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Identification of critical molecular targets associated with the etiology and pathophysiology of Primary Immunodeficiencies with emphasis on clinical manifestations of inflammation, immunodysregulation and autoimmunity

Grant number: 16/25615-6
Support type:Regular Research Grants
Duration: August 01, 2017 - January 31, 2020
Field of knowledge:Health Sciences - Medicine - Maternal and Child Health
Principal Investigator:Maria Marluce dos Santos Vilela
Grantee:Maria Marluce dos Santos Vilela
Home Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Assoc. researchers:Fernando Ferreira Costa ; Marcelo Ananias Teocchi


The present Research Project is formulated in two parts, Part I and Part II, associated with two cohorts of patients with primary immunedeficiencies (PIDs): autoimmune lymphoproliferative syndrome (ALPS) with undefined genetic etiology (ALPS-U) and agammaglobulinemia linked to X (XLA), respectively. Although different, such pathologies present some clinical manifestations in common characterized by inflammation, dysregulation of the number of lymphocytes (lymphoproliferation in ALPS-U and B-cell lymphopenia in XLA), and possible autoimmunity. The Regular Research Grant (RRG) (Process FAPESP: 2012/06194-9), concluded in December 2015, generated the Part I. That produced original results on the molecular pathophysiology of ALPS associated with FAS mutation (ALPS-FAS). Significant changes in gene expression and microRNAs provided new insights about variable clinical expressiveness in related patients, all heterozygous for the IVS4+1G>A mutation in FAS. In addition, by complete exome sequencing, pathogenic candidate genes were revealed for 12 unrelated individuals with ALPS-U phenotype. In this context, our aim is to confirm by molecular biology techniques and functional assays the role of these candidates as ALPS-U causing disease genes and to clarify, through the study of genes, microRNAS and proteins, the molecular pathophysiological mechanisms that may be associated with the numerous and complex patient's clinical manifestations. Also, original results from another RRG (Process FAPESP: 2011/50589-5) clearly suggested a new inflammatory mechanism for XLA, characterized by XBP1 (X-box binding protein 1) overexpression and activation of Toll-like receptors (TLRs). Thus, the main aim of Part II is the molecular and functional investigation of this new pathophysiological mechanism through the study of TLRs and their signaling pathways in the chronic inflammation inherent to XLA patients. The study of these two natural and human models of PIDs may not only provide relevant data for diagnosis, prognosis and therapy, but also contribute to the understanding of important biological phenomena such as cell proliferation, differentiation and death and their implications for the functioning of the immune system. (AU)