Severe Allergy as a Chronic Inflammatory Condition From a Systems Biology Perspective.

Persistent and unresolved inflammation is a common underlying factor observed in several and seemingly unrelated human diseases, including cardiovascular and neurodegenerative diseases. Particularly, in atopic conditions, acute inflammatory responses such as those triggered by insect venom, food or drug allergies possess also a life-threatening potential. However, respiratory allergies predominantly exhibit late immune responses associated with chronic inflammation, that can eventually progress into a severe phenotype displaying similar features as those observed in other chronic inflammatory diseases, as is the case of uncontrolled severe asthma. This review aims to explore the different facets and systems involved in chronic allergic inflammation, including processes such as tissue remodelling and immune cell dysregulation, as well as genetic, metabolic and microbiota alterations, which are common to other inflammatory conditions. Our goal here was to deepen on the understanding of an entangled disease as is chronic allergic inflammation and expose potential avenues for the development of better diagnostic and intervention strategies.

Epithelial Barrier: Protector and Trigger of Allergic Disorders.

The epithelial barrier has classically been considered as the only first line of defense against irritants, pathogens, and allergens. However, it is now known to play an essential role in the immune response to exogenous agents. In fact, recent reports postulate the epithelial barrier hypothesis as a possible explanation for the increasing incidence and severity of allergic diseases. The epithelial barrier preserves the isolation of internal tissues from potential external threats. Moreover, a coordinated interaction between epithelial and immune cells ensures the unique immune response taking place in mucosal tissues, which is reported to be dysregulated in allergic diseases. We and others have demonstrated that in severe allergic phenotypes, the epithelial barrier undergoes several histological modifications, with increased infiltration of immune cells, leading to dysfunction. This is common in atopic dermatitis, asthma, and food allergy. However, the precise role of the epithelial barrier in mucosal biology during progression of allergic diseases is not well understood. In this review, we aim to compile recent knowledge regarding the histological structure and immunological function of the epithelial barrier and to shed light on the role of this compartment in the onset and progression of allergic diseases.

Epithelial Barrier: Protector and Trigger of Allergic Disorders

The epithelial barrier has classically been considered as the only first line of defense against irritants, pathogens, and allergens. However,it is now known to play an essential role in the immune response to exogenous agents. In fact, recent reports postulate the epithelialbarrier hypothesis as a possible explanation for the increasing incidence and severity of allergic diseases.The epithelial barrier preserves the isolation of internal tissues from potential external threats. Moreover, a coordinated interaction betweenepithelial and immune cells ensures the unique immune response taking place in mucosal tissues, which is reported to be dysregulatedin allergic diseases.We and others have demonstrated that in severe allergic phenotypes, the epithelial barrier undergoes several histological modifications,with increased infiltration of immune cells, leading to dysfunction. This is common in atopic dermatitis, asthma, and food allergy. However,the precise role of the epithelial barrier in mucosal biology during progression of allergic diseases is not well understood.In this review, we aim to compile recent knowledge regarding the histological structure and immunological function of the epithelialbarrier and to shed light on the role of this compartment in the onset and progression of allergic diseases (AU)

La barrera epitelial se ha considerado clásicamente sólo como la primera línea de defensa contra los irritantes, patógenos y alérgenos,pero ahora sabemos que el epitelio también desempeña un papel esencial en la respuesta inmunológica frente los agentes exógenos.De hecho, informes recientes postulan la hipótesis de la barrera epitelial como una posible explicación de la creciente incidencia y lagravedad de las enfermedades alérgicas.La barrera epitelial preserva el aislamiento de los tejidos internos de las posibles amenazas exteriores. Se sabe que las células epiteliales,además de un papel meramente protector, también tienen una función esencial en el desarrollo de la respuesta inmune en las mucosas,favoreciendo un ambiente tolerogénico. Sin embargo, en enfermedades alérgicas, estas características se ven afectadas como demuestrauna repuesta exagerada ante antígenos inocuos. De hecho, en los fenotipos alérgicos graves, la barrera epitelial experimenta variasmodificaciones histológicas que se asocian con pérdida de integridad y aumento de los infiltrados celulares, lo que conduce a una disfunciónde la misma. Este proceso es común en la dermatitis atópica, el asma y/o la alergia alimentaria. Aunque todavía no se conoce bien lafunción exacta de la barrera epitelial en la biología de la mucosa durante las enfermedades alérgicas.En esta revisión, pretendemos recopilar los conocimientos recientes sobre la estructura histológica y la función inmunológica de la barreraepitelial, y arrojar luz sobre el papel de este compartimento en la aparición y la progresión de las enfermedades alérgicas (AU)

Clinical Approach to Mast Cell Activation Syndrome: A Practical Overview.

The diagnosis of mast cell activation syndrome (MCAS) is defined by 3 criteria: (1) typical clinical signs and symptoms of acute, recurrent (episodic), and systemic mast cell activation (MCA); (2) increase in tryptase level to >20% + 2 ng/mL within 1-4 hours after onset of the acute crisis; and (3) response of MCA symptoms to antimediator therapy. Classification of MCAS requires highly sensitive and specific methodological approaches for the assessment of clonal bone marrow mast cells at low frequencies. The Spanish Network on Mastocytosis score has been used successfully as a predictive model for selecting MCAS candidates for bone marrow studies based on a high probability of an underlying clonal mast cell disorder. In this article, we propose a diagnostic algorithm and focus on the practical evaluation and management of patients with suspected MCAS.

ARADyAL: The Spanish Multidisciplinary Research Network for Allergic Diseases.

Thematic cooperative health research networks (RETICS) are organizational structures promoted by the Instituto de Salud Carlos III of the Spanish Ministry of Science with the objective of carrying out cooperative research projects addressing challenges of general interest for society as a whole in the field of health care. The RETICS of Asthma, Adverse Drug Reactions, and Allergy (ARADyAL) received funding in 2016 for a 5-year program (2017-2021). ARADyAL integrates basic and clinical research in the areas of allergy, immunology, genetics, nanomedicine, pharmacology, and chemistry, with special interest in research on new biomarkers and the design and evaluation of new interventions for allergic patients with severe phenotypes. The consortium comprises 28 groups across Spain, including 171 clinical and basic researchers, 17 clinical groups that cover more than 10 000 000 patients of all ages from urban and rural areas and 11 basic groups active mostly at universities and research institutes. ARADyAL has proposed a research program organized into 3 different areas focusing on precision medicine, as follows: Program 1, Mechanisms and prediction of adverse drug reactions and allergic diseases; Program 2, Toward a precise diagnosis of allergic diseases; and Program 3, Predicting interventions in allergic diseases. There is also 1 common program dedicated to training. The network has a Steering Committee and an External Advisory Scientific Committee, which advise the global network coordinator, who has recognized expertise in the field. ARADyAL is a unique meeting point for clinicians and basic scientists who are already working in allergy.

ARADyAL: The Spanish Multidisciplinary Research Network for Allergic Diseases

Thematic cooperative health research networks (RETICS) are organizational structures promoted by the Instituto de Salud Carlos III of the Spanish Ministry of Science with the objective of carrying out cooperative research projects addressing challenges of general interest for society as a whole in the field of health care. The RETICS of Asthma, Adverse Drug Reactions, and Allergy (ARADyAL) received funding in 2016 for a 5-year program (2017-2021). ARADyAL integrates basic and clinical research in the areas of allergy, immunology, genetics, nanomedicine, pharmacology, and chemistry, with special interest in research on new biomarkers and the design and evaluation of new interventions for allergic patients with severe phenotypes. The consortium comprises 28 groups across Spain, including 171 clinical and basic researchers, 17 clinical groups that cover more than 10 000 000 patients of all ages from urban and rural areas and 11 basic groups active mostly at universities and research institutes. ARADyAL has proposed a research program organized into 3 different areas focusing on precision medicine, as follows: Program 1, Mechanisms and prediction of adverse drug reactions and allergic diseases; Program 2, Toward a precise diagnosis of allergic diseases; and Program 3, Predicting interventions in allergic diseases. There is also 1 common program dedicated to training. The network has a Steering Committee and an External Advisory Scientific Committee, which advise the global network coordinator, who has recognized expertise in the field. ARADyAL is a unique meeting point for clinicians and basic scientists who are already working in allergy. (AU)

Las Redes Temáticas de Investigación Cooperativa en Salud (RETICS) son unas estructuras organizativas promovidas por el Instituto de Salud Carlos III del Ministerio de e Sanidad, Consumo y Bienestar Social con el objetivo de llevar a cabo proyectos de investigación colaborativos que aborden desafíos de interés general para la sociedad en el campo de la salud. La RETICS de Asma, Reacciones Adversas a Fármacos y Alérgicas (ARADyAL) comenzó en 2016 y fue financiada por un periodo de 5 años (2017-2021). ARADyAL integra la investigación básica y clínica en diferentes áreas de conocimiento, alergia, inmunología, genética, nanomedicina, farmacología y química, con especial interés en la investigación de nuevos biomarcadores, y el diseño y evaluación de nuevas estrategias de intervención para pacientes alérgicos con fenotipos graves. El consorcio está compuesto por 28 grupos de toda España, que incluyen 171 investigadores clínicos y básicos: 17 grupos clínicos que cubren a más de 10.000.000 de pacientes de todas las edades y de áreas tanto urbanas como rurales; 11 grupos básicos que desarrollan sus actividades principalmente en universidades e institutos de investigación. ARADyAL propone un programa de investigación organizado en tres áreas diferentes centradas en la medicina de precisión: Programa 1. Mecanismos y predicción de reacciones adversas a medicamentos y enfermedades alérgicas; Programa 2. Hacia un diagnóstico preciso de enfermedades alérgicas; y Programa 3. Predicción de intervenciones en enfermedades alérgicas. Además, hay un programa transversal dedicado a la formación. La red cuenta con un Comité de Dirección y un Comité Científico Asesor Externo, que asesoran a la coordinadora de la red la cual tiene experiencia reconocida en el campo. ARADyAL es un punto de encuentro único para médicos y científicos básicos que ya están trabajando en alergias.

Clinical Approach to Mast Cell ActivationSyndrome: A Practical Overview

The diagnosis of mast cell activation syndrome (MCAS) is defined by 3 criteria: (1) typical clinical signs and symptoms of acute, recurrent (episodic), and systemic mast cell activation (MCA); (2) increase in tryptase level to >20% + 2 ng/mL within 1-4 hours after onset of the acute crisis; and (3) response of MCA symptoms to antimediator therapy. Classification of MCAS requires highly sensitive and specific methodological approaches for the assessment of clonal bone marrow mast cells at low frequencies. The Spanish Network on Mastocytosis score has been used successfully as a predictive model for selecting MCAS candidates for bone marrow studies based on a high probability of an underlying clonal mast cell disorder. In this article, we propose a diagnostic algorithm and focus on the practical evaluation and management of patients with suspected MCAS (AU)

El diagnóstico de síndrome de activación mastocitaria (SAM) se basa en 3 criterios: 1) signos y síntomas específicos de activación mastocitaria aguda, recurrente y sistémica, 2) aumento de los valores de triptasa en un 20% + 2 ng/ml sobre el valor basal de cada individuo en el periodo comprendido entre 1-4 horas desde el inicio del cuadro agudo, y 3) resolución de los síntomas con tratamiento antimediador. Para realizar el diagnóstico de SAM, es preciso emplear métodos diagnósticos altamente sensibles y específicos capaces de detectar bajas cantidades de mastocitos en la médula ósea. El modelo predictivo de la Red Española de Mastocitosis (REMA score) resulta útil para identificar a los pacientes con mayor probabilidad de padecer una patología mastocitaria clonal y que, por tanto, requieren que se nealice un estudio de médula ósea en el proceso diagnóstico. En este artículo, proponemos un algoritmo diagnóstico para SAM y abordamos el manejo de estos pacientes desde un punto de vista práctico en la consulta alergológica (AU)

New insight into cancer immunotherapy.

A key point for maintenance of the immune system homeostasis is the balance between the capacity to recognize and fight exogenous molecules and the capacity to avoid auto reactivity. The disruption of this balance induces the progression of several immune diseases such as autoimmune diseases, allergies, infections or cancer. A promising therapeutic approach to treat these diseases is immunotherapy. In cancer, both active and passive immunotherapies have been tested with promising results, such as the blocking of immunological checkpoints like CTLA-4 and PD-1. These treatments, in the market since a few years ago, aim to redirect the patient's immunological response by inhibiting the induction of regulatory T cells, both in the priming and effector phases. This strategy sheds light on the immunological mechanisms that control the regulatory response mediated by T cells and opens new lines of research into other immunological diseases such as allergy, in which the induction of a regulatory response is necessary to avoid allergic progression and which is the main objective of allergen-specific immunotherapies available today.

Dermatophagoides pteronyssinus immunotherapy changes the T-regulatory cell activity.

Subcutaneous specific immunotherapy (SCIT) has been shown to modify the Dermatophagoides pteronissinus (DP) allergic response, characterized by generation of Treg cells. However, studies have reported no changes in the proportion of Treg cells after immunotherapy, indicating that the effects may be due to modifications in their regulatory activities. We aimed to determine whether Tregs generated by DP-SCIT can switch the allergic response to tolerant and study the involvement of suppressive cytokines on it. Twenty-four DP-allergic rhinitis patients were recruited, 16 treated with DP-SCIT and 8 untreated. Treg and T effector cells were isolated before and after DP-SCIT, and cocultured in different combinations with α-IL-10, α-TGF-ß blocking antibodies and nDer p 1. Treg cells after DP-SCIT increased Th1 and decreased Th2 and Th9 proliferation. Similarly, they increased IL-10 and decreased IL-4 and IL-9-producing cells. α-IL-10 affected the activity of Treg cells obtained after DP-SCIT only. Finally, DP-specific IgG4 levels, Treg percentage and IL-10 production were correlated after DP-SCIT. These results demonstrate that DP-SCIT induces Treg cells with different suppressive activities. These changes could be mediated by IL-10 production and appear to play an important role in the induction of the tolerance response leading to a clinical improvement of symptoms.

Allergic asthma: an overview of metabolomic strategies leading to the identification of biomarkers in the field.

Allergic asthma is a prominent disease especially during childhood. Indoor allergens, in general, and particularly house dust mites (HDM) are the most prevalent sensitizers associated with allergic asthma. Available data show that 65-130 million people are mite-sensitized world-wide and as many as 50% of these are asthmatic. In fact, sensitization to HDM in the first years of life can produce devastating effects on pulmonary function leading to asthmatic syndromes that can be fatal. To date, there has been considerable research into the pathological pathways and structural changes associated with allergic asthma. However, limitations related to the disease heterogeneity and a lack of knowledge into its pathophysiology have impeded the generation of valuable data needed to appropriately phenotype patients and, subsequently, treat this disease. Here, we report a systematic and integral analysis of the disease, from airway remodelling to the immune response taking place throughout the disease stages. We present an overview of metabolomics, the management of complex multifactorial diseases through the analysis of all possible metabolites in a biological sample, obtaining a global interpretation of biological systems. Special interest is placed on the challenges to obtain biological samples and the methodological aspects to acquire relevant information, focusing on the identification of novel biomarkers associated with specific phenotypes of allergic asthma. We also present an overview of the metabolites cited in the literature, which have been related to inflammation and immune response in asthma and other allergy-related diseases.

Immune Polarization in Allergic Patients: Role of the Innate Immune System.

Allergens come into contact with the immune system as components of a very diverse mixture. The most common sources are pollen grains, food, and waste. These sources contain a variety of immunomodulatory components that play a key role in the induction of allergic sensitization. The way allergen molecules bind to the cells of the immune system can determine the immune response. In order to better understand how allergic sensitization is triggered, we review the molecular mechanisms involved in the development of allergy and the role of immunomodulators in allergen recognition by innate cells.

Immune polarization in allergic patients: role of the innate immune system

Los alérgenos entran en contacto con el sistema inmune como parte de una mezcla heterogénea de compuestos de muy diversa naturaleza. Las fuentes de alérgenos más comunes son los granos de polen, alimentos o restos de animales. Estas fuentes contienen una variedad de componentes inmunomoduladores que pueden desempeñar un papel importante en la inducción de la sensibilización alérgica. La unión de estas moléculas a las células inmunes pueden influir en el resultado inmunológico final. Actualmente, nuestro objetivo es revisar los mecanismos moleculares implicados en el desarrollo de la alergia, y el papel de estos inmunomoduladores en el reconocimiento de alérgenos por las células innatas, que es clave para entender cómo la sensibilización alérgica se desencadena (AU)

Allergens come into contact with the immune system as components of a very diverse mixture. The most common sources are pollen grains, food, and waste. These sources contain a variety of immunomodulatory components that play a key role in the induction of allergic sensitization. The way allergen molecules bind to the cells of the immune system can determine the immune response. In order to better understand how allergic sensitization is triggered, we review the molecular mechanisms involved in the development of allergy and the role of immunomodulators in allergen recognition by innate cells (AU)