of Parkinson's disease, has been implicated in the activation innate and adaptive immune system. This includes microgliosis, increased inflammatory cytokines, infiltration T cells into CNS. More recently, peripherally circulating CD4 CD8 derived from individuals with disease have shown to produce Th1/Th2 cytokines response α-synuclein, suggesting there may be chronic memory cell present disease. To understand potential effects these α-syn associated responses we used an α-synuclein overexpression mouse model, cell-deficient mice, combination immunohistochemistry flow cytometry. In this study, found that midbrain mice leads upregulation major histocompatibility complex II (MHCII) protein on CNS myeloid as well IFNγ producing Interestingly, genetic deletion TCRβ or CD4, use immunosuppressive drug fingolimod, were able reduce MHCII α-synuclein. Furthermore, observed CD4-deficient protected dopaminergic loss due overexpression. These results suggest pathology damaging areas targeting could avenue for modifying treatments.

Language: Английский

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Periphery and brain, innate and adaptive immunity in Parkinson’s disease

Acta Neuropathologica, Journal Year: 2021, Volume and Issue: 141(4), P. 527 - 545

Published: Feb. 8, 2021

Abstract Parkinson’s disease (PD) is a neurodegenerative disorder where alpha-synuclein plays central role in the death and dysfunction of neurons, both, central, as well peripheral nervous system. Besides neuronal events observed patients, PD also includes significant immune component. It suggested that PD-associated response will have consequences on health, thus opening immunomodulation potential therapeutic strategy PD. The changes during occur brain, involving microglia, but periphery with cells innate system, particularly monocytes, those adaptive immunity, such T-cells. This realization arises from multiple patient studies, data animal models disease, providing strong evidence for system crosstalk Here we review showing crucial activation We describe studies suggesting inflammation early develop dynamically through time contributing to degeneration symptomatology patients. novel finding has contributed definition multisystem should be approached more integratory manner rather than brain-focused classical approach.

Language: Английский

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HLA-DR15 Molecules Jointly Shape an Autoreactive T Cell Repertoire in Multiple Sclerosis

Cell, Journal Year: 2020, Volume and Issue: 183(5), P. 1264 - 1281.e20

Published: Oct. 21, 2020

The HLA-DR15 haplotype is the strongest genetic risk factor for multiple sclerosis (MS), but our understanding of how it contributes to MS limited. Because autoreactive CD4+ T cells and B as antigen-presenting are involved in pathogenesis, we characterized immunopeptidomes two allomorphs DR2a DR2b human primary monocytes, thymus, brain tissue. Self-peptides from HLA-DR molecules, particularly themselves, abundant on thymic cells. Furthermore, identified cell clones that can cross-react with HLA-DR-derived self-peptides (HLA-DR-SPs), peptides MS-associated foreign agents (Epstein-Barr virus Akkermansia muciniphila), autoantigens presented by DR2b. Thus, both jointly shape an repertoire serving structures epitope sources presenting same MS.

Language: Английский

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B cells in multiple sclerosis — from targeted depletion to immune reconstitution therapies

Nature Reviews Neurology, Journal Year: 2021, Volume and Issue: 17(7), P. 399 - 414

Published: June 1, 2021

Language: Английский

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Gut microbiota–specific IgA ⁺ B cells traffic to the CNS in active multiple sclerosis

Science Immunology, Journal Year: 2020, Volume and Issue: 5(53)

Published: Nov. 13, 2020

Changes in gut microbiota composition and a diverse role of B cells have recently been implicated multiple sclerosis (MS), central nervous system (CNS) autoimmune disease. Immunoglobulin A (IgA) is key regulator at the mucosal interface. However, whether shape IgA responses what IgA+ neuroinflammation are unknown. Here, we identify IgA-bound taxa MS show that IgA-producing specific for MS-associated traffic to inflamed CNS, resulting strong, compartmentalized enrichment active other neuroinflammatory diseases. Unlike previously characterized polyreactive anti-commensal responses, CNS cross-reacts with surface structures on bacterial strains but not brain tissue. These findings establish microbiota-specific as systemic mediator suggest critical during broad implications an informative biomarker immune subset harness therapeutic interventions.

Language: Английский

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CD39/CD73/A2AR pathway and cancer immunotherapy

Molecular Cancer, Journal Year: 2023, Volume and Issue: 22(1)

Published: March 2, 2023

Abstract Cancer development is closely associated with immunosuppressive tumor microenvironment (TME) that attenuates antitumor immune responses and promotes cell immunologic escape. The sequential conversion of extracellular ATP into adenosine by two important cell-surface ectonucleosidases CD39 CD73 play critical roles in reshaping an TME. accumulated mediates its regulatory functions binding to one four receptors (A1R, A2AR, A2BR A3R). A2AR elicits profound function via regulating cAMP signaling. increasing evidence suggests CD39, could be used as novel therapeutic targets for manipulating the immunity. In recent years, monoclonal antibodies or small molecule inhibitors targeting CD39/CD73/A2AR pathway have been investigated clinical trials single agents combination anti-PD-1/PD-L1 therapies. this review, we provide updated summary about pathophysiological adenosinergic cancer development, metastasis drug resistance. more components therapy circumvention immunotherapy resistance are also discussed. Emerging biomarkers may guide selection CD39/CD73/A2AR-targeting treatment strategies individual patients deliberated.

Language: Английский

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Immune cell compartmentalization for brain surveillance and protection

Nature Immunology, Journal Year: 2021, Volume and Issue: 22(9), P. 1083 - 1092

Published: Aug. 24, 2021

Language: Английский

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Oxidative Stress and 4-hydroxy-2-nonenal (4-HNE): Implications in the Pathogenesis and Treatment of Aging-related Diseases

Journal of Immunology Research, Journal Year: 2022, Volume and Issue: 2022, P. 1 - 12

Published: March 23, 2022

Oxidative stress plays an important role in the development of aging-related diseases by accelerating lipid peroxidation polyunsaturated fatty acids cell membrane, resulting production aldehydes, such as malondialdehyde and 4-hydroxy-2-nonenal (4-HNE) other toxic substances. The compound 4-HNE forms adducts with DNA or proteins, disrupting many signaling pathways including regulation apoptosis signal transduction pathways. binding proteins to (4-HNE-protein) acts marker peroxidation, its increasing concentration brain tissues fluids because aging, ultimately gives rise some hallmark disorders, neurodegenerative (Alzheimer’s Parkinson’s diseases), ophthalmic (dry eye, macular degeneration), hearing loss, cancer. This review aims describe physiological origin 4-HNE, elucidate toxicity diseases, discuss detoxifying effect aldehyde dehydrogenase glutathione 4-HNE-driven diseases.

Language: Английский

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