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2.
Nat Aging ; 4(7): 969-983, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38834884

RESUMO

Inclusion body myositis (IBM) is the most prevalent inflammatory muscle disease in older adults with no effective therapy available. In contrast to other inflammatory myopathies such as subacute, immune-mediated necrotizing myopathy (IMNM), IBM follows a chronic disease course with both inflammatory and degenerative features of pathology. Moreover, causal factors and molecular drivers of IBM progression are largely unknown. Therefore, we paired single-nucleus RNA sequencing with spatial transcriptomics from patient muscle biopsies to map cell-type-specific drivers underlying IBM pathogenesis compared with IMNM muscles and noninflammatory skeletal muscle samples. In IBM muscles, we observed a selective loss of type 2 myonuclei paralleled by increased levels of cytotoxic T and conventional type 1 dendritic cells. IBM myofibers were characterized by either upregulation of cell stress markers featuring GADD45A and NORAD or protein degradation markers including RNF7 associated with p62 aggregates. GADD45A upregulation was preferentially seen in type 2A myofibers associated with severe tissue inflammation. We also noted IBM-specific upregulation of ACHE encoding acetylcholinesterase, which can be regulated by NORAD activity and result in functional denervation of myofibers. Our results provide promising insights into possible mechanisms of myofiber degeneration in IBM and suggest a selective type 2 fiber vulnerability linked to genomic stress and denervation pathways.


Assuntos
Miosite de Corpos de Inclusão , Humanos , Miosite de Corpos de Inclusão/patologia , Miosite de Corpos de Inclusão/metabolismo , Miosite de Corpos de Inclusão/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Músculo Esquelético/patologia , Músculo Esquelético/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Fibras Musculares Esqueléticas/patologia , Fibras Musculares Esqueléticas/metabolismo , Masculino , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo , Idoso , Inflamação/patologia , Inflamação/metabolismo , Inflamação/genética , Células Dendríticas/patologia , Células Dendríticas/metabolismo , Proteínas GADD45
3.
Sci Immunol ; 5(53)2020 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-33219152

RESUMO

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


Assuntos
Linfócitos B/imunologia , Microbioma Gastrointestinal/imunologia , Imunoglobulina A/metabolismo , Esclerose Múltipla/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos B/metabolismo , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Biomarcadores/metabolismo , Biópsia , Encéfalo/diagnóstico por imagem , Encéfalo/imunologia , Encéfalo/patologia , Estudos de Casos e Controles , Feminino , Humanos , Imunidade nas Mucosas , Imunoglobulina A/sangue , Imunoglobulina A/líquido cefalorraquidiano , Mucosa Intestinal/citologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/sangue , Esclerose Múltipla/líquido cefalorraquidiano , Esclerose Múltipla/diagnóstico
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