Somatic mutation profile in lymphocytes of patients with CTLA4 deficiency

• Grant number: 23/10187-2
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: December 01, 2023
• End date: November 30, 2024
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Rodrigo do Tocantins Calado de Saloma Rodrigues
• Grantee: Rhuan Carlos Maduro
• 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 research grant: 20/07055-9 - Nucleus of Cellular Therapy - NuTeC, AP.NPOP

Abstract

The cytotoxic T lymphocyte antigen 4 (CTLA-4) is a cellular receptor that plays a fundamental role as an immune checkpoint, responsible for regulating the immune response and preventing an attack against the body's own cells. On the other hand, tumor cells can exploit this pathway to suppress an immune response, and the CTLA-4 inhibitor ipilimumab is successfully used in the treatment of certain types of neoplasms. Heterozygous pathogenic germline variants in CTLA-4 lead to a rare syndrome (CTLA-4 deficiency), characterized by autoimmune reactions of the immune system, lymphocytic infiltrations in non-lymphoid organs, cytopenias, and cutaneous manifestations. Two patients with this deficiency due to the pathogenic variant CTLA-4 p.Pro137Leu (mother and daughter) are being followed up at the Bone Marrow Failure Outpatient Clinic of our institution. In one of the patients, a survivor of aplastic anemia (AA) treated with immunosuppression, somatic variants in BCOR (p.Gln1058Arg fs*55) and STAT3 (p.Gly534Arg) were also observed in peripheral blood mononuclear cells. Patients with immune AA, characterized by an expansion of cytotoxic T cells, present somatic variants enriched in STAT3 in CD8+ T cells. However, the profile of pathogenic somatic variants in other cellular populations has been poorly explored, as well as the relationship between the allele burden in STAT3 and other genes, and the impact of these alterations on the dynamics of different cell types and the development of autoreactive cells. We propose to evaluate the profile of somatic variants in hematopoietic cell subpopulations (B lymphocytes, CD4+ and CD8+ T cells, and granulocytes) using samples from patients with CTLA-4 deficiency as a biological model. We will employ next-generation sequencing of immuno-magnetically separated cells and a customized panel covering 154 genes associated with hematological neoplasms. Through this investigation, we aim to contribute to the understanding of the molecular mechanisms involved in the pathogenesis of immunomediated diseases.