RESUMEN
The canine diaphragm is a muscular and tendinous dome-like plate and is largely involved in digestive and respiratory functions. Very few studies compared morphology of the diaphragm between dogs and cats and no studies have investigated the effects of individual factors on this morphology. So the aim of this study was to (1) study the effects of individual factors on the morphology of the diaphragm and (2) to compare its morphology between cats and dogs. Surface measurements of 86 diaphragms were performed. The tendinous centre (TC), the lumbar part of the peripheral muscular (LP) and the sternal and costal parts of the peripheral muscular (SCPM) were measured. Measurement ratios (surface of anatomical part of the diaphragm/total surface of the diaphragm) were used for statistical analysis (TC%S, LP%S, SCPM%S). The SCPM%S are significantly lower, and the LP%S are significantly higher when bodyweight increases in dogs and cats. The TC%S are significantly lower when the body condition score of dogs increases. The SCPM%S are significantly higher, and therefore, the TC%S and LP%S lower in brachycephalic animals as opposed to mesocephalic animals. The TC%S are significantly higher in dogs than in cats and the SCPM%S are significantly higher in cats than in dogs. This study proposed a cartography of the diaphragm morphology in cats and dogs taking into account individual animal factors. Significant differences in the diaphragm morphology between cats and dogs and between mesocephalic and brachycephalic animals were found. Further studies are necessary to confirm these results and to investigate the consequences of these variations.
Asunto(s)
Enfermedades de los Gatos , Enfermedades de los Perros , Gatos , Animales , Perros , Diafragma , Tórax , TendonesRESUMEN
Signals that determine the differentiation of naïve CD4+ T helper (TH) cells into specific effector cell subsets are primarily stimulated by cytokines, but additional signals are required to adjust the magnitude of TH cell responses and set the balance between effective immunity and immunological tolerance. By inducing the post-thymic deletion of the T cell lineage signaling protein THEMIS, we showed that THEMIS promoted the development of optimal type 1 immune responses to foreign antigens but stimulated signals that favored encephalitogenic responses to self-neuroantigens. THEMIS was required to stimulate the expression of the gene encoding the transcriptional regulator T-BET and the production of the cytokine interferon-γ (IFN-γ), and it enhanced the ability of encephalitogenic CD4+ T cells to migrate into the central nervous system. Consistently, analysis of THEMIS expression in polarized CD4+ T cells showed that THEMIS was selectively increased in abundance in TH1 cells. The stimulation of predifferentiated effector CD4+ T cells with antigen-presenting cells revealed a stimulatory function for THEMIS on type 1 cytokine responses, similar to those observed ex vivo after immunization. In contrast, THEMIS exerted opposing effects on naïve CD4+ T cells in vitro by inhibiting the T cell receptor (TCR)-mediated signals that lead to TH1 cell responses. These data suggest that THEMIS exerts TCR-independent functions in effector T cells, which increase the magnitude of normal and pathogenic TH1 cell-mediated responses.
Asunto(s)
Receptores de Antígenos de Linfocitos T , Linfocitos T , Células Presentadoras de Antígenos , Citocinas , Inmunidad , Receptores de Antígenos de Linfocitos T/metabolismo , Linfocitos T/metabolismo , Células TH1RESUMEN
CD5 is characterized as an inhibitory coreceptor with an important regulatory role during T cell development. The molecular mechanism by which CD5 operates has been puzzling and its function in mature T cells suggests promoting rather than repressing effects on immune responses. Here, we combined quantitative mass spectrometry and genetic studies to analyze the components and the activity of the CD5 signaling machinery in primary T cells. We found that T cell receptor (TCR) engagement induces the selective phosphorylation of CD5 tyrosine 429, which serves as a docking site for proteins with adaptor functions (c-Cbl, CIN85, CRKL), connecting CD5 to positive (PI3K) and negative (UBASH3A, SHIP1) regulators of TCR signaling. c-CBL acts as a coordinator in this complex enabling CD5 to synchronize positive and negative feedbacks on TCR signaling through the other components. Disruption of CD5 signalosome in mutant mice reveals that it modulates TCR signal outputs to selectively repress the transactivation of Foxp3 and limit the inopportune induction of peripherally induced regulatory T cells during immune responses against foreign antigen. Our findings bring insights into the paradigm of coreceptor signaling, suggesting that, in addition to providing dualistic enhancing or dampening inputs, coreceptors can engage concomitant stimulatory and inhibitory signaling events, which act together to promote specific functional outcomes.
Asunto(s)
Antígenos/inmunología , Antígenos CD5/metabolismo , Diferenciación Celular/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Linfocitos T Reguladores/fisiología , Animales , Antígenos CD5/genética , Diferenciación Celular/genética , Regulación de la Expresión Génica/inmunología , Activación de Linfocitos/genética , Espectrometría de Masas , Ratones , Ratones Transgénicos , Cultivo Primario de Células , Receptores de Antígenos de Linfocitos T/antagonistas & inhibidores , Transducción de Señal/genética , Transducción de Señal/inmunologíaRESUMEN
Neisseria meningitidis recruits host human complement inhibitors to its surface to down-regulate complement activation and enhance survival in blood. We have investigated whether such complement inhibitor binding occurs after vaccination with native outer membrane vesicles (nOMVs), and limits immunogenicity of such vaccines. To this end, nOMVs reactogenic lipopolysaccharide was detoxified by deletion of the lpxl1 gene (nOMVlpxl1). nOMVs unable to bind human complement factor H (hfH) were generated by additional deletions of the genes encoding factor H binding protein (fHbp) and neisserial surface protein A (NspA) (nOMVdis). Antibody responses elicited in mice with nOMVdis were compared to those elicited with nOMVlpxl1 in the presence of hfH. Results demonstrate that the administration of human fH to mice immunized with fHbp containing OMVlpxl1 decreased immunogenicity against fHbp (but not against the OMV as a whole). The majority of the OMV-induced bactericidal immune response (OMVlpxl1 or OMVdis) was versus PorA. Despite a considerable reduction of hfH binding to nOMVdis, and the absence of the vaccine antigen fHbp, immunogenicity in mice was not different from nOMVlpxl1, in the absence or presence of hfH (serum bactericidal titers of 1:64 vs 1:128 after one dose in the nOMVdis and nOMVlpxl1-immunized groups respectively). Therefore, partial inhibition of fH binding did not enhance immunity in this model.
Asunto(s)
Proteínas de la Membrana Bacteriana Externa/inmunología , Inactivadores del Complemento/inmunología , Meningitis Meningocócica/inmunología , Meningitis Meningocócica/prevención & control , Vacunas Meningococicas/inmunología , Neisseria meningitidis/inmunología , Animales , Formación de Anticuerpos , Proteínas de la Membrana Bacteriana Externa/uso terapéutico , Factor H de Complemento/inmunología , Femenino , Humanos , Inmunización , Vacunas Meningococicas/uso terapéutico , Ratones , Ratones Endogámicos C57BLRESUMEN
Neisseria meningitidis is a major global pathogen causing invasive disease with a mortality of 5-10%. Most disease in developed countries is caused by serogroup B infection, against which there is no universal vaccine. Opacity-associated adhesin (Opa) proteins are major meningococcal outer membrane proteins, which have shown recent promise as a potential novel vaccine. Immunisation of mice with different Opa variants elicited high levels of meningococcal-specific bactericidal antibodies, demonstrating proof in principle for this approach. Opa proteins are critical in meningococcal pathogenesis, mediating bacterial adherence to host cells, and modulating human cellular immunity via interactions with T cells and neutrophils, although there are conflicting data regarding their effects on CD4(+) T cells. We constructed Opa-positive and Opa-negative meningococcal strains to allow further evaluation of Opa as a vaccine component. All four opa genes from N. meningitidis strain H44/76 were sequentially disrupted to construct all possible combinations of N. meningitidis strains deficient in one, two, three, or all four opa genes. The transformations demonstrated that homologous recombination of exogenous DNA into the meningococcal chromosome can occur with as little as 80 bp, and that minor sequence differences are permissible. Anti-Opa bactericidal antibody responses following immunisation of mice with recombinant Opa were specific to the Opa variant used in immunisation. No immunomodulatory effects were observed when Opa was contained within meningococcal outer membrane vesicles (OMVs), compared to Opa-negative OMVs. These observations support the incorporation of Opa in meningococcal vaccines.
Asunto(s)
Proteínas de la Membrana Bacteriana Externa/genética , Inmunización , Meningitis Meningocócica/prevención & control , Vacunas Meningococicas/inmunología , Neisseria meningitidis/inmunología , Proteínas Recombinantes/genética , Animales , Proteínas de la Membrana Bacteriana Externa/inmunología , Meningitis Meningocócica/inmunología , Ratones , Neisseria meningitidis/genética , Proteínas Recombinantes/inmunologíaRESUMEN
The RcsCDB signal transduction system is an atypical His-Asp phosphorelay. Notably, the response regulator RcsB can be activated either by phosphorylation through the RcsCD pathway or by an accessory cofactor RcsA. Although conserved in Enterobacteriaceae, the role of this system in adaptation to environmental stress conditions is largely unknown. This study reveals that the response regulator RcsB is essential to glutamate-dependent acid resistance, a condition pertinent to the lifestyle of Escherichia coli. The requirement for RcsB is independent of its activation by either the RcsCD or the RcsA pathway. The basal activity of RcsB appears to be necessary and sufficient for acid resistance. The sensitivity of the rcsB strain to low pH is correlated to a strong reduction of the expression of the glutamate decarboxylase genes, gadA and gadB, during the stationary phase of growth. This effect on gadA/B expression is not mediated by the general stress sigma factor RpoS, but does require a functional gadE allele and the previously identified GadE box. Therefore activation of gadAB expression and acid resistance absolutely requires both GadE and RcsB. In contrast, an increase in RcsB activity through the activation of the RcsCD phosphorelay or the RcsA pathway or through overproduction of the protein leads to general repression of the expression of the gad genes and a corresponding reduction in acid resistance.