Actualización sobre vacunas y nuevas perspectivas

Many changes have occurred in vaccinology along the last years. Vaccines had been available since more than a century, but in recent times the number of preparations increased in exponential way. The change was not only numerical, in parallel; there was high technological complexity. In addition to these structural changes, the indications also were changed, and even the degrees of benefits are now referring to new concepts of risk and of cost / benefit. At present, the social response to vaccines has been modified, sometimes generating reject, and a growing number of people participate in the implementation process of vaccines.A lo largo de estos años se han producido muchos cambios en la vacunología. Disponemos de vacunas desde hace mas de un siglo pero en los últimos tiempos el número de preparados se incrementó de forma exponencial. El cambio no fue sólo numérico, paralelamente se produjo un aumento de su complejidad tecnológica. Además de estos cambios estructurales, también cambiaron las indicaciones de las vacunas, e incluso el grado de su beneficio, refiriéndose en estos momentos a nuevos conceptos de riesgo, y de coste/beneficio. En el presente, la respuesta social a las vacunas ha ido cambiado generando a veces rechazo y un número creciente de personas participan en el proceso de implementación de las vacunas

Tachyphylaxis to β2-agonists in Spanish asthmatic patients could be modulated by β2-adrenoceptor gene polymorphisms

Producción CientíficaThe study of determinants of asthma is a subject of much interest currently, especially the pharmacogenetic aspects of asthma management. Genetic polymorphisms affecting amino-acids at positions 16 and 27 within β2-adrenoceptor (β2AR) gene have been implicated in the asthma phenotypes and influence on the variability observed in response to use of bronchodilator agents used in the treatment of asthma. Whether these polymorphisms alter the bronchoprotection response to -agonist treatment in Spanish asthmatic population is unknown. The aim of this study was to investigate whether genetic polymorphisms within β2AR gene modulate the clinical outcomes of the individual response to β2-agonist therapy and the development of desensitization in Spanish asthmatic patients.Fondo de Investigación Sanitaria y Ministerio de Sanidad, Consumo y Bienestar Social (FIS00648 and 02/3068)Junta de Castilla y León (VA032/04

High Levels of Proinflammatory Cytokines, but Not Markers of Tissue Injury, in Unaffected Intestinal Areas from Patients with IBD

Intestinal alterations in IBD are triggered and maintained by an overexpression of proinflammatory cytokines. Additionally, increased immune activation has been found in the adjacent intestinal areas without displaying any apparent histological alterations, however, the regulatory environment is not well established. Biopsy specimens from patients with ulcerative colitis (UC) and Crohn's disease (CD), from both affected and unaffected areas, and also from a group of colonic biopsies from healthy controls, were included in our study. Cytokines and markers of mucosal damage were analyzed by real-time PCR, and some of the results confirmed by western-blot and ELISA. Levels of IFNγ, TNFα, IL-6, IL-15, IL-18, and IL-23 were increased (above healthy controls) in both affected and unaffected areas from IBD. IL-1β, IL-6, IL-12, and IL-27 were higher in affected areas compared to unaffected ones in UC but not CD. In general, a correlation was observed between mRNA levels of these cytokines and both iNOS and Granzyme B. SOCS-2 and SOCS-3 were also increased in the affected areas. In conclusion, the unaffected areas from IBD show increased levels of a restricted set of cytokines that may exert immune activating roles in these areas without being able to trigger tissue damage

Interleukin 18 maintains a long-standing inflammation in coeliac disease patients

Producción CientíficaDietary gluten induces an early response in the intestine of coeliac disease patients (CD), within a few hours, and this is driven by high levels of proinflammatory cytokines, including IFNg and IL-15, as has been thoroughly shown by gluten stimulation of biopsy explants. Our aim was to identify the immune mediators involved in the long-standing inflammation in untreated CD patients at diagnosis. mRNA and protein levels of TNFa, IL-12(p35), IL-12(p40), IL-15, IL-18 and IL-23(p19) were quantified in biopsies from active CD patients, CD patients on a gluten-free diet (GFD), healthy controls, and patients with non-CD inflammation and mild histological changes in the intestine. Biopsies from CD patients on a GFD were also stimulated in vitro with gliadin, and protein expression of IL-15 and IL-18 was analysed. Levels of IL-12 and IL-23 mRNA are nearly absent, and TNFa levels remain unchanged among different groups. Both the active and inactive forms of IL-18 protein have been found in all samples from active CD, and protein expression was only localized within the crypts. Levels of IL-15 mRNA remain unchanged, and protein expression, localized within the lamina propria, is found in a small number of samples. In vitro stimulation with gluten induces the expression of IL-15 and IL-18. In active CD, the early response following gluten intake characterized by high IFNg levels is driven by IL-18, and probably IL-15, and this alternates with periods of long-standing inflammation with moderate IFNg levels, maintained by IL-18 alone

Is it true coeliacs do not digest gliadin ?. Degradation pattern of gliadin in coeliac disease small intestinal mucosa

Prolyl-endopeptidase supplementation has been proposed to favour gliadin degradation as an alternative treatment for coeliac disease (CD), although the real usefulness of this therapy in vivo is still under discussion. 1 However, our data point to alternative treatments aiming to modify the intestinal microbiota in patients with CD by the use of probiotics and/or prebiotics. We propose that the induction of gliadin proteolysis in the human gut might not be the solution but the origin of CD

Higher constitutive IL15Rα expression and lower IL‐15 response threshold in coeliac disease patients

The IL-15 triggering effect of gliadin is not exclusive to coeliac disease (CD) patients, whereas the secondary response is CD specific. We have studied the expression of the IL-15 receptor, and the IL-15 response upon stimulation, in non-CD and CD patients, and the possible existence of a lower immunological threshold in the latter. Forty-two CD patients (20 on a gluten-containing diet, GCD, and 22 on gluten-free diet, GFD) and 24 non-CD healthy individuals were studied. IL15Rα mRNA expression, and tissue characterization, were assayed in the duodenum. Biopsies from six CD patients on GFD and 10 non-CD individuals were studied in vitro using organ culture in basal conditions, as well as after IL-15 stimulation discarding basal IL-15 production. Secretion of immune mediators was measured in the culture supernatants. IL15Rα mRNA expression was increased in CD patients, as compared with non-CD controls (on GFD P = 0·0334, on GCD P = 0·0062, respectively), and confirmed also by immunofluorescence. No differences were found between CD patients on GFD and on GCD. After in vitro IL-15 stimulation, IL15Rα expression was only triggered in non-CD controls (P = 0·0313), though it remained increased in CD patients. Moreover, IL-15 induced a more intense immunological response in CD patients after triggering the production of both nitrites and IFNγ (P = 0·0313, P = 0·0313, respectively). Gliadin-induced IL15 has a lower response threshold in CD patients, leading to the production of other immune mediators and the development of the intestinal lesion, and thus magnifying its effects within the CD intestine.Facultad de Ciencias ExactasLaboratorio de Investigaciones del Sistema Inmun

Spatiotemporal Characteristics of the Largest HIV-1 CRF02_AG Outbreak in Spain: Evidence for Onward Transmissions

Background and Aim: The circulating recombinant form 02_AG (CRF02_AG) is the predominant clade among the human immunodeficiency virus type-1 (HIV-1) non-Bs with a prevalence of 5.97% (95% Confidence Interval-CI: 5.41–6.57%) across Spain. Our aim was to estimate the levels of regional clustering for CRF02_AG and the spatiotemporal characteristics of the largest CRF02_AG subepidemic in Spain.Methods: We studied 396 CRF02_AG sequences obtained from HIV-1 diagnosed patients during 2000–2014 from 10 autonomous communities of Spain. Phylogenetic analysis was performed on the 391 CRF02_AG sequences along with all globally sampled CRF02_AG sequences (N = 3,302) as references. Phylodynamic and phylogeographic analysis was performed to the largest CRF02_AG monophyletic cluster by a Bayesian method in BEAST v1.8.0 and by reconstructing ancestral states using the criterion of parsimony in Mesquite v3.4, respectively.Results: The HIV-1 CRF02_AG prevalence differed across Spanish autonomous communities we sampled from (p < 0.001). Phylogenetic analysis revealed that 52.7% of the CRF02_AG sequences formed 56 monophyletic clusters, with a range of 2–79 sequences. The CRF02_AG regional dispersal differed across Spain (p = 0.003), as suggested by monophyletic clustering. For the largest monophyletic cluster (subepidemic) (N = 79), 49.4% of the clustered sequences originated from Madrid, while most sequences (51.9%) had been obtained from men having sex with men (MSM). Molecular clock analysis suggested that the origin (tMRCA) of the CRF02_AG subepidemic was in 2002 (median estimate; 95% Highest Posterior Density-HPD interval: 1999–2004). Additionally, we found significant clustering within the CRF02_AG subepidemic according to the ethnic origin.Conclusion: CRF02_AG has been introduced as a result of multiple introductions in Spain, following regional dispersal in several cases. We showed that CRF02_AG transmissions were mostly due to regional dispersal in Spain. The hot-spot for the largest CRF02_AG regional subepidemic in Spain was in Madrid associated with MSM transmission risk group. The existence of subepidemics suggest that several spillovers occurred from Madrid to other areas. CRF02_AG sequences from Hispanics were clustered in a separate subclade suggesting no linkage between the local and Hispanic subepidemics

Nasopharyngeal aspirate cytokine levels 1 yr after severe respiratory syncytial virus infection

et al.Respiratory syncytial virus (RSV) infection is an important cause of recurrent wheezing in infants. Nevertheless, the link between RSV infection and wheezing has yet to be elucidated at the molecular level. Here, we present a preliminary study on the evolution of the immune response in the respiratory tract at long-term after RSV infection. Twenty-seven immune mediators were profiled in nasopharyngeal aspirates (NPAs) obtained from 20 children hospitalized due to a severe infection by RSV at discharge from hospital and again 1 yr later. The same mediators were profiled in parallel in NPAs from 12 healthy controls. In the year following discharge, 85% (17/20) of children of the RSV group suffered at least one episode of wheezing documented by the pediatrician. On the contrary, wheezing episodes were observed only in 25% (3/12) of children in the control group. While most of the mediators profiled returned to normal levels by 1 yr after discharge from hospital, RSV children showed a persistent nasal hyper-secretion of VEGF, G-CSF, IL-10, IL-6, IFN-γ, IL-7 and IL-13. In previous works VEGF, IL-10 and IFN-γ have been put in relation with the pathogenesis of post-virus induced asthma. G-CSF, IL-6, IL-7 and IL-13 are increased in respiratory and plasma samples of asthmatic patients. Here, we evidence for the first time a persistent elevation of these mediators as late as 1 yr after severe RSV disease resolution, reinforcing their possible implication in the pathogenesis of wheezing. © 2009 Blackwell Munksgaard.This work has been possible thanks to the financial support from “Fondo de Investigaciones Sanitarias, FIS, Programa para favorecer la incorporación de grupos de investigación en las Instituciones del Sistema Nacional de Salud, EMER07/050”.Peer Reviewe

Sublingual immunotherapy is safe in children, but the challenge is how to increase its efficiency?

Peer Reviewe

Common variable immunodeficiency. Old questions are getting clearer

Common variable immunodeficiency (CVID) is a heterogeneous entity characterized by an impaired ability to produce antibodies. The failure is localized in partially mature B lymphocytes, though T lymphocyte abnormalities are occasionally present. This deficiency affects antibody synthesis and class switch from IgD and IgM, to IgG and IgA. CVID is related to selective IgA deficiency, and both abnormalities may coincide in one same family, and evolve from one to another in the same patient. The symptoms generally manifest in adults, but can occur at any age, even in infancy. Recurrent bacterial infections or pneumonias are frequent, and may be complicated by gastrointestinal problems, granulomas, autoimmune disorders or malignancies. A defect in memory B cells seems to condition the clinical severity. Recently, several mutations in genes encoding for molecules (CD19, TACI, ICOS) involved in B cell survival and isotype switch have been identified in patients with CVID. Nevertheless, genetic abnormalities have been found in less than 25% of cases with CVID; the underlying mechanism thus remains unknown in the majority of CVID patients, and research in this field must continue.Peer Reviewe