Immunogenetics of the inflammasome and translational study "from bed to bench and back": analysis of variations in inflammasome genes in monogenic and multifactorial autoinflammatory diseases for differential diagnosis and therapeutic applications

Abstract

The inflammasome plays a central role in the first defence the organism to pathogens and/or to injury/damage and mediates the inflammatory response by IL-1ß and IL-18 secretion. Conversely an excess of activation of the complex, and the consequent exacerbated production of these cytokines, is related both to the development of rare monogenic inflammatory diseases (auto-inflammatory syndromes) as well as of multifactorial diseases (autoimmune diseases, cancer, metabolic diseases, etc.), emphasizing that inflammatory mechanisms are an important trigger in the development of the most common diseases in the general population. Despite being well studied, most of the information nowadays available on the inflammasome derived from studies in experimental models, while little is known about the action of inflammasome in humans. Association studies about SNPs in inflammasome genes in patients with different multifactorial diseases revealed the contribution of one or another inflammasome in the pathogenesis of specific diseases, however there is a shortage of essential functional data to interpret these associations. In addition, the diagnosis of auto-inflammatory syndromes could benefit from a simpler and cheaper laboratory test than the sequencing of candidate genes, nowadays not disclosed by the Brazilian public health system. Considering these three aspects (association studies, lack of assays to study inflammasome in humans, and necessity of diagnostic tools for auto-inflammatory syndromes), in this project we intend to deepen the genetic contribution of inflammasome in the immune response modulation and in the pathogenesis and/or development of diseases with dysregulation of inflammation by association studies of multifactorial diseases, and by an in vitro assay for the study of inflammasome in primary human cells as a tool for the evaluation of the complex in different situations challenge or disease. This cellular assay will be imply to (a) evaluate the functional effects of genetic variants (b) confirm data obtained in animal models and (c) for clinical and translational research. (AU)