title: Differential capacity of therapeutic drugs to induce Rods/Rings structures in vitro and in vivo and generation of anti-Rods/Rings autoantibodies.
abstract: Some HCV patients using ribavirin and interferon alpha (IFN-α) develop anti-rods and rings (RR) autoantibodies, the main target of which is inosine monophosphate dehydrogenase (IMPDH), the rate-determining enzyme in de novo GTP biosynthesis. In vitro inhibition of IMPDH by ribavirin induces RR formation. Here we investigate whether other commonly used drugs that interfere with GTP biosynthesis can induce RR structures in vitro and vivo and elicit generation of autoantibodies. HEp-2 cells treated for 24h with ribavirin, mycophenolic acid (MPA), azathioprine, methotrexate or acyclovir were positive for RR structures. However, adefovir, entecavir, tenofovir and lamivudine did not induce RR structures in these cells. Structures induced by ribavirin in HEp-2 cells are stable after 24h drug-washout, while structures induced by other drugs are relatively labile, disappearing within 2h. Looking at patients treated with these drugs, HCV patients treated with ribavirin (n=17) showed higher average percentage of RR-positive peripheral mononuclear cells than autoimmune patients treated with RR-inducing immunosuppressant drugs (n=21). Serum from 173 autoimmune patients who had been treated with MPA, azathioprine or methotrexate was tested for presence of anti-RR autoantibodies, and only one sample was found to be positive. Conversely, of 48 anti-RR autoantibody positive samples identified at Fleury Laboratories over 30months, 94% were from HCV patients treated with ribavirin plus IFN-α. These data indicate that RR structures can be induced by a variety of drugs in vitro and in vivo, but anti-RR autoantibody production is mostly restricted to HCV patients under ribavirin+IFN-α treatment.
authors.affiliation: Rheumatology Division, Federal University of Sao Paulo, Sao Paulo, SP 04023-062, Brazil. Electronic address: gerson.keppeke@gmail.com.
authors.forename: Gerson Dierley
authors.initials: GD
authors.lastname: Keppeke
authors.affiliation: Rheumatology Division, Federal University of Sao Paulo, Sao Paulo, SP 04023-062, Brazil.
authors.forename: Monica Simon
authors.initials: MS
authors.lastname: Prado
authors.affiliation: Gastroenterology Division, Federal University of Sao Paulo, Sao Paulo, SP 04023-062, Brazil.
authors.forename: Eunice
authors.initials: E
authors.lastname: Nunes
authors.affiliation: Rheumatology Division, Federal University of Sao Paulo, Sao Paulo, SP 04023-062, Brazil; Immunology Division, Fleury Medicine and Health Laboratories, Sao Paulo SP 04102-050, Brazil.
authors.forename: Sandro Felix
authors.initials: SF
authors.lastname: Perazzio
authors.affiliation: Rheumatology Division, Federal University of Sao Paulo, Sao Paulo, SP 04023-062, Brazil.
authors.forename: Silvia Helena
authors.initials: SH
authors.lastname: Rodrigues
authors.affiliation: Gastroenterology Division, Federal University of Sao Paulo, Sao Paulo, SP 04023-062, Brazil.
authors.forename: Maria Lucia Gomes
authors.initials: ML
authors.lastname: Ferraz
authors.affiliation: Department of Oral Biology, University of Florida, Gainesville, FL 32610-0424, USA.
authors.forename: Edward K L
authors.initials: EK
authors.lastname: Chan
authors.affiliation: Rheumatology Division, Federal University of Sao Paulo, Sao Paulo, SP 04023-062, Brazil; Immunology Division, Fleury Medicine and Health Laboratories, Sao Paulo SP 04102-050, Brazil. Electronic address: luis.andrade@unifesp.br.
authors.forename: Luis Eduardo Coelho
authors.initials: LE
authors.lastname: Andrade
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology*; D045744:Cell Line, Tumor; D019698:Hepatitis C, Chronic / Q000097:blood / Q000276:immunology*; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology* / Q000627:therapeutic use; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000276:immunology*
chemical_list: D000998:Antiviral Agents; D001323:Autoantibodies; D007155:Immunologic Factors