RESUMEN
Rare genetic variants in toll-like receptor 7 (TLR7) are known to cause lupus in humans and mice. UNC93B1 is a transmembrane protein that regulates TLR7 localization into endosomes. In the present study, we identify two new variants in UNC93B1 (T314A, located proximally to the TLR7 transmembrane domain, and V117L) in a cohort of east Asian patients with childhood-onset systemic lupus erythematosus. The V117L variant was associated with increased expression of type I interferons and NF-κB-dependent cytokines in patient plasma and immortalized B cells. THP-1 cells expressing the variant UNC93B1 alleles exhibited exaggerated responses to stimulation of TLR7/-8, but not TLR3 or TLR9, which could be inhibited by targeting the downstream signaling molecules, IRAK1/-4. Heterozygous mice expressing the orthologous Unc93b1V117L variant developed a spontaneous lupus-like disease that was more severe in homozygotes and again hyperresponsive to TLR7 stimulation. Together, this work formally identifies genetic variants in UNC93B1 that can predispose to childhood-onset systemic lupus erythematosus.
Asunto(s)
Predisposición Genética a la Enfermedad , Lupus Eritematoso Sistémico , Receptor Toll-Like 7 , Lupus Eritematoso Sistémico/genética , Humanos , Animales , Receptor Toll-Like 7/genética , Receptor Toll-Like 7/metabolismo , Ratones , Niño , Femenino , Proteínas de Transporte de Membrana/genética , Proteínas de Transporte de Membrana/metabolismo , Masculino , Edad de Inicio , Variación Genética , FN-kappa B/metabolismo , Linfocitos B/inmunología , Linfocitos B/metabolismo , Adolescente , Células THP-1 , Interferón Tipo I/metabolismoRESUMEN
BACKGROUND: Severe pneumonia frequently causes irreversible sequelae and represents a major health burden for children under the age of 5. Matrix Metallopeptidase 9 (MMP9) is a zinc-dependent endopeptidase that is involved in various cellular processes. The correlation between MMP9 and the risk of severe childhood pneumonia remains unclear. METHODS: Here we assemble a case-control cohort to study the association of genetic variants in MMP9 gene with severe childhood pneumonia susceptibility in a Southern Chinese population (1034 cases and 8426 controls). RESULTS: Our results indicate that the allele G in rs3918262 SNP was significantly associated with an increased risk of severe pneumonia. Bioinformatic analyses by expression quantitative trait loci (eQTL), RegulomeDB and FORGEdb database analysis showed that rs3918262 SNP has potential regulatory effect on translational efficiency and protein level of MMP9 gene. Furthermore, MMP9 concentrations were significantly up-regulated in the bronchoalveolar lavages (BALs) of children with severe pneumonia. CONCLUSION: In summary, our findings suggest that MMP9 is a novel predisposing gene for childhood pneumonia.
Asunto(s)
Predisposición Genética a la Enfermedad , Metaloproteinasa 9 de la Matriz , Neumonía , Niño , Humanos , Estudios de Casos y Controles , China , Genotipo , Metaloproteinasa 9 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/metabolismo , Polimorfismo de Nucleótido Simple , Neumonía/diagnóstico , Neumonía/epidemiología , Neumonía/genéticaRESUMEN
Human adenovirus (HAdV) pneumonia poses a major health burden for young children, however, factors that contribute to disease severity remain elusive. We analyzed immune cells from bronchoalveolar lavage (BAL) of children with HAdV pneumonia and found that CD19+CD21low B cells were significantly enriched in the BAL and were associated with increased autoantibody concentrations and disease severity. Myeloid cells, PD-1+CD4+ T helper cells and CD21low B cells formed tertiary lymphoid structures within the respiratory tracts. Myeloid cells promoted autoantibody production by expressing high amounts of B cell activating factor (BAFF). In contrast, PD-1+CD4+ T helper cells induced production of IgG1 and IgG3 antibodies but suppressed autoreactive IgGs by initiating B cell receptor editing. In summary, this study reveals cellular components involved in protective versus autoreactive immune pathways in the respiratory tract, and these findings provide potential therapeutic targets for severe HAdV lower respiratory tract infections.