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1.
Proc Natl Acad Sci U S A ; 118(47)2021 11 23.
Artículo en Inglés | MEDLINE | ID: mdl-34782469

RESUMEN

Insulin-dependent or type 1 diabetes (T1D) is a polygenic autoimmune disease. In humans, more than 60 loci carrying common variants that confer disease susceptibility have been identified by genome-wide association studies, with a low individual risk contribution for most variants excepting those of the major histocompatibility complex (MHC) region (40 to 50% of risk); hence the importance of missing heritability due in part to rare variants. Nonobese diabetic (NOD) mice recapitulate major features of the human disease including genetic aspects with a key role for the MHC haplotype and a series of Idd loci. Here we mapped in NOD mice rare variants arising from genetic drift and significantly impacting disease risk. To that aim we established by selective breeding two sublines of NOD mice from our inbred NOD/Nck colony exhibiting a significant difference in T1D incidence. Whole-genome sequencing of high (H)- and low (L)-incidence sublines (NOD/NckH and NOD/NckL) revealed a limited number of subline-specific variants. Treating age of diabetes onset as a quantitative trait in automated meiotic mapping (AMM), enhanced susceptibility in NOD/NckH mice was unambiguously attributed to a recessive missense mutation of Dusp10, which encodes a dual specificity phosphatase. The causative effect of the mutation was verified by targeting Dusp10 with CRISPR-Cas9 in NOD/NckL mice, a manipulation that significantly increased disease incidence. The Dusp10 mutation resulted in islet cell down-regulation of type I interferon signature genes, which may exert protective effects against autoimmune aggression. De novo mutations akin to rare human susceptibility variants can alter the T1D phenotype.


Asunto(s)
Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/inmunología , Fosfatasas de Especificidad Dual/genética , Predisposición Genética a la Enfermedad/genética , Mutación de Línea Germinal , Animales , Enfermedades Autoinmunes/genética , Femenino , Estudio de Asociación del Genoma Completo , Haplotipos , Humanos , Islotes Pancreáticos/metabolismo , Complejo Mayor de Histocompatibilidad , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Fosfatasas de la Proteína Quinasa Activada por Mitógenos , Mutación
2.
RMD Open ; 10(3)2024 Aug 28.
Artículo en Inglés | MEDLINE | ID: mdl-39209370

RESUMEN

INTRODUCTION: The therapeutic interest of targeting B-cell activating factor (BAFF) in Sjögren's disease (SjD) can be suspected from the results of two phase II clinical trials but has not been evaluated in an animal model of the disease. We aimed to evaluate the therapeutic efficacy of this strategy on dryness and salivary gland (SG) infiltrates in the NOD mouse model of SjD. MATERIAL AND METHODS: Female NOD mice between ages 10 and 18 weeks were treated with a BAFF-blocking monoclonal antibody, Sandy-2 or an isotype control. Dryness was measured by the stimulated salivary flow. Salivary lymphocytic infiltrates were assessed by immunohistochemistry. Blood, SGs, spleen and lymph-node lymphocyte subpopulations were analysed by flow cytometry. SG mRNA expression was analysed by transcriptomic analysis. RESULTS: BAFF inhibition significantly decreased SG lymphocytic infiltrates, which was inversely correlated with salivary flow. The treatment markedly decreased B-cell number in SGs, blood, lymph nodes and spleen and increased Foxp3+ regulatory and CD3+CD4-CD8- double negative T-cell numbers in SGs. CONCLUSION: A monoclonal antibody blocking BAFF and depleting B cells had therapeutic effectiveness in the NOD mouse model of SjD. The increase in regulatory T-lymphocyte populations might underlie the efficacy of this treatment.


Asunto(s)
Factor Activador de Células B , Linfocitos B , Modelos Animales de Enfermedad , Ratones Endogámicos NOD , Síndrome de Sjögren , Animales , Factor Activador de Células B/antagonistas & inhibidores , Factor Activador de Células B/metabolismo , Síndrome de Sjögren/inmunología , Ratones , Femenino , Linfocitos B/inmunología , Linfocitos B/metabolismo , Glándulas Salivales/patología , Glándulas Salivales/metabolismo , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/farmacología , Depleción Linfocítica
3.
Front Immunol ; 11: 595003, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33643284

RESUMEN

Allergic asthma is characterized by airway inflammation with a Th2-type cytokine profile, hyper-IgE production, mucus hypersecretion, and airway hyperreactivity (AHR). It is increasingly recognized that asthma is a heterogeneous disease implicating complex immune mechanisms resulting in distinct endotypes observed in patients. In this study, we showed that non-obese diabetic (NOD) mice, which spontaneously develop autoimmune diabetes, undergo more severe allergic asthma airway inflammation and AHR than pro-Th2 BALB/c mice upon house dust mite (HDM) sensitization and challenge. The use of IL-4-deficient NOD mice and the in vivo neutralization of IL-17 demonstrated that both IL-4 and IL-17 are responsible by the exacerbated airway inflammation and AHR observed in NOD mice. Overall, our findings indicate that autoimmune diabetes-prone NOD mice might become useful as a new HDM-induced asthma model to elucidate allergic dysimmune mechanisms involving Th2 and Th17 responses that could better mimic some asthmatic endoytpes.


Asunto(s)
Asma/inmunología , Interleucina-17/inmunología , Interleucina-4/inmunología , Pyroglyphidae/inmunología , Células Th17/inmunología , Células Th2/inmunología , Animales , Asma/patología , Modelos Animales de Enfermedad , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos NOD , Células Th17/patología , Células Th2/patología
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