RESUMEN
Tripartite motif-containing 21 (TRIM21) is a cytosolic immunoglobulin receptor that mediates antibody-dependent intracellular neutralization (ADIN). Here we show that TRIM21 potently inhibits the spreading infection of a replicating cytopathic virus and activates innate immunity. We used a quantitative PCR (qPCR)-based assay to measure in vitro replication of mouse adenovirus type 1 (MAV-1), a virus that causes dose-dependent hemorrhagic encephalitis in mice. Using this assay, we show that genetic ablation of TRIM21 or chemical inhibition of either the AAA ATPase p97/valosin-containing protein (VCP) or the proteasome results in a >1,000-fold increase in the relative level of infection in the presence of immune serum. Moreover, the TRIM21-mediated ability of antisera to block replication was a consistent feature of the humoral immune response in immunized mice. In the presence of immune sera and upon infection, TRIM21 also activates a proinflammatory response, resulting in secretion of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6). These results demonstrate that TRIM21 provides a potent block to spreading infection and induces an antiviral state.
Asunto(s)
Infecciones por Adenoviridae/inmunología , Anticuerpos Neutralizantes/inmunología , Encefalitis Viral/inmunología , Inmunidad Innata/inmunología , Mastadenovirus/inmunología , Ribonucleoproteínas/inmunología , Adenosina Trifosfatasas/genética , Animales , Proteínas de Ciclo Celular/genética , Cartilla de ADN/genética , Fibroblastos , Interleucina-5/inmunología , Ratones , Pruebas de Neutralización , Reacción en Cadena de la Polimerasa , Complejo de la Endopetidasa Proteasomal/genética , Ribonucleoproteínas/genética , Factor de Necrosis Tumoral alfa/inmunología , Proteína que Contiene Valosina , Replicación Viral/fisiologíaRESUMEN
This report describes cerebral venous sinus thrombosis, a rare and perhaps under-diagnosed complication of nephrotic syndrome. We review the pathophysiology of the coagulopathy associated with nephrotic syndrome including abrupt renal loss of antithrombin III. We propose a rationale approach to treating this condition with low-molecular-weight heparin and antithrombin III replacement.
Asunto(s)
Síndrome Nefrótico/complicaciones , Trombosis de los Senos Intracraneales/complicaciones , Anciano , Antitrombina III/análisis , Antitrombina III/uso terapéutico , Ciclosporina/uso terapéutico , Femenino , Humanos , Imagen por Resonancia Magnética , Síndrome Nefrótico/tratamiento farmacológicoRESUMEN
Activation of T cells leading to graft-vs-host disease (GVHD) requires two signaling events: the Ag-specific signal generated through the engagement of the TCR/CD3 complex with antigenic peptide fragments presented by MHC molecules on APCs and the second signal provided through additional costimulatory ligands. T cells have preferential costimulatory requirements depending on their state of activation-induced maturation. In the present study, we investigated the role of the receptor-ligand pair VLA-4 (alpha 4 beta 1) and VCAM-1 in allogeneic T cell responses in vitro and in vivo. Anti-VCAM-1 mAb effectively inhibited mixed lymphocyte culture (MLC) across several major MHC barriers and secondary MLC across minor histocompatibility Ags (95.5% and 90.0% inhibition, respectively). In contrast, anti-VLA-4 mAb inhibited a CD8(+)-mediated primed CTL response in vitro by 100%, yet had little effect on proliferative responses. In the B10.D2/nSnJ-->BALB/c (both H-2d) system of GVHD, BALB/c received anti-VCAM-1, or anti-VLA-4 or controls NS-1 or Y13-259 for the first 5 wk after transplant. Anti-VLA-4 mAb delayed the onset of GVHD, but failed to reduce incidence, severity or GVHD-related mortality. In contrast, anti-VCAM-1 reduced the incidence of GVHD from 100% (18/18) in control animals to 53.3% (8/15) (p < 0.01) on day 70 post-transplant and significantly decreased GVHD-related mortality. Sixty percent (9/15) of anti-VCAM-1 recipients survived more than 180 days after transplant. Long-term engraftment of allogeneic bone marrow was documented in all transplanted mice by PCR analysis of a microsatellite region in the IL-1 beta gene.
Asunto(s)
Enfermedad Injerto contra Huésped/prevención & control , Activación de Linfocitos , Antígenos de Histocompatibilidad Menor/inmunología , Linfocitos T Citotóxicos/inmunología , Molécula 1 de Adhesión Celular Vascular/uso terapéutico , Animales , Presentación de Antígeno/inmunología , Secuencia de Bases , Moléculas de Adhesión Celular/uso terapéutico , Citotoxicidad Inmunológica , Enfermedad Injerto contra Huésped/mortalidad , Enfermedad Injerto contra Huésped/terapia , Antígenos de Histocompatibilidad/inmunología , Hibridomas , Prueba de Cultivo Mixto de Linfocitos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos CBA , Datos de Secuencia Molecular , Transducción de Señal/inmunología , VolumetríaRESUMEN
In the nonobese diabetic (NOD) mouse, susceptibility to insulin-dependent diabetes mellitus is in part controlled by a single expressed class II major histocompatibility complex (MHC) molecule, I-Ag7. This molecule probably exerts its control through the representation of a self-peptide, derived from an unknown beta cell antigen, leading to T cell activation and eventual islet destruction. In this paper, synthetic peptides have been used to compete for binding to the I-Ag7 molecule in an attempt to suppress the autoimmune response. The administration of an I-Ag7-binding immunogenic peptide, lambda repressor (cI) 12-26, in a water and oil emulsion (incomplete Freund's adjuvant) can prevent the transfer of IDDM into irradiated recipients by spleen cells from diabetic donors. Nonbinding, nonimmunogenic peptides have no effect in this situation. However, the immune response to the "blocking" peptide in these experiments was a complicating factor in interpreting the results. To establish that the effect was at the level of competition for MHC binding, two additional approaches were tried. First, tolerance was induced to the immunogenic peptide, cI 12-26, before using it to "block" disease. Tolerance abolished the effect on diabetes transfer. Second, an effort was made to identify peptides that were nonimmunogenic but that bound to I-Ag7. Such a peptide, mouse prostatic secretory glycoprotein precursor 63-76, had no effect on the incidence of transferred disease. We conclude that the "blocking" effects seen in initial experiments in the NOD mouse were not caused by blockade of MHC presentation, but by other unknown effects related to the immunogenicity of the "blocking" peptide.
Asunto(s)
Enfermedades Autoinmunes/prevención & control , Proteínas de Unión al ADN , Diabetes Mellitus Tipo 1/prevención & control , Antígenos de Histocompatibilidad Clase II/inmunología , Inmunización , Fragmentos de Péptidos/uso terapéutico , Proteínas Represoras/uso terapéutico , Secuencia de Aminoácidos , Animales , Presentación de Antígeno , Antígenos/química , Antígenos/inmunología , Autoantígenos/inmunología , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/inmunología , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/inmunología , Femenino , Adyuvante de Freund , Glicoproteínas/inmunología , Antígenos de Histocompatibilidad Clase II/genética , Tolerancia Inmunológica , Inmunoterapia Adoptiva , Ganglios Linfáticos/citología , Ganglios Linfáticos/inmunología , Ratones , Ratones Endogámicos NOD , Ratones Endogámicos , Datos de Secuencia Molecular , Fragmentos de Péptidos/inmunología , Proteínas Represoras/inmunología , Bazo/citología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/trasplante , Proteínas Virales , Proteínas Reguladoras y Accesorias ViralesRESUMEN
Graft-versus-host disease across minor histocompatibility barriers was induced in two different models by transplanting allogeneic bone marrow and spleen cells into irradiated H-2-compatible recipient mice. In this report, we show that administration of peptides with high binding affinity for the respective class II major histocompatibility complex molecules after transplantation is capable of preventing the development of graft-versus-host disease in two different murine models. The peptides used were myelin basic protein residues 1 through 11 with alanine at position 4 (Ac 1-11[4A]) for I-Au (A alpha uA beta u), and the antigenic core sequence 323 through 339 of ovalbumin with lysine and methionine extension (KM core) for I-As (A alpha sA beta s). In both systems, the mechanism of prevention was found to be major histocompatibility complex-associated, because nonbinding control peptides did not have any effect. Engraftment of allogeneic bone marrow cells was shown by polymerase chain reaction analysis of DNA polymorphisms in a microsatellite region within the murine interleukin-5 gene.
Asunto(s)
Enfermedad Injerto contra Huésped/prevención & control , Antígenos de Histocompatibilidad Clase II/metabolismo , Fragmentos de Péptidos/uso terapéutico , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Trasplante de Médula Ósea , Femenino , Antígenos H-2/análisis , Antígenos H-2/inmunología , Histocompatibilidad , Interleucina-5/genética , Ratones , Datos de Secuencia Molecular , Proteína Básica de Mielina/química , Proteína Básica de Mielina/uso terapéutico , Ovalbúmina/química , Ovalbúmina/uso terapéutico , Fragmentos de Péptidos/inmunología , Fragmentos de Péptidos/metabolismo , Reacción en Cadena de la Polimerasa , Secuencias Repetitivas de Ácidos Nucleicos , Bazo/trasplante , Linfocitos T/inmunologíaRESUMEN
Competition between peptides for binding to class II major histocompatibility complex (MHC) molecules has been demonstrated both in vitro and in vivo. Peptide competition may provide a way to interfere with T cell activation in the treatment of autoimmune diseases. It may be possible to provide a substitute 'blocking' peptide to compete for presentation of an autoantigenic peptide to T cells. The approach described is a general one, which may be applicable to a number of T cell mediated MHC-linked autoimmune diseases, and to other undesirable immune responses. So far, peptide competitors have only been successfully used in the prevention of experimental autoimmune encephalomyelitis (EAE). Whether or not this approach will work in treating spontaneous disease models remains to be tested, although work in other test systems is encouraging.