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1.
PLoS Genet ; 16(6): e1008788, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32497089

RESUMEN

The control of chronic inflammation is dependent on the possibility of limiting bystander activation of autoreactive and potentially pathogenic T cells. We have identified a non-sense loss of function single nucleotide polymorphism in the C-type lectin receptor, Clec4b, and have shown that it controls chronic autoimmune arthritis in rat models of rheumatoid arthritis. Clec4b is specifically expressed in CD4+ myeloid cells, mainly classical dendritic cells (DCs), and is defined by the markers CD4+/MHCIIhi/CD11b/c+. We found that Clec4b limited the activation of arthritogenic CD4+αßT cells and the absence of Clec4b allowed development of arthritis already 5 days after adjuvant injection. Clec4b sufficient CD4+ myeloid dendritic cells successfully limited the arthritogenic T cell expansion immediately after activation both in vitro and in vivo. We conclude that Clec4b expressed on CD4+ myeloid dendritic cells regulate the expansion of auto-reactive and potentially pathogenic T cells during an immune response, demonstrating an early checkpoint control mechanism to avoid autoimmunity leading to chronic inflammation.


Asunto(s)
Artritis Experimental/genética , Lectinas Tipo C/fisiología , Activación de Linfocitos , Linfocitos T/inmunología , Animales , Artritis Experimental/inmunología , Efecto Espectador , Células Cultivadas , Células Dendríticas/inmunología , Lectinas Tipo C/genética , Mutación con Pérdida de Función , Ratas
2.
Proc Natl Acad Sci U S A ; 113(26): E3716-24, 2016 06 28.
Artículo en Inglés | MEDLINE | ID: mdl-27303036

RESUMEN

Genome-wide association studies have revealed many genetic loci associated with complex autoimmune diseases. In rheumatoid arthritis (RA), the MHC gene HLA-DRB1 is the strongest candidate predicting disease development. It has been suggested that other immune-regulating genes in the MHC contribute to the disease risk, but this contribution has been difficult to show because of the strong linkage disequilibrium within the MHC. We isolated genomic regions in the form of congenic fragments in rats to test whether there are additional susceptibility loci in the MHC. By both congenic mapping in inbred strains and SNP typing in wild rats, we identified a conserved, 33-kb large haplotype Ltab-Ncr3 in the MHC-III region, which regulates the onset, severity, and chronicity of arthritis. The Ltab-Ncr3 haplotype consists of five polymorphic immunoregulatory genes: Lta (lymphotoxin-α), Tnf, Ltb (lymphotoxin-ß), Lst1 (leukocyte-specific transcript 1), and Ncr3 (natural cytotoxicity-triggering receptor 3). Significant correlation in the expression of the Ltab-Ncr3 genes suggests that interaction of these genes may be important in keeping these genes clustered together as a conserved haplotype. We studied the arthritis association and the spliceo-transcriptome of four different Ltab-Ncr3 haplotypes and showed that higher Ltb and Ncr3 expression, lower Lst1 expression, and the expression of a shorter splice variant of Lst1 correlate with reduced arthritis severity in rats. Interestingly, patients with mild RA also showed higher NCR3 expression and lower LST1 expression than patients with severe RA. These data demonstrate the importance of a conserved haplotype in the regulation of complex diseases such as arthritis.


Asunto(s)
Artritis Reumatoide/genética , Antígenos de Histocompatibilidad/genética , Animales , Artritis Reumatoide/inmunología , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Genotipo , Haplotipos , Antígenos de Histocompatibilidad/inmunología , Humanos , Péptidos y Proteínas de Señalización Intracelular , Linfotoxina-alfa/genética , Linfotoxina-alfa/inmunología , Linfotoxina beta/genética , Linfotoxina beta/inmunología , Masculino , Proteínas de la Membrana/genética , Proteínas de la Membrana/inmunología , Receptor 3 Gatillante de la Citotoxidad Natural/genética , Receptor 3 Gatillante de la Citotoxidad Natural/inmunología , Ratas , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunología
3.
PLoS Genet ; 10(2): e1004151, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24586191

RESUMEN

Genetic variation in the major histocompatibility complex (MHC) affects CD4∶CD8 lineage commitment and MHC expression. However, the contribution of specific genes in this gene-dense region has not yet been resolved. Nor has it been established whether the same genes regulate MHC expression and T cell selection. Here, we assessed the impact of natural genetic variation on MHC expression and CD4∶CD8 lineage commitment using two genetic models in the rat. First, we mapped Quantitative Trait Loci (QTLs) associated with variation in MHC class I and II protein expression and the CD4∶CD8 T cell ratio in outbred Heterogeneous Stock rats. We identified 10 QTLs across the genome and found that QTLs for the individual traits colocalized within a region spanning the MHC. To identify the genes underlying these overlapping QTLs, we generated a large panel of MHC-recombinant congenic strains, and refined the QTLs to two adjacent intervals of ∼0.25 Mb in the MHC-I and II regions, respectively. An interaction between these intervals affected MHC class I expression as well as negative selection and lineage commitment of CD8 single-positive (SP) thymocytes. We mapped this effect to the transporter associated with antigen processing 2 (Tap2) in the MHC-II region and the classical MHC class I gene(s) (RT1-A) in the MHC-I region. This interaction was revealed by a recombination between RT1-A and Tap2, which occurred in 0.2% of the rats. Variants of Tap2 have previously been shown to influence the antigenicity of MHC class I molecules by altering the MHC class I ligandome. Our results show that a restricted peptide repertoire on MHC class I molecules leads to reduced negative selection of CD8SP cells. To our knowledge, this is the first study showing how a recombination between natural alleles of genes in the MHC influences lineage commitment of T cells.


Asunto(s)
Transportadoras de Casetes de Unión a ATP/genética , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Diferenciación Celular/inmunología , Complejo Mayor de Histocompatibilidad/genética , Miembro 3 de la Subfamilia B de Transportadores de Casetes de Unión a ATP , Alelos , Animales , Presentación de Antígeno , Diferenciación Celular/genética , Linaje de la Célula , Regulación de la Expresión Génica , Antígenos de Histocompatibilidad/genética , Complejo Mayor de Histocompatibilidad/inmunología , Ratas , Recombinación Genética , Selección Genética
4.
J Transl Med ; 14(1): 311, 2016 11 03.
Artículo en Inglés | MEDLINE | ID: mdl-27809921

RESUMEN

BACKGROUND: An infection-immune association of periodontal disease with rheumatoid arthritis has been suggested. This study aimed to investigate the effect of pre-existing periodontitis on the development and the immune/inflammatory response of pristane-induced arthritis. METHODS: We investigated the effect of periodontitis induced by ligature placement and Porphyromonas gingivalis (P. gingivalis) infection, in combination with Fusobacterium nucleatum to promote its colonization, on the development of pristane-induced arthritis (PIA) in rats (Dark Agouti). Disease progression and severity of periodontitis and arthritis was monitored using clinical assessment, micro-computed tomography (micro-CT)/intraoral radiographs, antibody response, the inflammatory markers such as α-1-acid glycoprotein (α-1-AGP) and c-reactive protein (CRP) as well as cytokine multiplex profiling at different time intervals after induction. RESULTS: Experimentally induced periodontitis manifested clinically (P < 0.05) prior to pristane injection and progressed steadily until the end of experiments (15 weeks), as compared to the non-ligated arthritis group. Injection of pristane 8 weeks after periodontitis-induction led to severe arthritis in all rats demonstrating that the severity of arthritis was not affected by the pre-existence of periodontitis. Endpoint analysis showed that 89% of the periodontitis-affected animals were positive for antibodies against arginine gingipain B and furthermore, the plasma antibody levels to a citrullinated P. gingivalis peptidylarginine deiminase (PPAD) peptide (denoted CPP3) were significantly (P < 0.05) higher in periodontitis rats with PIA. Additionally, there was a trend towards increased pro-inflammatory and anti-inflammatory cytokine levels, and increased α-1-AGP levels in plasma from periodontitis-challenged PIA rats. CONCLUSIONS: Pre-existence of periodontitis induced antibodies against citrullinated peptide derived from PPAD in rats with PIA. However, there were no differences in the development or severity of PIA between periodontitis challenged and periodontitis free rats.


Asunto(s)
Artritis Experimental/complicaciones , Periodontitis/inducido químicamente , Periodontitis/complicaciones , Adhesinas Bacterianas/sangre , Adhesinas Bacterianas/inmunología , Animales , Formación de Anticuerpos/inmunología , Artritis Experimental/diagnóstico por imagen , Peso Corporal , Proteína C-Reactiva/metabolismo , Quimiocinas/metabolismo , Cisteína Endopeptidasas/sangre , Cisteína Endopeptidasas/inmunología , Cisteína-Endopeptidasas Gingipaínas , Hidrolasas/sangre , Hidrolasas/inmunología , Masculino , Orosomucoide/metabolismo , Periodontitis/diagnóstico por imagen , Periodontitis/microbiología , Porphyromonas gingivalis/fisiología , Arginina Deiminasa Proteína-Tipo 3 , Ratas , Terpenos , Microtomografía por Rayos X
5.
Nat Commun ; 12(1): 610, 2021 01 27.
Artículo en Inglés | MEDLINE | ID: mdl-33504785

RESUMEN

The introduction of the CTLA-4 recombinant fusion protein has demonstrated therapeutic effects by selectively modulating T-cell activation in rheumatoid arthritis. Here we show, using a forward genetic approach, that a mutation in the SH3gl1 gene encoding the endocytic protein Endophilin A2 is associated with the development of arthritis in rodents. Defective expression of SH3gl1 affects T cell effector functions and alters the activation threshold of autoreactive T cells, thereby leading to complete protection from chronic autoimmune inflammatory disease in both mice and rats. We further show that SH3GL1 regulates human T cell signaling and T cell receptor internalization, and its expression is upregulated in rheumatoid arthritis patients. Collectively our data identify SH3GL1 as a key regulator of T cell activation, and as a potential target for treatment of autoimmune diseases.


Asunto(s)
Aciltransferasas/deficiencia , Artritis Reumatoide/enzimología , Artritis Reumatoide/inmunología , Enfermedades Autoinmunes/enzimología , Enfermedades Autoinmunes/inmunología , Activación de Linfocitos/inmunología , Linfocitos T/inmunología , Aciltransferasas/genética , Aciltransferasas/metabolismo , Animales , Artritis Reumatoide/prevención & control , Autoinmunidad , Endocitosis , Femenino , Humanos , Células Jurkat , Ganglios Linfáticos/metabolismo , Ganglios Linfáticos/patología , Masculino , Ratones , Mutación/genética , Ratas , Receptores de Antígenos de Linfocitos T/metabolismo , Transducción de Señal , Regulación hacia Arriba/genética
6.
Nat Genet ; 45(7): 767-75, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23708188

RESUMEN

Genetic mapping on fully sequenced individuals is transforming understanding of the relationship between molecular variation and variation in complex traits. Here we report a combined sequence and genetic mapping analysis in outbred rats that maps 355 quantitative trait loci for 122 phenotypes. We identify 35 causal genes involved in 31 phenotypes, implicating new genes in models of anxiety, heart disease and multiple sclerosis. The relationship between sequence and genetic variation is unexpectedly complex: at approximately 40% of quantitative trait loci, a single sequence variant cannot account for the phenotypic effect. Using comparable sequence and mapping data from mice, we show that the extent and spatial pattern of variation in inbred rats differ substantially from those of inbred mice and that the genetic variants in orthologous genes rarely contribute to the same phenotype in both species.


Asunto(s)
Ansiedad/genética , Mapeo Cromosómico/métodos , Cardiopatías/genética , Esclerosis Múltiple/genética , Análisis de Secuencia de ADN/métodos , Animales , Animales no Consanguíneos , Variación Genética/genética , Genotipo , Humanos , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Fenotipo , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo/genética , Ratas
7.
Antioxid Redox Signal ; 14(12): 2373-83, 2011 Jun 15.
Artículo en Inglés | MEDLINE | ID: mdl-21275845

RESUMEN

The Ncf1 gene, encoding the P47(PHOX) protein that regulates production of reactive oxygen species (ROS) by the phagocyte NADPH oxidase (NOX2) complex, is associated with autoimmunity and arthritis severity in rats. We have now identified that the single-nucleotide polymorphism (SNP) resulting in an M153T amino acid substitution mediates arthritis resistance and thus explains the molecular polymorphism underlying the earlier identified Ncf1 gene effect. We identified the SNP in position 153 to regulate ROS production using COS(PHOX) cells transfected with mutated Ncf1. To determine the role of this SNP for control of arthritis, we used the Wistar strain, identified to carry only the postulated arthritis resistant SNP in position 153. When this Ncf1 allele was backcrossed to the arthritis susceptible DA strain, both granulocyte ROS production and arthritis resistance were restored. Position 153 is located in the hinge region between the PX and SH3 domains of P47(PHOX). Mutational analysis of this position revealed a need for an -OH group in the side chain but we found no evidence for phosphorylation. The polymorphism did not affect assembly of the P47(PHOX)/P67(PHOX) complex in the cytosol or membrane localization, but is likely to operate downstream of assembly, affecting activity of the membrane NOX2 complex.


Asunto(s)
Artritis/genética , Artritis/fisiopatología , NADPH Oxidasas/genética , Polimorfismo de Nucleótido Simple , Estallido Respiratorio/fisiología , Animales , Artritis/patología , Células COS , Chlorocebus aethiops , Humanos , NADPH Oxidasas/metabolismo , Fagosomas/metabolismo , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo
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