Antibodies anti-"Rods & Rings", HCV and ribavirin/interferon: A human model of autoantibodies generation.

• Grant number: 11/12448-0
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: November 01, 2011
• End date: April 30, 2015
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: Luiz Eduardo Coelho Andrade
• Grantee: Gerson Dierley Keppeke
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil

Abstract

This the first descriptions of patients producing autoantibodies in the first half of last century, several theories were presented discussing how they are produced and why. Breaking of tolerance by the immune system itself is of great importance, especially considering the enormous importance of autoantibodies in the context of autoimmune diseases. Our group recently demonstrated that the use of ribavirin and interferon-alpha induces the generation of autoantibodies against cytoplasmic structures of preliminarily called "Rods & Rings." Chan and colleagues found evidence that the CTP synthase (CTP) is an antigenic target of these autoantibodies. In this paper we will study, describe and seek clarification on the steps of a model for the generation of autoantibodies in humans. We intend to study how the change in the structure of a protein itself (CTPs) caused by administration of a drug (ribavirin) administered for an infection (HCV) leads to an immune system destabilized by another medicine (IFN1-±) produce autoantibodies against this protein . It is a model for the generation of autoantibodies observed in patients with HCV and, curiously, does not seem to influence the course of the disease and response to treatment used to combat virus infection. We know that almost 40% of HCV patients treated with IFN1-± + Ribavirin produce autoantibodies against cytoplasmic structures called "Rods & Rings." To describe the process of generation of these autoantibodies will: 1 - To develop an animal model that helps to understand aspects of the pathophysiology of the process of generation of anti-R &R; 2 - To identify the protein targets of autoantibodies produced by patients; 3 - Monitoring the expression possible target antigen (CTP synthase) in cells subjected to treatment with Ribavirin; 4 - Studying the effects of ribavirin in vitro on the physicochemical properties of purified CTPs. The description of this model should contribute significantly to the understanding of the mechanisms underlying the production of autoantibodies and autoimmune diseases.

Scientific publications

(7)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

KEPPEKE, GERSON DIERLEY; CALISE, S. JOHN; CHAN, EDWARD K. L.; ANDRADE, LUIS EDUARDO C.. Anti-rods/rings autoantibody generation in hepatitis C patients during interferon-alpha/ribavirin therapy. WORLD JOURNAL OF GASTROENTEROLOGY, v. 22, n. 6, p. 1966-1974, FEB 14 2016. (11/12448-0)

KEPPEKE, GERSON DIERLEY; ANDRADE, LUIS EDUARDO C.; GRIESHABER, SCOTT S.; CHAN, EDWARD K. L.. Microinjection of specific anti-IMPDH2 antibodies induces disassembly of cytoplasmic rods/rings that are primarily stationary and stable structures. CELL AND BIOSCIENCE, v. 5, JAN 5 2015. (11/12448-0)

KEPPEKE, GERSON DIERLEY; CALISE, S. JOHN; CHAN, EDWARD K. L.; ANDRADE, LUIS EDUARDO C.. Ribavirin induces widespread accumulation of IMP dehydrogenase into rods/rings structures in multiple major mouse organs. Antiviral Research, v. 162, p. 130-135, FEB 2019. (11/12448-0)

AGUSTINELLI, R. A.; RODRIGUES, S. H.; MARIZ, H. A.; PRADO, M. S.; ANDRADE, L. E. C.. Distinctive features of positive anti-cell antibody tests (indirect immunofluorescence on HEp-2 cells) in patients with non-autoimmune diseases. Lupus, v. 28, n. 5, p. 629-634, APR 2019. (11/12448-0)

KEPPEKE, GERSON DIERLEY; PRADO, MONICA SIMON; NUNES, EUNICE; PERAZZIO, SANDRO FELIX; RODRIGUES, SILVIA HELENA; GOMES FERRAZ, MARIA LUCIA; CHAN, EDWARD K. L.; COELHO ANDRADE, LUIS EDUARDO. Differential capacity of therapeutic drugs to induce Rods/Rings structures in vitro and in vivo and generation of anti-Rods/Rings autoantibodies. Clinical Immunology, v. 173, p. 149-156, DEC 2016. (11/12448-0)

KEPPEKE, GERSON DIERLEY; JOHN CALISE, S.; CHAN, EDWARD K. L.; ANDRADE, LUIS EDUARDO C.. Assembly of IMPDH2-Based, CTPS-Based, and Mixed Rod/Ring Structures Is Dependent on Cell Type and Conditions of Induction. JOURNAL OF GENETICS AND GENOMICS, v. 42, n. 6, p. 287-299, JUN 20 2015. (11/12448-0)

KEPPEKE, GERSON DIERLEY; SATOH, MINORU; GOMES FERRAZ, MARIA LUCIA; CHAN, EDWARD K. L.; ANDRADE, LUIS EDUARDO C.. Temporal evolution of human autoantibody response to cytoplasmic rods and rings structure during anti-HCV therapy with ribavirin and interferon-alpha. IMMUNOLOGIC RESEARCH, v. 60, n. 1, p. 38-49, OCT 2014. (11/12448-0, 10/50710-6)