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Assembly of IMPDH2-Based,CTPS-Based,and Mixed Rod/Ring Structures Is Dependent on Cell Type and Conditions of Induction

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Journal of Genetics and Genomics 2015年第6期42卷 287-299页

作者： gerson dierley keppeke S.John Calise Edward K.L.Chan Luis Eduardo C.Andrade Rheumatology Division Federal University of Sao Paulo Department of Oral Biology University of Florida Immunology Division Fleury Medicine and Health Laboratories

Inhibition of guanosine triphosphate（GTP） and cytidine triphosphate（CTP） biosynthetic pathways induces cells to assemble rod/ring（RR） structures,also named cytoophidia,which consist of the enzymes cytidine triphosphate synthase（CTPS） and inosine-50-monophosphate dehydrogenase 2（IMPDH2）.We aim to explore the interaction of CTPS and IMPDH2 in the generation of RR *** La and COS-7 cells were cultured in normal conditions or in the presence of 6-diazo-5-oxo-L-norleucine（DON）,ribavirin,or mycophenolic acid（MPA）.Over 90% of DON-treated cells presented RR *** He La cells,35% of the RR structures were positive for IMPDH2 alone,26% were CTPS alone,and 31% were IMPDH2/CTPS mixed,while in COS-7 cells,42% of RR were IMPDH2 alone,41% were CTPS alone,and 10% were IMPDH2/CTPS *** and MPA treatments induced only IMPDH2-based *** were also transfected with an N-terminal hemagglutinin（NHA）-tagged CTPS1 *** 95% of NHA-CTPS1 transfected cells with DON treatment presented IMPDH2-based RR and almost 100% presented CTPS1-based RR;when treated with ribavirin,over 94% of transfected cells presented IMPDH2-based RR and 37% presented CTPS1-based RR,whereas 2% of untreated transfected cells presented IMPDH2-based RR and 28% presented CTPS1-based *** results may help in understanding the relationship between CTP and GTP biosynthetic pathways,especially concerning the formation of filamentous RR structures.

关键词： Nucleotide synthesis Enzyme aggregation Enzyme inhibition IMPDH2 CTPS

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Anti-rods/rings autoantibody generation in hepatitis Cpatients during interferon-α/ribavirin therapy

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World Journal of Gastroenterology 2016年第6期22卷 1966-1974页

作者： gerson dierley keppeke S John Calise Edward KL Chan Luis Eduardo C Andrade Rheumatology Division Escola Paulista de MedicinaUniversidade Federal de São PauloSP 04023-062Brazil Department of Oral Biology University of FloridaGainesvilleFL 32610-0424United States 3 Immunology DivisionFleury Medicine and Health Laboratories São PauloSP 04102-050Brazil

Chronic inflammation associated with hepatitis C virus(HCV) infection can lead to disabling liver diseases with progression to liver cirrhosis and hepatocellular carcinoma. Despite the recent availability of more effective and less toxic therapeutic options, in most parts of the world the standard treatment consists of a weekly injection of pegylated interferon α(IFN-α) together with a daily dose of ribavirin. HCV patients frequently present circulating non-organ-specific autoantibodies demonstrating a variety of staining patterns in the indirect immunofluorescence assay for antinuclear antibodies(ANA). Between 20% to 40% of HCV patients treated with IFN-α and ribavirin develop autoantibodies showing a peculiar ANA pattern characterized as rods and rings(RR) structures. The aim of this article is to review the recent reports regarding RR structures and anti-rods/rings(antiRR) autoantibody production by HCV patients after IFN-α/ribavirin treatment. Anti-RR autoantibodies first appear around the sixth month of treatment and reach a plateau around the twelfth month. After treatment completion, anti-RR titers decrease/disappear in half the patients and remain steady in the other half. Some studies have observed a higher frequency of anti-RR antibodies in relapsers, i.e., patients in which circulating virus reappears after initially successful therapy. The main target of anti-RR autoantibodies in HCV patients is inosine-5'-monophosphate dehydrogenase 2(IMPDH2), the rate-limiting enzyme involved in the guanosine triphosphate biosynthesis pathway. Ribavirin is a direct IMPDH2 inhibitor and is able to induce the formation of RR structures in vitro and in vivo. In conclusion, these observations led to the hypothesis that anti-RR autoantibody production is a human model of immunologic tolerance breakdown that allows us to explore the humoral autoimmune response from the beginning of the putative triggering event: exposure to ribavirin and interferon.

关键词： Rods and rings autoantibodies Hepatitis C ribavirin Interferon-α

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