Systemic integrative characterization of the role of autoantibodies targeting G protein coupled receptors on neutrophil cell migration

• Grant number: 23/14417-2
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: September 01, 2024
• End date: September 30, 2028
• Field of knowledge: Biological Sciences - Immunology
• Principal Investigator: Otávio Cabral Marques
• Grantee: Júlia Nakanishi Usuda
• Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Autoantibodies (AAbs) are antibodies which react with self-molecules (autoantigens). Molecules whose own existence and functionality were once contested, have now been accepted in the context of autoimmune diseases. Although considered mainly pathological, these are ubiquitously present molecules which contribute to homeostasis. One particular class of are the functional AAbs, which can bind to cell surface receptors such as G protein-coupled receptors (GPCRs) and modulate their functions. Our group has characterized the role of AAbs against endothelin type A receptor in neutrophil migration, and we believe that other AAbs to GPCRs, such as those targeting the angiotensin II type 1 receptor and the chemokine receptors CXCR3 and CXCR4, may also play this role. We hypothesize that AAbs to GPCRs are present in the physiological context and play a functional role in neutrophil migration, and that an imbalance in the homeostasis of these AAbs is associated with pathological conditions. Thus, we propose a comprehensive meta-analysis of high-throughput arrays of AAbs (autoantibodyome) to GPCRs to characterize the landscape of molecule networks in the healthy context and the altered pathways in disease. In addition, we will analyze the array of AAbs from transplant patients for the unprecedented characterization of the AAbs to GPCRs associated with neutrophil migration in this context. Pairs of AAbs and GPCRs with greater potential as biomarkers or therapeutic targets will be individually measured and studied in vitro to validate their effect on neutrophil migration functionally and to evaluate the most relevant binding sites. The study of the interactions of these molecules will contribute to a better understanding of human pathophysiology by identifying and characterizing AAbs to GPCRs with greater potential for use in early diagnosis and as modulation targets.