Early infections and later allergic diseases

No disponible

No disponible

From autoimmune enteropathy to the IPEX (immune dysfunction, polyendocrinopathy, enteropathy, X-linked) syndrome.

The term autoimmune enteropathy (AIE) was applied to a form of "intractable diarrhoea" with serum gut autoantibodies, characterized by male predominance, early onset, poor response to parenteral nutrition and several autoimmune diseases, mainly type 1 diabetes. In recent years the vague concept of AIE has became more precise thanks to the discovery of its genetic and molecular basis. The FOXP3 molecule is crucial for the generation and maturation of regulatory T cells (Treg) expressing CD4+ and CD25+ molecules. Mutations of the FOXP3 gene, located in X chromosome, produce a syndrome with Immune dysfunction, Polyendocrinopathy, Enteropathy and X-linked inheritance (IPEX). The majority of the ancient so-called AIE cases probably correspond to the new IPEX syndrome, even in female patients who may have some autosomal genetic variants. Besides FOXP3, other molecules are likely to be involved in the generation and function of Treg and its deficiency may also enhance autoimmune disease and IPEX-like syndromes. Meanwhile, the important pathogenic role previously ascribed to gut autoantibodies has vanished, with it remaining as having only certain screening usefulness.

From autoimmune enteropathy to the IPEX (immune dysfunction, polyendocrinopathy, enteropathy, X-linked) syndrome

The term autoimmune enteropathy (AIE) was applied to a form of “intractable diarrhoea” with serum gut autoantibodies, characterized by male predominance, early onset, poor response to parenteral nutrition and several autoimmune diseases, mainly type 1 diabetes. In recent years the vague concept of AIE has became more precise thanks to the discovery of its genetic and molecular basis. The FOXP3 molecule is crucial for the generation and maturation of regulatory T cells (Treg) expressing CD4+ and CD25+ molecules. Mutations of the FOXP3 gene, located in X chromosome, produce a syndrome with Immune dysfunction, Polyendocrinopathy, Enteropathy and X-linked inheritance (IPEX). The majority of the ancient so-called AIE cases probably correspond to the new IPEX syndrome, even in female patients who may have some autosomal genetic variants. Besides FOXP3, other molecules are likely to be involved in the generation and function of Treg and its deficiency may also enhance autoimmune disease and IPEX-like syndromes. Meanwhile, the important pathogenic role previously ascribed to gut autoantibodies has vanished, with it remaining as having only certain screening usefulness(AU)

Luz solar, vitamina D y tuberculosis / Sunlight, vitamin D and tuberculosi

La helioterapia fue utilizada de forma empírica desde la medicina antigua hasta el siglo XX para tratar múltiples enfermedades, entre ellas la tuberculosis y la Vit Dexplicó algunas de las acciones de la luz solar. En 1983, se descubrió el receptor de Vit. D y su presencia en células inmunitarias sugirió las acciones inmunitarias de la Vit. D y su posible aplicación en la patología humana. Reiteradamente se han comunicado niveles séricos descendidos de Vit. D en enfermos con tuberculosis activa o latente, aunque estos ensayos transversales no pudieron probar el sentido de la causa-efecto. Además, estudios experimentales han probado que la Vit. D mejora la defensa frente a M. tuberculosis. Recientemente se comunicó que los macrófagos infectados por M. tuberculosis, a través de los receptoresTLR1,2, activan la respuesta innata y además la producción local de Vit. D activa (1,25-OH) lo que explicaría la hipercalcemia y la calcificación del granuloma caseoso características de la tuberculosis. A la vista de estos datos, se ha aconsejado administrar Vit. D como terapéutica coadyuvante de la tuberculosis y en las formas resistentes. Sin embargo, los ensayos clínicos no han sido concluyentes por fallos metodológicos. Por otra parte, preocupa la conocida acción hipercalcemiante de la Vit. D y su modulación de los linfocitos Th1 que son fundamentales frente a microorganismos intracelulares, como M. tuberculosis. Sería recomendable la realización de potentes ensayos clínicos para aclarar si la terapia con Vit. D es útil y cuál es la dosis óptima a utilizar en cada situación (AU)

The heliotherapy was empirically used since antique medicine till XX century for treating many diseases, included tuberculosis, and the discovery of Vit. D has explained the effect of sunlight. The vitamin D receptor (VDR) was discovered in 1983, and their presence in immune cell suggested the immune role of Vit. D and its use in human pathology were considered. Low Vit. D serum levels were consistently reported in patients with active and latent tuberculosis, but these cross assays were enabling to prove the cause-effect sense. In other way, experimental studies proved that Vit. D increases the protection against tuberculosis. Recently, it was observed that macrophage cells infected with M. tuberculosis by TLR 2,1 receptors enhances simultaneously the innate immune response and the local production of active Vit. D (1,25-OH), that has explained the hypercalcemia and the calcification of the granulomas, two characteristic facts of tuberculosis disease. On view these findings, Vit. D has been advised as an adjuvant treatment of tuberculosis and for resistant cases. Nevertheless, the clinical assays have been not conclusive due to methodological fails. Besides, there is concern about the known hypercalcemicaction of Vit. D and because it modulates the function of Th1 lymphocytes, that are essential for the defense against intracellular microorganisms, as M. tuberculosis. The Vit. D (..) (AU)

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.

Common variable immunodeficiency. Old questions are getting clearer / Inmunodeficiencia variable común. Antiguas dudas que se van aclarando

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

La inmunodeficiencia variable común (IDVC) es una entidad heterogénea caracterizada por la deteriorada capacidad para producir anticuerpos. El fallo se localiza en los linfocitos B parcialmente maduros, pero ocasionalmente existen anormalidades en los linfocitos T. Esta deficiencia afecta a la síntesis de anticuerpos y la clase cambia de IgD e IgM a IgG e IgA. La IDVC se relaciona con el déficit selectivo de IgA y ambas anomalías podrían coincidir en la misma familia y evolucionar de una a otra en el mismo paciente. Los síntomas generalmente comienzan en adultos, aunque pueden aparecer a cualquier edad, incluso en el lactante. Son frecuentes las infecciones bacterianas recurrentes o neumonías, y pueden estar complicadas con problemas gastrointestinales, granulomas, trastornos autoinmunes o neoplasias. Un defecto de los linfocitos B de memoria parece ser la causa de la gravedad de la clínica. Recientemente en pacientes con IDVC se han identificado varias mutaciones de genes que codifican moléculas (CD19, TACI, ICOS) que están implicadas en la supervivencia de los linfocitos B y el isotipo implicado en el cambio. Sin embargo, las anomalías genéticas se han encontrado en menos del 25% de los pacientes con IDVC, por lo que el mecanismo sigue siendo desconocido en la mayoría de los casos, por lo que la investigación debe continuar

Estrategias de inmunomodulación en la enfermedad celíaca / No disponible

No disponible

[Meningococcal sepsis in pediatrics. Parameters associated with poor outcome]. / Sepsis meningocócica en pediatría. Parámetros asociados a mala evolución.

BACKGROUND: Mortality due to meningococcal sepsis continues to be extremely high. Patients with a poor prognosis require aggressive therapy and should be identified early. OBJECTIVE: To investigate the clinical and biological factors associated with poor outcome. PATIENTS AND METHOD: Seventy-one children aged 2 months to 13 years with meningococcal sepsis were studied. Inclusion criteria were meningococcus isolation in cultures or characteristic clinical features with purpuric exanthema. METHODS: A correlational descriptive study was performed. In all patients we evaluated the Pediatric Risk of Mortality (PRISM), the Glasgow Scale for Meningococcal Sepsis (GSMS), polymorphonuclear (PMN) count and prolactin (PRL), leptin (LPT) and C-reactive protein (CRP) levels. RESULTS: Fourteen children (19.7 %) died. Death was associated with multiple organ dysfunction syndrome (MODS) (p = 0.0001), high GSMS and PRISM scores (p = 0.0001) and to a lesser extent with shock (p = 0.01). In patients who died, the determinations showing greatest alteration at admission were PRL levels (p = 0.0009) and PMN count (p = 0.0005). CRP levels were not associated with differences in mortality but were high in patients with shock (p = 0.008). Children with high body weight percentiles were at greater risk of death and showed higher levels of PRL, PCT (p = 0.006) and LPT (p = 0.006), without differences in GSMS or PRISM scores. Age did not influence mortality or PRL levels but did influence GMSM and PRISM scores and PMN and CRP levels. These differences disappeared after the age of 2-3 years. In patients with MODS or shock, the only differences found were reduced PMN count (p = 0.0001) and elevated PRL levels (p = 0.0001). CONCLUSIONS: In meningococcal sepsis, death is more frequent in children with high body weight percentiles. Moreover, these children present elevated PRL and LPT levels, although whether these variables act independently remains to be elucidated.

Sepsis meningocócica en pediatría. Parámetros asociados a mala evolución / Meningococcal sepsis in pediatrics. PArameters associated with poor outcome

Antecedentes: La mortalidad por sepsis meningocócica continúa siendo muy elevada. Los enfermos con mal pronóstico precisan terapias agresivas y deben ser identificados precozmente. Objetivo: Investigar los factores clínicos y biológicos asociados a una mala evolución. Pacientes y método: Se estudiaron 71 niños de 2 meses a 13 años de edad con sepsis meningocócica. Los criterios de inclusión fueron aislamiento de meningococo en cultivos o sintomatología característica con exantema purpúrico. Se realizó un estudio descriptivo correlacional. En todos los enfermos se valoró el PRISM (Pediatric Risk of Mortality), la Escala de Glasgow para Sepsis Meningocócicas (EGSM), el recuento de polimorfonucleares y los niveles de procalcitonina, leptina y proteína C reactiva (PCR). Resultados: Fallecieron 14 enfermos (19,7 por ciento). La muerte se asoció a síndrome de disfunción multiorgánica (SDMO) (p=0,0001), alta puntuación en la EGSM y el PRISM (p=0,0001) y con menor significación a shock (p=0,01). En el grupo de fallecidos, las determinaciones más alteradas al ingreso fueron la procalcitonina (p=0,0009) y los polimorfonucleares (p=0,0005). Los valores de PCR no se asociaron a diferencia de mortalidad pero estaban altos en los casos con shock (p=0,008). Los niños con percentiles elevados de peso fallecieron con mayor frecuencia y mostraron niveles más altos de procalcitonina (p=0,006) y leptina (p=0,006), pero sin diferencias de valores de EGSM y PRISM. La edad no influyó ni en la mortalidad ni en la procalcitonina, pero sí en el EGSM y PRISM y en los niveles de polimorfonucleares y PCR, desapareciendo estas diferencias antes de los 2-3 años. En los casos con SDMO o shock sólo presentaron diferencias el recuento disminuido de polimorfonucleares (p=0,0001) y la procalcitonina elevada (p=0,0001). Conclusiones: En la sepsis meningocócica el fallecimiento es más frecuente en niños con altos percentiles de peso. Además presentan elevaciones de procalcitonina y leptina, quedando sin aclarar si actúan de forma independiente (AU)

Agammaglobulinemia de Bruton (1952-2002). Cincuenta alis de inmunodeficiencias primarias / Bruton agammaglobulinemia (1952-2002). Fifty years of primary immunodeficiencies

Hace 50 años Bruton publicó en Pediatrics el primer enfermo de agammaglobulinemia ligada al sexo. El primer caso publicado en España apareció el año 1962 en el Boletín de la SCALP. Desde esas fechas la evolución del concepto y diagnóstico de las inmunodeficiencias primarias ha sido muy importante. Por otra parte, las técnicas genéticas identifican al gen de la tirosín kinasa del Bruton ("btk") como responsable de la agammaglobulinemia, lo que ha permitido identificar diferentes formas. Además, cada vez parece más probable que el gen btk esté implicado en otro tipo de infecciones muy alejadas clínicamente del cuadro de agammaglobulinemia de Bruton (AU)

[The tumor necrosis factor system and leptin in coeliac disease]. / Sistema factor de necrosis tumoral y leptina en la enfermedad celíaca.

OBJECTIVE: Patients with coeliac disease (CD) present anorexia and malnutrition. Leptin is a significant anorexigenic factor, with a close relationship to the body mass index. The aims of this study were to asses serum leptin levels in CD and their possible influence on appetite, as well as to compare and relate leptin with tumor necrosis factor (TNF) activity, which has similar functions. METHODS: Leptin and TNF receptor-1 (TNFr-1) were measured by enzyme-linked immunosorbent assay. Sixty-five serum samples from patients with CD (28 boys and 37 girls) were analyzed. In all patients, small bowel biopsy and anti-endomysium determination were performed simultaneously. Twenty-nine patients presented active CD and 36 were in remission. RESULTS: Leptin concentrations were reduced in active CD (p = 0.002). In patients in remission, leptin was related to the body mass index (p = 0.001), but this correlation was not found during the active phase of the disease. Contrary to normal differences between sexes, in active CD leptin levels were similar in boys and girls. TNFr-1 was found in all serum samples and levels were statistically higher in patients with active CD (p = 0.0003), suggesting that the TNF system is activated in this disease. CONCLUSIONS: Leptin concentrations were reduced in active CD, but we did not find the usual positive correlation with body mass index and higher concentrations in girls. These results suggest that leptin does not contribute to anorexia and failure to thrive in patients with CD; in contrast, the TNF system might be involved.

Sistema factor de necrosis tumoral y leptina en la enfermedad celíaca / The tumor necrosis factor system and leptin in coeliac disease

Objetivo: Los enfermos celíacos presentan malnutrición y una gran anorexia. La leptina es un importante factor anorexígeno estrechamente relacionado con el índice de masa corporal (IMC). El objetivo fue estudiar la leptina sérica en la enfermedad celíaca y su posible acción sobre el apetito, compararla y relacionarla con el factor de necrosis tumoral (TNF), que tiene funciones similares. Métodos: La leptina y el receptor I de TNF (TNF-R-I) se midieron mediante enzimoinmunoanálisis (ELISA). Se analizaron 65 sueros de enfermos celíacos (28 varones y 37 mujeres). En todos los casos se practicó simultáneamente biopsia intestinal y se determinaron anticuerpos antiendomisio. Estaban en actividad 29 casos y 36 en remisión. Resultados: Los valores de leptina estaban disminuidos en la fase de actividad de la enfermedad celíaca (p 0,002), lo que no apoya su participación sobre la anorexia y la desnutrición del paciente celíaco. Durante la remisión de la enfermedad celíaca la leptina se relaciona con el IMC (p 0,001), pero en la fase activa se rompe esta relación habitual. En la fase aguda también se rompe la diferencia entre sexos, y son similares los valores en varones y mujeres. El TNF-R-I se detectó en todos los sueros y mostró una elevación significativa durante la fase aguda (p 0,0003) lo que parece indicar una activación del sistema TNF en la enfermedad celíaca. Conclusiones: La leptina está disminuida durante la fase activa de la enfermedad, y se pierde su habitual correlación con el IMC y el sexo femenino. Los resultados señalan que no participa en la anorexia y la desnutrición de la enfermedad celíaca y, sin embargo, sí podría hacerlo el sistema TNF (AU)

Valor de los marcadores serológicos en el diagnóstico de la enfermedad celíaca. Propuesta de un protocolo / Value of serological markers in the diagnosis of celiac disease. A proposed guidelinebackground

OBJETIVO: La alta frecuencia de casos atípicos de enfermedad celíaca y de formas con pobre sintomatología ha potenciado la búsqueda de marcadores analíticos que apoyen la indicación de la biopsia intestinal. Las pruebas más extendidas son la determinación de anticuerpos antigliadina de clase IgG e IgA (AAGIgG y AAGIgA) y antiendomisio (AEmIgA). MÉTODOS: Se presenta la experiencia de 10 años, estudiando AAG en 1.075 sueros de pacientes con enfermedad celíaca y AEmIgA en 534. Los marcadores séricos se compararon a la biopsia intestinal en 152 casos en los que se realizaron simultáneamente. RESULTADOS: En los casos con atrofia intestinal grave fue la alta sensibilidad de los AAGIgG (91 por ciento) y de los AEmIgA (94 por ciento), quienes además mostraron el valor predictivo positivo (88 por ciento) y negativo (97 por ciento) más altos. Un título positivo de AEmIgA coincidió con una biopsia alterada al 100 por ciento de los casos. Los AEmIgA fueron también el marcador más eficaz para el control de la dieta sin gluten. Sin embargo, en los casos con atrofia parcial de la mucosa intestinal ningún marcador fue lo bastante indicativo. CONCLUSIÓN: Los AEmIgA son el mejor marcador serológico de enfermedad celíaca. A la luz de los resultados y según la prevalencia estimada de esta enfermedad, se proponen protocolos de utilización de los marcadores serológicos para el diagnóstico de los síndromes malabsortivos, para estudios de poblaciones de bajo y alto riesgo de enfermedad celíaca y para el seguimiento de los pacientes diagnosticados (AU)

[Value of serological markers in the diagnosis of celiac disease. A proposed protocol]. / Valor de los marcadores serológicos en el diagnóstico de la enfermedad celíaca. Propuesta de un protocolo.

AIM: In recent years, the high frequency of atypical cases of celiac disease (CD) and of forms of this disease with minor symptoms has prompted the search for analytical markers that may support indications for intestinal biopsy. The commonest tests are those for serum class IgG and IgA antigliadin antibodies (IgG-AGA, IgA-AGA) and IgA antiendomysial antibodies (IgA-EmA). METHODS: We report our 10 year experience of studying AGA in 1,075 serum samples from patients with CD and IgA-EmA in 534 samples. The serological markers were compared with 152 intestinal biopsies performed simultaneously with the other tests. RESULTS: In patients with severe intestinal atrophy the sensitivity of IgA-AGA (91%) and IgA-EmA (94%) was high. IgA-EmA and the latter showed the highest positive (88%) and negative (97%) predictive values. In all patients, IgA-EmA positivity coincided with alterations in the biopsy. Determination of IgA-EmA was also the most efficient marker for monitoring the gluten free diet phase. However, in patients in whom minimal histological changes were found in the intestinal mucosa, none of the markers was sufficiently accurate. RESULTS: IgA- EmA antibodies are the most accurate serological marker of CD. In view of these results and the estimated prevalence of the disease, protocols for the use of serological markers are proposed for the differential diagnosis of malabsorption symptoms, for use in patients at low and high risk of CD and for the followup of those with a diagnosis of CD.

[Value of salivary antibodies for determining seropositivity to measles, rubella, and mumps in children and adults]. / Valor de los anticuerpos salivares para la determinación de la seropositividad frente a sarampión, rubéola y parotiditis en niños y adultos.

BACKGROUND: IgA and IgG antibodies can be detected in saliva in order to assess the immune status against measles, rubella and mumps. PATIENTS AND METHODS: Serum and saliva were simultaneously obtained from 50 adults between 19 and 52 years of age that were non-vaccinated and from 50 children from 15 months to 13 years of age that had been vaccinated against measles, rubella and mumps at 15 months of age. Specific IgG and IgA antibodies were determined by ELISA. Values higher than the 95% confidence interval obtained in 39 non-vaccinated and non-infected infants were considered as positive. RESULTS: In adults 96-100% and in children 90-98% were seropositive for the viral antigens studied. A positive result in saliva was always higher than 50%, with the percentage being higher in children than in adults and mainly for IgA antibodies. According to the present study, the combined determination of IgG and IgA antibodies in saliva would detect 86% of the children seropositive for measles, 87% for rubella and 82% to mumps, with these results being slightly lower in adults. Children without salivary antibodies were frequently younger than 3 years of age and were negative for more than one viral antigen. CONCLUSIONS: The study of salivary antibodies is a non-invasive method to assess seropositivity against measles, rubella and mumps, but it is advisable that both IgG and IgA antibodies be determined.

[Serum eosinophil cationic protein in children with allergic and nonallergic inflammation]. / Proteína catiónica eosinófila sérica en niños con inflamación alérgica y no alérgica.

Serum eosinophil cationic protein (ECP) levels increase in inflammation processes with activation of eosinophils. We studied serum ECP in (I) 32 pollinic children without symptoms, in June and October and (II) 10 children with acute asthma crisis. As control groups we included (III) 25 children sent to the hospital with suspected allergic diseases in which an IgE mediated process could be ruled out; (IV) 34 coeliac patients; (V) 15 children with cystic fibrosis and (VI) 48 normal children. The pollinic children had increased figures of ECP in June (21.2 +/- 9.2 micrograms/L) compared to normal controls (p < 0.001) and they continued to have high levels in October (13.5 +/- 9.2 micrograms/L, p < 0.05). The patients with very high ECP (> 20 micrograms/K), in spite of being asymptomatic, showed a negative correlation between ECP/peak-flow (p: 0.038). In addition, in these patients the ECP also had a negative correlation with the recovery of bronchospasm from June to October (p: 0.024). Some asthmatic children also had high ECP, but the results were too heterogeneous to draw any conclusions, possibly due to the drugs received. The ECP was independent of age and sex. It not correlated with serum IgE, nevertheless, in non-atopic patients it did correlate with blood eosinophilia (p < 0.005). In coeliac and cystic fibrosis patients, we did not find ECP to be increased. In conclusion, serum ECP increases in some allergic patients and suspected allergy, but not in all cases. It does not increase in other chronic mucosal inflammations, such as coeliac or cystic fibrosis. It correlates with bronchospasms and would have some value in predicting short-term evolution.