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1.
Immunity ; 53(5): 952-970.e11, 2020 11 17.
Artículo en Inglés | MEDLINE | ID: mdl-33098766

RESUMEN

Precise targeting of activation-induced cytidine deaminase (AID) to immunoglobulin (Ig) loci promotes antibody class switch recombination (CSR) and somatic hypermutation (SHM), whereas AID targeting of non-Ig loci can generate oncogenic DNA lesions. Here, we examined the contribution of G-quadruplex (G4) nucleic acid structures to AID targeting in vivo. Mice bearing a mutation in Aicda (AIDG133V) that disrupts AID-G4 binding modeled the pathology of hyper-IgM syndrome patients with an orthologous mutation, lacked CSR and SHM, and had broad defects in genome-wide AIDG133V chromatin localization. Genome-wide analyses also revealed that wild-type AID localized to MHCII genes, and AID expression correlated with decreased MHCII expression in germinal center B cells and diffuse large B cell lymphoma. Our findings indicate a crucial role for G4 binding in AID targeting and suggest that AID activity may extend beyond Ig loci to regulate the expression of genes relevant to the physiology and pathology of activated B cells.


Asunto(s)
Cromatina/genética , Cromatina/metabolismo , Citidina Desaminasa/genética , Citidina Desaminasa/metabolismo , G-Cuádruplex , Síndrome de Inmunodeficiencia con Hiper-IgM/etiología , Síndrome de Inmunodeficiencia con Hiper-IgM/metabolismo , Mutación , Animales , Linfocitos B/inmunología , Linfocitos B/metabolismo , Biología Computacional/métodos , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Activación Enzimática , Técnica del Anticuerpo Fluorescente , Perfilación de la Expresión Génica , Estudio de Asociación del Genoma Completo , Centro Germinal/inmunología , Centro Germinal/metabolismo , Antígenos HLA/genética , Antígenos HLA/inmunología , Humanos , Síndrome de Inmunodeficiencia con Hiper-IgM/diagnóstico , Cambio de Clase de Inmunoglobulina/genética , Cambio de Clase de Inmunoglobulina/inmunología , Inmunofenotipificación , Activación de Linfocitos/genética , Linfoma de Células B Grandes Difuso/etiología , Linfoma de Células B Grandes Difuso/metabolismo , Linfoma de Células B Grandes Difuso/patología , Ratones , Ratones Transgénicos
2.
J Immunol ; 202(11): 3137-3142, 2019 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-31028119

RESUMEN

The DNA damage response protein ATM has long been known to influence class switch recombination in ex vivo-cultured B cells. However, an assessment of B cell-intrinsic requirement of ATM in humoral responses in vivo was confounded by the fact that its germline deletion affects T cell function, and B:T cell interactions are critical for in vivo immune responses. In this study, we demonstrate that B cell-specific deletion of ATM in mice leads to reduction in germinal center (GC) frequency and size in response to immunization. We find that loss of ATM induces apoptosis of GC B cells, likely due to unresolved DNA lesions in cells attempting to undergo class-switch recombination. Accordingly, suboptimal GC responses in ATM-deficient animals are characterized by decreased titers of class-switched Abs and decreased rates of somatic hypermutation. These results unmask the critical B cell-intrinsic role of ATM in maintaining an optimal GC response following immunization.


Asunto(s)
Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Linfocitos B/fisiología , Centro Germinal/fisiología , Linfocitos T/fisiología , Animales , Proteínas de la Ataxia Telangiectasia Mutada/genética , Células Cultivadas , Reparación del ADN/genética , Cambio de Clase de Inmunoglobulina , Ratones , Ratones Noqueados , Receptores de Complemento 3d/genética , Hipermutación Somática de Inmunoglobulina
3.
Science ; 368(6487): 186-189, 2020 04 10.
Artículo en Inglés | MEDLINE | ID: mdl-32273468

RESUMEN

Bleeding and altered iron distribution occur in multiple gastrointestinal diseases, but the importance and regulation of these changes remain unclear. We found that hepcidin, the master regulator of systemic iron homeostasis, is required for tissue repair in the mouse intestine after experimental damage. This effect was independent of hepatocyte-derived hepcidin or systemic iron levels. Rather, we identified conventional dendritic cells (cDCs) as a source of hepcidin that is induced by microbial stimulation in mice, prominent in the inflamed intestine of humans, and essential for tissue repair. cDC-derived hepcidin acted on ferroportin-expressing phagocytes to promote local iron sequestration, which regulated the microbiota and consequently facilitated intestinal repair. Collectively, these results identify a pathway whereby cDC-derived hepcidin promotes mucosal healing in the intestine through means of nutritional immunity.


Asunto(s)
Células Dendríticas/metabolismo , Microbioma Gastrointestinal , Hepcidinas/metabolismo , Enfermedades Intestinales/microbiología , Mucosa Intestinal/microbiología , Mucosa Intestinal/fisiología , Hierro/metabolismo , Animales , Proteínas de Transporte de Catión/metabolismo , Trasplante de Microbiota Fecal , Eliminación de Gen , Hepcidinas/genética , Homeostasis , Ratones , Ratones Mutantes , Fagocitos/metabolismo
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