RESUMO
The protease activity of the paracaspase Malt1 has recently gained interest as a drug target for immunomodulation and the treatment of diffuse large B-cell lymphomas. To address the consequences of Malt1 protease inactivation on the immune response in vivo, we generated knock-in mice expressing a catalytically inactive C472A mutant of Malt1 that conserves its scaffold function. Like Malt1-deficient mice, knock-in mice had strong defects in the activation of lymphocytes, NK and dendritic cells, and the development of B1 and marginal zone B cells and were completely protected against the induction of autoimmune encephalomyelitis. Malt1 inactivation also protected the mice from experimental induction of colitis. However, Malt1 knock-in mice but not Malt1-deficient mice spontaneously developed signs of autoimmune gastritis that correlated with an absence of Treg cells, an accumulation of T cells with an activated phenotype and high serum levels of IgE and IgG1. Thus, removal of the enzymatic activity of Malt1 efficiently dampens the immune response, but favors autoimmunity through impaired Treg development, which could be relevant for therapeutic Malt1-targeting strategies.
Assuntos
Autoimunidade/genética , Caspases/metabolismo , Colite/imunologia , Proteínas de Ligação a DNA/metabolismo , Encefalomielite Autoimune Experimental/imunologia , Proteínas de Neoplasias/metabolismo , Transferência Adotiva , Análise de Variância , Animais , Caspases/genética , Colite/patologia , Primers do DNA/genética , Proteínas de Ligação a DNA/genética , Encefalomielite Autoimune Experimental/patologia , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Imunofluorescência , Técnicas de Introdução de Genes , Inativação Gênica , Imunoglobulina E/sangue , Imunoglobulina G/sangue , Imuno-Histoquímica , Células Matadoras Naturais/imunologia , Camundongos , Camundongos Knockout , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa , Proteínas de Neoplasias/genética , Mutação Puntual/genética , Reação em Cadeia da Polimerase em Tempo RealRESUMO
The worldwide incidence and prevalence of asthma continues to increase. Asthma is now understood as an umbrella term for different phenotypes or endotypes, which arise through different pathophysiologic pathways. Understanding the many factors contributing to development of the disease is important for the identification of novel therapeutic targets for the treatment of certain asthma phenotypes. The hygiene hypothesis has been formulated to explain the increasing prevalence of allergic disease, including asthma. This hypothesis postulates that decreased exposure at a young age to certain infectious agents as a result of improved hygiene, increased antibiotic use and vaccination, and changes in lifestyle and dietary habits is associated with changes in the immune system, which predispose subjects to allergy. Many microbes, during their coevolution with human subjects, developed mechanisms to manipulate the human immune system and to increase their chances of survival. Improving models of asthma, as well as choosing adequate end points in clinical trials, will lead to a more complete understanding of the underlying mechanisms, thus providing an opportunity to devise primary and secondary interventions at the same time as identifying new molecular targets for treatment. This article reports the discussion and conclusion of a workshop under the auspices of the Netherlands Lung Foundation to extend our understanding of how modulation of the immune system by bacterial, parasitic, and viral infections might affect the development of asthma and to map out future lines of investigation.