Malt1 protease inactivation efficiently dampens immune responses but causes spontaneous autoimmunity.

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

Comparative primary paediatric nasal epithelial cell culture differentiation and RSV-induced cytopathogenesis following culture in two commercial media

The culture of differentiated human airway epithelial cells allows the study of pathogen-host interactions and innate immune responses in a physiologically relevant in vitro model. As the use of primary cell culture has gained popularity the availability of the reagents needed to generate these cultures has increased. In this study we assessed two different media, Promocell and PneumaCult, during the differentiation and maintenance of well-differentiated primary nasal epithelial cell cultures (WD-PNECs). We compared and contrasted the consequences of these media on WD-PNEC morphological and physiological characteristics and their responses to respiratory syncytial virus (RSV) infection. We found that cultures generated using PneumaCult resulted in greater total numbers of smaller, tightly packed, pseudostratified cells. However, cultures from both media resulted in similar proportions of ciliated and goblet cells. There were no differences in RSV growth kinetics, although more ciliated cells were infected in the PneumaCult cultures. There was also significantly more IL-29/IFNλ1 secreted from PneumaCult compared to Promocell cultures following infection. In conclusion, the type of medium used for the differentiation of primary human airway epithelial cells may impact experimental results.</p

The Climate of the Mediterranean Region in Future Climate Projections

Future climate change over the Mediterranean area is investigated by means of climate model simulations covering the twenty-first century that take into account different anthropogenic greenhouse-gas-emission scenarios. This chapter first gives some new insights on these projections coming from the use of new methods, including the coupling at the regional scale of the atmospheric component to a Mediterranean Sea component. A synthesis of the expected changes of key aspects of the Mediterranean regional climate, obtained with a wide range of models and downscaling methods, is then presented. This includes an overview of not only expected changes in the mean climate and climate extremes but also possible changes in Mediterranean Sea temperature, salinity, circulation, water and heat budgets, and sea level. The chapter ends with some advanced results on the way to deal with uncertainties in climate projections and some discussion on the confidence that we can attribute to these projections

Induction and function of virus-specific CD4+ T cell responses

CD4+ T cells -- often referred to as T-helper cells -- play a central role in immune defense and pathogenesis. Virus infections and vaccines stimulate and expand populations of antigen-specific CD4+ T cells in mice and in man. These virus-specific CD4+ T cells are extremely important in antiviral protection: deficiencies in CD4+ T cells are associated with virus reactivation, generalized susceptibility to opportunistic infections, and poor vaccine efficacy. As described below, CD4+ T cells influence effector and memory CD8+ T cell responses, humoral immunity, and the antimicrobial activity of macrophages and are involved in recruiting cells to sites of infection. This review summarizes a few key points about the dynamics of the CD4+ T cell response to virus infection, the positive role of pro-inflammatory cytokines in the differentiation of virus-specific CD4+ T cells, and new areas of investigation to improve vaccines against virus infection

Developments in the mechanisms of allergy in 2018 through the eyes of Clinical and Experimental Allergy, Part I

In the first of two linked articles, we describe the development in the mechanisms underlying allergy as described by Clinical & Experimental Allergy and other journals in 2018. Experimental models of allergic disease, basic mechanisms and clinical mechanisms are all covered.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152969/1/cea13532.pd