Carlos Bravo-Perez, MD, PhD

Autoimmunity and immunodeficiency can coexist. Inborn errors of immunity are a heterogeneous group of genetic disorders in which the immune system is disturbed, not only affecting its ability to combat pathogens, but also to trigger autoimmunity. Despite early-onset and severe disease being expected for these disorders with the advent of modern DNA sequencing technologies, an increasing number of adult-onset errors of immunity has been identified. With this proposal, we aim to assess the presence of inherited gene variants predisposing to immunodeficiency as determinants of PNH and AA. First, to increase the power of our pilot study and validate our results, we will additionally perform genome sequencing to analyze an overall cohort of 250 PNH/AA patients (100 with PNH and 150 with AA). We will assess the presence of rare variants in 485 genes with previous implication in inborn errors of immunity. Next, we will integrate genomic data with other laboratory and clinical information for the identified patients, use artificial intelligence to identify similarities between cases, and analyze the clinical impact of these mutations as predictive markers for the outcome of therapy, and PNH clone size and expansion. We will also evaluate the additive effect of somatic hits in immune or myeloid genes on the evolution of AA to secondary PNH or MDS.
This research proposal aims to get novel insights into the pathogenesis of PNH and AA with an original perspective, focused on the search of inherited variants associated with immunodeficiency as a predisposing cause of disease initiation and clonal evolution. My engagement in this 2-year project will significantly contribute to consolidate my research experience and career in translational hematology.