RESUMEN
The phenylalanyl-glycyl-glycyl-alanyl-prolyl (FG-GAP) domain plays an important role in protein-protein interactions, including interaction of integrins with their ligands. Integrin-α FG-GAP repeat-containing protein 2 (Itfg2) is a highly conserved protein in vertebrates that carries two FG-GAP domains, but its role in mammalian physiology is unknown. In this article, we show that Itfg2 is an intracellular protein and it plays a critical role in B cell differentiation and development of autoimmunity. Itfg2-deficient mice displayed a phenotype consistent with retention of B cells in the spleen and had a lower concentration of IgG in the blood when compared with wild-type littermates. Itfg2-deficient splenocytes also showed a defect in cell migration in vitro. After immunization with a thymus-dependent Ag, the absence of Itfg2 caused a shift in B cell maturation from the germinal centers to the extrafollicular regions of the spleen and blocked deposition of Ag-specific plasma cells in the bone marrow. In support of hematopoietic cell intrinsic activity of Itfg2, bone marrow transplantation of Itfg2-deficient cells was sufficient to impair germinal center development in wild-type mice. Furthermore, Itfg2 deficiency exacerbated development of autoimmune disease in MRL/lpr lupus-prone mice. These results identify Itfg2 as a novel contributor to B cell differentiation and a negative regulator of the autoimmune response during lupus.
Asunto(s)
Enfermedades Autoinmunes/genética , Linfocitos B/citología , Linfocitos B/metabolismo , Diferenciación Celular/genética , Cadenas alfa de Integrinas/genética , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/metabolismo , Animales , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/metabolismo , Secuencia de Bases , Diferenciación Celular/inmunología , Núcleo Celular/metabolismo , Citoplasma/metabolismo , Modelos Animales de Enfermedad , Orden Génico , Marcación de Gen , Genotipo , Centro Germinal/inmunología , Centro Germinal/metabolismo , Células Madre Hematopoyéticas/metabolismo , Inmunoglobulinas/sangre , Cadenas alfa de Integrinas/química , Cadenas alfa de Integrinas/metabolismo , Lupus Eritematoso Sistémico/inmunología , Ratones , Ratones Noqueados , Datos de Secuencia Molecular , Fenotipo , Alineación de Secuencia , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismoRESUMEN
Osteoblasts are essential for maintaining bone mass, avoiding osteoporosis, and repairing injured bone. Activation of osteoblast G protein-coupled receptors (GPCRs), such as the parathyroid hormone receptor, can increase bone mass; however, the anabolic mechanisms are poorly understood. Here we use "Rs1," an engineered GPCR with constitutive G(s) signaling, to evaluate the temporal and skeletal effects of G(s) signaling in murine osteoblasts. In vivo, Rs1 expression induces a dramatic anabolic skeletal response, with midfemur girth increasing 1,200% and femur mass increasing 380% in 9-week-old mice. Bone volume, cellularity, areal bone mineral density, osteoblast gene markers, and serum bone turnover markers were also elevated. No such phenotype developed when Rs1 was expressed after the first 4 weeks of postnatal life, indicating an exquisite temporal sensitivity of osteoblasts to Rs1 expression. This pathway may represent an important determinant of bone mass and may open future avenues for enhancing bone repair and treating metabolic bone diseases.
Asunto(s)
Densidad Ósea/fisiología , Subunidades alfa de la Proteína de Unión al GTP Gs/biosíntesis , Subunidades alfa de la Proteína de Unión al GTP Gs/genética , Osteoblastos/química , Osteoblastos/metabolismo , Ingeniería de Proteínas , Receptores de Serotonina 5-HT4/biosíntesis , Receptores de Serotonina 5-HT4/genética , Secuencia de Aminoácidos , Animales , Línea Celular , Femenino , Subunidades alfa de la Proteína de Unión al GTP Gs/metabolismo , Subunidades alfa de la Proteína de Unión al GTP Gs/fisiología , Humanos , Ligandos , Masculino , Ratones , Ratones Transgénicos , Datos de Secuencia Molecular , Ingeniería de Proteínas/métodos , Agonistas del Receptor de Serotonina 5-HT4 , Transducción de Señal/genética , Transducción de Señal/fisiologíaRESUMEN
This study was to evaluate the clinical impact of whole body positron emission tomography (PET) with 18F-fluoro-2-deoxyglucose (FDG) to detect recurrent cervical cancer based on asymptomatically elevated tumor marker levels. Whole-body FDG-PET was performed in 20 patients with suspected recurrent squamous cell carcinoma (SCC) of the cervix and asymptomatic tumor marker of SCC antigen increased serum levels but negative or equivocal other imaging modality results. All of these 20 asymptomatic patients have serum levels of SCC antigen > 1.5 ng/mL. The final diagnosis of recurrent cervical cancer was established by operation/biopsy histopathological findings or clinical follow-up after more than 1 year by additional morphological imaging techniques. Among the 20 patients, the final diagnosis of recurrent cervical cancer was established in 81 lesions of 19 patients. The FDG-PET accurately detected 78/81 lesions. With asymptomatically elevated SCC antigen serum levels, the diagnostic sensitivity and accuracy of FDG-PET to detect recurrent cervical cancer lesions were 97.5% and 94.0%, respectively. The FDG-PET is a useful technique to detect recurrent cervical cancer for patients with asymptomatically elevated SCC antigen serum levels.