RESUMEN
BACKGROUND: Herpes simplex virus type 1 (HSV-1) infects >70% of the United States population. We identified a 3-megabase region on human chromosome 21 containing 6 candidate genes associated with herpes simplex labialis (HSL, "cold sores"). METHODS: We conducted single nucleotide polymorphism (SNP) scans of the chromosome 21 region to define which of 6 possible candidate genes were associated with cold sore frequency. We obtained the annual HSL frequency for 355 HSV-1 seropositive individuals and determined the individual genotypes by SNPlex for linkage analysis and parental transmission disequilibrium testing (ParenTDT). RESULTS: Two-point linkage analysis showed positive linkage between cold sore frequency and 2 SNPs within the C21orf91 region, 1 of which is nonsynonymous. ParenTDT analysis revealed a strong association between another C21orf91 SNP, predicted to lie in the 3' untranslated region, and frequent HSL (P = .0047). C21orf 91 is a predicted open reading frame of unknown function that encodes a cytosolic protein. CONCLUSIONS: We evaluated candidate genes in the cold sore susceptibility region using fine mapping with 45 SNP markers. 2 complementary techniques identified C21orf91 as a gene of interest for susceptibility to HSL. We propose that C21orf91 be designated the Cold Sore Susceptibility Gene-1 (CSSG1).
Asunto(s)
Cromosomas Humanos Par 21 , Predisposición Genética a la Enfermedad , Herpes Labial/genética , Polimorfismo de Nucleótido Simple , Anticuerpos Antivirales/sangre , Mapeo Cromosómico , Estudios de Asociación Genética , Ligamiento Genético , Haplotipos , Herpes Labial/virología , Herpesvirus Humano 1/inmunología , Humanos , FenotipoRESUMEN
Antibody-mediated intracellular delivery of therapeutic agents has been considered for treatment of a variety of diseases. These approaches involve targeting cell-surface receptor proteins expressed by tumors or viral proteins expressed on infected cells. We examined the intracellular trafficking of a viral cell-surface-expressed protein, rabies G, with or without binding a specific antibody, ARG1. We found that antibody binding shifts the native intracellular trafficking pathway of rabies G in an Fc-independent manner. Kinetic studies indicate that the ARG1/rabies G complex progressively co-localized with clathrin, early endosomes, late endosomes, and lysosomes after addition to cells. This pathway was different from that taken by rabies G without addition of antibody, which localized with recycling endosomes. Findings were recapitulated using a cellular receptor with a well-defined endogenous recycling pathway. We conclude that antibody binding to cell-surface proteins induces redirection of intracellular trafficking of unbound or ligand bound receptors to a specific degradation pathway. These findings have broad implications for future developments of antibody-based therapeutics.
Asunto(s)
Anticuerpos/inmunología , Antígenos Virales , Glicoproteínas , Proteínas de la Membrana , Transporte de Proteínas/inmunología , Proteínas del Envoltorio Viral , Animales , Reacciones Antígeno-Anticuerpo , Antígenos Virales/inmunología , Antígenos Virales/metabolismo , Línea Celular Tumoral , Glicoproteínas/inmunología , Glicoproteínas/metabolismo , Células HEK293 , Humanos , Proteínas de la Membrana/inmunología , Proteínas de la Membrana/metabolismo , Ratones , Plásmidos , Unión Proteica , Receptores de Transferrina/inmunología , Receptores de Transferrina/metabolismo , Transducción de Señal , Transfección , Transferrina , Proteínas del Envoltorio Viral/inmunología , Proteínas del Envoltorio Viral/metabolismoRESUMEN
Osteolysis of bone following total hip replacement is a major clinical problem. Examination of the areas surrounding failed implants has indicated an increase in the bone-resorption-inducing cytokine, interleukin 1ß (IL-1ß). NALP3, a NOD-like receptor protein located in the cytosol of macrophages, signals the cleavage of pro-IL-1ß into its mature, secreted form, IL-1ß. Here we showed that titanium particles stimulate the NALP3 inflammasome. We demonstrated that titanium induces IL-1ß secretion from macrophages. This response depended on the expression of components of the NALP3 inflammasome, including NALP3, ASC, and Caspase-1. We also showed that titanium particles trigger the recruitment of neutrophils and that this acute inflammatory response depends on the expression of the IL-1 receptor and IL-1α/ß. Moreover, administration of the IL-1 receptor antagonist (IL-1Ra) diminished neutrophil recruitment in response to titanium particles. Together, these results suggest that titanium particle-induced acute inflammation is due to activation of the NALP3 inflammasome, which leads to increased IL-1ß secretion and IL-1-associated signaling, including neutrophil recruitment. Efficacy of IL-1Ra treatment introduces the potential for antagonist-based therapies for implant osteolysis.