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Introduction: Patients with end-stage renal disease (ESRD) display defects in adaptive and innate immunity, increasing susceptibility to infection. Staphylococcus aureus (S. aureus) is a major cause of bacteraemia in this population and is associated with increased mortality. More information on the immune response to S. aureus in these patients is needed to inform effective vaccine development. Methods: A longitudinal prospective study was carried out at two medical centers and included 48 ESRD patients who started chronic hemodialysis (HD) treatment ≤3 months before inclusion. Control samples were taken from 62 consenting healthy blood donors. Blood samples were obtained from ESRD patients at each visit, on month (M) 0 (beginning of HD), M6 and M12. Around 50 immunological markers of adaptive and innate immunity were assessed to compare immune responses to S. aureus in ESRD patients versus controls to document the changes on their immune profile during HD. Results: S. aureus survival in whole blood was significantly higher in ESRD patients than in controls at M0 (P=0.049), while impaired oxidative burst activity was observed in ESRD patients at all timepoints (P<0.001). S. aureus-specific immunoglobulin G (IgG) responses to iron surface determinant B (IsdB) and S. aureus α hemolysin (Hla) antigens were lower in ESRD patients than in healthy donors at M0 (P=0.003 and P=0.007, respectively) and M6 (P=0.05 and P=0.03, respectively), but were restored to control levels at M12. Moreover, S. aureus-specific T-helper cell responses were comparable to controls for IsdB but were impaired for Hla antigen at all timepoints: 10% of ESRD patients responded to Hla at M0, increasing to 30% at M12, compared with 45% of healthy donors. B-cell and T-cell concentrations in blood were significantly reduced (by 60% and 40%, respectively) compared with healthy controls. Finally, upregulation of Human Leucocyte Antigen-DR (HLA-DR) and C-C chemokine Receptor type 2 (CCR2) was impaired at M0 but was restored during the first year of HD. Conclusion: All together, these results show that adaptive immunity was largely impaired in ESRD patients, whereas innate immunity was less impacted and tended to be restored by HD.
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Fallo Renal Crónico , Staphylococcus aureus , Humanos , Estudios Longitudinales , Estudios Prospectivos , Fallo Renal Crónico/terapia , Diálisis Renal , Inmunidad Adaptativa , Inmunoglobulina G , HierroRESUMEN
Toll-like receptors (TLRs) are considered as potential targets for vaccine adjuvants. Here, we explored the impact of TLR agonists on the B cell response to a prototypic thymus-independent (TI) antigen: a Streptococcus pneumoniae capsular polysaccharide (PS). In adult mice, all TLR agonists (and CpG oligodeoxynucleotides [ODN] in particular) enhance the PS antibody response, provided that their administration is delayed until the second day after PS vaccination. In infant mice, CpG ODN not only potentiated the PS3 antibody response but also restored responsiveness to PS3 vaccination. Moreover, the immune protection induced by the plain PS3 vaccine adjuvanted by CpG ODN was comparable to that conferred by the conjugate vaccine in terms of efficiency and longevity. CpG ODN exert their adjuvant effect by increasing the survival rate of antigen-stimulated B cells as well as the output of plasmablasts. Our results provide a rationale for broader application of polysaccharidic vaccines.
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Anticuerpos Antivirales/sangre , Vacunas Neumococicas/inmunología , Polisacáridos Bacterianos/inmunología , Streptococcus pneumoniae/inmunología , Receptores Toll-Like/agonistas , Adyuvantes Inmunológicos/administración & dosificación , Animales , Ratones , Ratones Endogámicos C57BL , Oligodesoxirribonucleótidos/administración & dosificaciónRESUMEN
It was recently shown that bacterial thymus-independent (TI) antigens confer long-lasting immunity and generate memory B lymphocytes. However, reactivation of TI memory B cells is repressed in immunocompetent mice, thus raising the issue of the mechanism whereby TI vaccines confer immune protection. Here, we propose an explanation to this apparent paradox by showing that a Streptococcus pneumoniae capsular polysaccharide (PS) generates long-lived bone marrow (BM) plasma cells which frequency can be increased by CpG oligodeoxynucleotides (ODNs). The adjuvant effect of CpG ODNs on the PS3 Ab response is directly targeted to B cells and does not involve B-1a cells. We also demonstrated that BM plasma cells generated in response to the thymus-dependent (TD) form of the PS vaccine have a higher secretion capacity than those produced after immunization with the CpG-adjuvanted PS vaccine. Finally, we show that the PS-specific BM plasma cell compartment is sufficient to confer full protection of vaccinated mice against S pneumoniae infection. Altogether, our results show that TI antigens like their TD counterparts can generate both the lymphoid and the plasma cell component of B-cell memory. They also provide a framework for the improvement and widespread usage of TI vaccines.
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Antígenos T-Independientes/inmunología , Proteínas Bacterianas/inmunología , Memoria Inmunológica/inmunología , Células Plasmáticas/inmunología , Polisacáridos Bacterianos/inmunología , Adyuvantes Inmunológicos , Animales , Cápsulas Bacterianas/inmunología , Células de la Médula Ósea/inmunología , Ensayo de Inmunoadsorción Enzimática , Ratones , Oligodesoxirribonucleótidos/inmunología , Vacunas Neumococicas/inmunología , Streptococcus pneumoniae/inmunología , TimoRESUMEN
The CCR4-associated protein CAF1 has been demonstrated to play several roles in the control of transcription and of mRNA decay. To gain further insight into its physiological function, we generated CAF1-deficient mice. They are viable, healthy, and normal in appearance; however, mCAF1(-/-) male mice are sterile. The crossing of mCAF1(+/-) mice gave a Mendelian ratio of mCAF1(+/+), mCAF1(+/-), and mCAF1(-/-) pups, indicating that haploid mCAF1-deficient germ cells differentiate normally. The onset of the defect occurs during the first wave of spermatogenesis at 19 to 20 days after birth, during progression of pachytene spermatocytes to haploid spermatids and spermatozoa. Early disruption of spermatogenesis was evidenced by Sertoli cell vacuolization and tubular disorganization. The most mature germ cells were the most severely depleted, but progressively all germ cells were affected, giving Sertoli cell-only tubes, large interstitial spaces, and small testes. This phenotype could be linked to a defect(s) in germ cells and/or to inadequate Sertoli cell function, leading to seminiferous tubule disorganization and finally to a total disappearance of germ cells. The mCAF1-deficient mouse provides a new model of failed spermatogenesis in the adult that may be relevant to some cases of human male sterility.