Immune signature in telomeropathies

• Grant number: 19/17520-3
• Support Opportunities: Regular Research Grants
• Start date: January 01, 2020
• End date: December 31, 2022
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Agreement: King's College London
• Principal Investigator: Rodrigo do Tocantins Calado de Saloma Rodrigues
• Grantee: Rodrigo do Tocantins Calado de Saloma Rodrigues
• Principal researcher abroad: Judith Christine Watson MARSH
• Institution abroad: King's College London, England
• Host Institution: Hemocentro de Ribeirão Preto. Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da USP (HCMRP). Secretaria da Saúde (São Paulo - Estado). Ribeirão Preto , SP, Brazil
• Associated researchers: Diego Villa Clé ; Flávia Sacilotto Donaires Ramos ; Luiz Fernando Bazzo Catto ; Willian Robert Gomes

Abstract

Telomeres are the repetitive nucleotide structures at the end of the linear chromosomes that, when critically short, engage cell senescence, apoptosis, or chromosome instability. In cells with high proliferative demand, telomeres are repaired by telomerase, a reverse transcriptase that adds hexanucleotides to the 3' end of the DNA leading strand. In humans, germline mutations in telomere-biology genes may cause disorders (telomeropathies) associated with defective cell regeneration and may affect the bone marrow, skin, lungs, and liver, and a proclivity for cancer development. In the haematopoietic compartment, abnormal telomere erosion provokes an exhaustion of the haematopoietic stem cell pool, resulting in a hypocellular bone marrow and pancytopenia, which may be clinically diagnosed as aplastic anaemia. Telomere dysfunction also may trigger failure of other organs, such as the lungs, causing pulmonary fibrosis, and the liver, causing cirrhosis. Particularly characteristic of the lungs and liver is the profibrotic damage to the organs. Recent studies have compelling evidence that the immune system contributes to disease phenotype. Our preliminary findings suggest a Th1-biased profile in the liver of telomerase-deficient mice when challenged by S. mansoni infection. Their hepatocytes are metabolic dysfunctional and more likely to trigger chronic injury/repair. Additionally, it has been demonstrated in humans that short telomeres cause primary T cell immunodeficiency and activate distinct molecular pathways of T cell apoptosis with aging. In this collaborative study between the University of São Paulo (USP) and the King's College Hospital (KCH), we plan to join the cohorts of patients with telomeropathies from both institutions and immunologically characterize those patients with bone marrow failure, pulmonary fibrosis, and cirrhosis to determine the immunologic signature of their lymphocytes in each phenotype. We will apply technical expertise from each group utilizing mass cytometry (CyTOF), flow cytometry, and cytokine analysis. This study will strengthen the existing collaboration between USP and KCH in hematology for the understanding of the telomere diseases at the molecular level. (AU)