Trigo y sistema inmune (3 de 4)

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

Los autores nos explican que, en el modelo más aceptado de cómo se inicia la celiaquía, la gliadina desencadena una reacción innata caracterizada por la producción de interleucina 15 (IL-15) por parte de las células epiteliales:

gliadin toxic peptides (i.e. the 19-mer) trigger an innate immune response [10], mainly characterized by the production of IL-15 by epithelial cells

En este estudio encontraron que el sistema inmune de la mitad de las personas no celíacas percibe el gluten como un antígeno y se pone en marcha el sistema inmune innato segregando IL-15. Los autores interpretan textualmente esa observación como “dañino efecto“:

The data obtained in this pilot study support the hypothesis that gluten elicits its harmful effect, throughout an IL15 innate immune response, on all the individuals. This innate response is found in both patients with and without CD, although the triggering of an adaptive response is CD specific. (fuente,fuente)

La hipótesis de los autores es que las personas que sufren celiaquía necesitan niveles más bajos de la IL-15 para desencadenar la respuesta adaptativa, lo que explicaría que ellos sí tengan una respuesta inflamatoria cuando lo cierto es que el gluten no sólo produce la reacción del sistema inmune innato en esas personas:

The results shown here, the increased expression of both IL15Rα and pro-inflammatory mediators, and the higher response to IL-15, support the hypothesis that CD patients have a lower IL-15 threshold response. This hypothesis may explain why the (innate) IL-15-mediated response to gluten is not restricted to CD, though the secondary inflammatory response is only observed in genetically susceptible CD patients.

Intestinal cell damage and systemic immune activation in individuals reporting sensitivity to wheat in the absence of coeliac disease

En este estudio encontraron que las personas que sin ser celíacas decían tener sensibilidad al gluten tenían indicadores de translocación microbiana más elevados.

we measured the levels of LBP and sCD14 as indicators of the translocation of microbial products, particularly LPS, across the epithelial barrier. […] We found significantly elevated serum levels of both LBP and sCD14 in individuals with NCWS in comparison with patients with coeliac disease and healthy controls.

Lo que según ellos sugiere que la translocación de productos desde el tracto intestinal contribuye a la activación del sistema inmune innato y adaptativo observada en las personas que tenían sensibilidad al gluten no celíaca:

We found that levels of IgG and IgM antibodies to flagellin were significantly elevated in the NCWS cohort. Considering that no individuals in this study had evidence of infection, these observations are suggestive of a translocation of microbial products from the GI tract that contributes to the observed innate and adaptive immune activation in the NCWS cohort

Y cuando esos sujetos seguían una dieta sin trigo (o cereales relacionados) los marcadores de activación inmune, los marcadores de daño epitelial en el intestino y los síntomas mejoraban:

we examined the above markers in a subset of NCWS subjects before and after a diet that excluded wheat and related cereals. The results indicated a significant decline in the markers of immune activation and gut epithelial cell damage, in conjunction with the improvement of symptoms.

The Prevalence of Antibodies against Wheat and Milk Proteins in Blood Donors and Their Contribution to Neuroimmune Reactivities

Los datos de este artículo muestran que un notable porcentaje de personas presenta anticuerpos frente al trigo, es decir, una reacción del sistema inmune adaptativo ante los distintos antígenos del trigo.

Además en este estudio se encontró una gran coincidencia entre generar anticuerpos contra el gluten o la leche y generar anticuerpos contra proteínas del propio cuerpo:

Statistical analysis showed significant clustering when certain wheat and milk protein antibodies were cross-referenced with neural antibodies. Approximately half of the sera with antibody elevation against gliadin reacted significantly with GAD-65 and cerebellar peptides; about half of the sera with elevated antibodies against α + β-casein and milk butyrophilin also showed antibody elevation against MBP and MOG.

La gráfica muestra una análisis de grupos de dos vías de los coeficientes de correlación de Pearson entre proteínas de la comida y proteínas del cerebro:

¿Un resultado causado por la reactividad cruzada?

This cross-reactivity between α-gliadin and cerebellar peptides, and between milk butyrophilin and MOG peptides, could be responsible for the simultaneous detection of antibodies against these molecules in a small percentage of tested blood samples.

Ante estos resultados los autores plantean la posibilidad de que debido al “mimetismo molecular” entre el gluten y algunas proteínas del cuerpo, especialmente proteínas del sistema nervioso, la respuesta inmune ante el trigo acabe produciendo un problema neuroinmune en un pequeño porcentaje de personas:

With these experiments we demonstrated that cerebellar and MOG peptides, which are known to be important autoantigens in gluten ataxia and MS, can cross-react with wheat and milk proteins. The demonstration of molecular mimicry between α-gliadin, cerebellar peptide, milk butyrophilin, and MOG, and the simultaneous detection of antibodies against these proteins in a small percentage of the general population may have broader implications in the induction of neuroimmune disorders. In these individuals, due to a regulatory defect in mucosal immunity, the consumption of wheat and milk products provides a source of α-gliadin, γ-gliadin, and milk butyrophilin-derived peptides that can cross the gut mucosa to stimulate antigen-specific immune responses both locally in the gut as well as in the periphery. In the majority of the population the cerebellar and MOG normally remains sequestered behind the blood brain barrier (BBB). However, CNS inflammation and BBB breakdown can render the neural tissue antigens accessible to the cross-reactive antibodies and auto-reactive lymphocytes, subsequently resulting in neuroimmune disorder

Según uno de los autores del artículo, las personas con sensibilidad al gluten y los lácteos tienen un riesgo mayor de lo que se creía de desarrollar una enfermedad autoinmune neurológica:

those with a gluten and dairy sensitivity have a much higher risk of developing neurological autoimmunity than previously suspected (fuente)

Correlation of Tissue Antibodies and Food Immune Reactivity in Randomly Selected Patient Specimens

En la figura se muestra el mecanismo de reactividad cruzada que puede llevar a autoinmunidad: el cuerpo genera anticuerpos contra el gluten (gliadina) pero parte de esos anticuerpos confunden tejido del cerebelo con el gluten y se produce la neuroautoinmunidad.

Según los autores del artículo, el mecanismo de reactividad cruzada que acabamos de ver deja claro cómo de potencialmente dañina para el cuerpo humano es la gliadina, es decir, el gluten:

With this information, it is clear how potentially damaging gliadin can be to the human body.

En la siguiente gráfica se aprecia cómo el porcentaje de personas con anticuerpos IgG frente al gluten (gluten positive) que también tienen anticuerpos contra las propias proteínas del cuerpo es mucho mayor que en la población que no desarrolla anticuerpos contra el gluten (gluten negative).

Los autores del artículo resaltan que los médicos no han entendido todavía que no son los celíacos los únicos que deben ser estrictos con una dieta sin gluten, pues el daño en las personas que tienen sensibilidad al gluten no celíaca puede ser tan grave como el que sufre un celíaco:

Interestingly, the gluten-free diet (GFD) is generally recommended for specific autoimmune disorders, as the GFD may reduce systemic inflammation, cut down on the frequency of flares, or arrest the autoantibody production against targeted tissues [49-52].  Unfortunately, much of the clinical world has not yet grasped the idea that gluten can trigger autoimmune disorders other than CD, which leads to misleading notions that only CD patients have to be strict with the gluten-free diet (GFD), while NCGS patients can “cheat” once-in-a-while. Statements such as, patients with “NCGS can be more liberal and titrate their exposure to gluten as needed to avoid symptoms,” [53] can be harmful to the patient. CD is a gastrointestinal disorder in which patients make elevated IgA to gliadin and tissue transglutaminse-2. What if the NCGS patient makes significant levels of IgG against gliadin and cerebellar protein? Is protecting the brain really less important than protecting the gut?

Los autores del artículo resaltan que la prevención de la autoinmunidad de causa dietaria es posible: basta con retirar de la dieta la sustancia que detona el proceso autoinmune:

There are three main ingredients for environmentally-induced autoimmunity, genetic susceptibility, dysfunctional body barrier and environmental trigger [75-78]. If the environmental trigger is removed, even with a broken body barrier and a genetic susceptibility, autoimmunity can be evaded. Alternatively, if the environmental trigger, in our case, food protein is still present, once the intestinal barrier has been breached, the offending food protein ignites the immune system and pathogenesis begins its slow progression toward tissue damage. Autoantibody biomarkers can be detected at this point. A patient is at greater risk for developing a disease, if certain markers are present and the more detectable markers, the higher the positive predictive value for disease [79,80]. Prevention of environmentally-induced autoimmunity is possible.

Anuncios

7 thoughts on “Trigo y sistema inmune (3 de 4)

  1. Mechanisms of gliadin-induced zonulin release, increased intestinal permeability, and onset of autoimmunity. The production of specific gliadin-derived peptides by digestive enzymes causes CXCR3-mediated, MyD88-dependent zonulin release (2) and subsequent transactivation of EGFR by PAR2 leading to small intestine TJ disassembly (3). The increased intestinal permeability allows non-self antigens (including gliadin) to enter the lamina propria (4), where they are presented by HLA-DQ, -DR molecules (5). The presentation of one or more gliadin peptides leads to abrogation of oral tolerance (switch to Th1/Th17 response) and a marked increase in peripheral immune responses to gliadin. Furthermore, gliadin-loaded dendritic cells migrate from the small intestine to mesenteric and/or pancreatic lymph nodes (6) where they present gliadin-derived antigens. This presentation leads to migration of CD4−CD8− γδ and CD4−CD8+ αβ T cells to the target organ (gut and/or pancreas) where they cause inflammation (7). Implementation of a gluten-free diet or treatment with the zonulin inhibitor AT1001 (8) prevents the activation of the zonulin pathway and, therefore, of the autoimmune process targeting the gut or pancreatic β-cells.

    Zonulin and Its Regulation of Intestinal Barrier Function: The Biological Door to Inflammation, Autoimmunity, and Cancer

    Me gusta

  2. The innate immune system provides an early response to many microbial and chemical stimuli and is critical for successful priming of adaptive immunity. Responsive innate cells are primarily macrophages, monocytes, DCs, and polymorphonuclear leukocytes that by means of their pattern-recognition receptors, such as TLRs, induce the release of proinflammatory cytokines and chemokines, resulting in recruitment and activation of additional inflammatory cells

    Gliadin leads to secretion of inflammatory cytokines

    (D) PT gliadin stimulation of monocyte-derived DCs of healthy controls (n = 10) and of patients with celiac disease on a gluten-free (gfd; n = 8) or regular diet (n = 3).

    As is expected for innate responses, we found a similar extent of activation of DCs from healthy controls and celiac patients in vitro.

    Wheat amylase trypsin inhibitors drive intestinal inflammation via activation of toll-like receptor 4

    Me gusta

  3. Regarding the pathogenic mechanism of NCG/WS, a recent study conducted by Uhde et al. [29] clarified some aspects of this condition [10]. This study also suggested that some biomarkers (fatty acid-binding protein 2 or FABP2, soluble CD14 or sCD14, lipopolysaccharide (LPS)-binding protein or LBP, endotoxin-core antibodies or EndoCAb IgM, anti-flagellin IgM and IgG) could be useful as possible diagnostic tools, although they are yet to be confirmed and validated. Uhde demonstrated thepresence of enterocyte injury and translocation of microbial components from the intestinal lumen to the blood circulation, resulting in activation of the systemic innate and adaptive immune response [29]. This study confirmed the already verified [30,31] existence of an increased intestinal permeability in individuals with NCG/WS, and provided evidence for a possible pathogenic role of the intestinal microbiota [12].

    Regarding intestinal permeability, the early belief that it was reduced in NCG/WS [81] has been definitively rejected [9]. Several studies have shown that an increased one is present even in non-coeliac patients, in particular in NCG/WS [30,31], IBS [31,82], and generic “non-coeliac” patients with persistent dyspeptic complaints [83].

    http://www.mdpi.com/2072-6643/9/11/1203/pdf

    Me gusta

  4. Gluten contributes to autoimmune disease in three key ways. First, it is the primary cause of leaky gut because gluten triggers the release of zonulin in your intestines, a chemical that tells your gut lining to “open up”. Second, it is highly inflammatory, meaning it stresses your immune system. Thirdly, the gluten protein has a similar chemical structure to some of your body’s tissues (specifically your thyroid), which can lead to molecular mimicry, where your body mistakes your tissues for gluten and attacks them. Amy Myers

    Me gusta

Deja un comentario. Si los comentarios no contribuyen/aportan a los artículos publicados no los publico. Tampoco los publico si intentan forzar un debate o una toma de postura que el autor no ha planteado o que ha dado por cerrada. No publico comentarios descalificativos ni críticas fuera de lugar o que considere que no aportan nada. Si percibo intención de molestar en lugar de participar, o si no detecto vida inteligente, tampoco será publicado.

Introduce tus datos o haz clic en un icono para iniciar sesión:

Logo de WordPress.com

Estás comentando usando tu cuenta de WordPress.com. Cerrar sesión / Cambiar )

Imagen de Twitter

Estás comentando usando tu cuenta de Twitter. Cerrar sesión / Cambiar )

Foto de Facebook

Estás comentando usando tu cuenta de Facebook. Cerrar sesión / Cambiar )

Google+ photo

Estás comentando usando tu cuenta de Google+. Cerrar sesión / Cambiar )

Conectando a %s