Rod & Ring Structures: Targets of Emerging Autoantibodies
Historically, there have been few examples of human autoantibodies used in elucidating novel subcellular macromolecular complexes and structures. Dr. Chan and colleagues have identified novel human autoantibodies recognizing conserved rods and rings (RR) in the cytoplasm of many cell types examined to date. The data has been validated using newly acquired cells from the American Type Culture Collection to rule out artifacts from continued in vitro culturing. Candidate RR proteins have been identified and will allow for a number of interesting studies to investigate the biology of these structures at the cellular level. Continuing identification of key RR protein components will better define the function of these structures.
From the clinical perspective, preliminary data show that a majority of patients with the RR antibody are positive for hepatitis C virus. The overall goal of the proposed studies is to elucidate the structure and function of RR and gain insight into patients positive for anti-RR autoantibodies. The proposed studies will span across molecular and cell biology, virology, and autoimmunity.
Current Project Members
- S. John Calise
- Daniel L. Purich, Ph.D., Dept. of Biochemistry and Molecular Biology, UF College of Medicine, Gainesville, FL
- Luis E.C. Andrade, M.D., Ph.D., Rheumatology Division, Universidade Federal de São Paulo, São Paulo, Brazil
Calise, S.J., Bizzaro, N., Nguyen, T., Bassetti, D., Porcelli, B., Almi, P., Barberio, G., Pesce, G., Satoh, M., and Chan, E.K. Anti-rods/rings autoantibody seropositivity does not affect response to telaprevir treatment for chronic hepatitis C infection. Autoimmun Highlights. 7(1):15.
Keppeke, G.D., Prado, M.S., Nunes, E., Perazzio, S.F., Rodrigues, S.H., Ferraz, M.L., Chan, E.K., and Andrade, L.E. Differential capacity of therapeutic drugs to induce Rods/Rings structures in vitro and in vivo and generation of anti-Rods/Rings autoantibodies. Clin Immunol. In press.
Calise, S.J., Purich, D.L., Nguyen, T., Saleem, D.A., Krueger, C., Yin, J.D., and Chan, E.K. ‘Rod and ring’ formation from IMP dehydrogenase is regulated through the one-carbon metabolic pathway. J Cell Sci. 129(15):3042-52.
Keppeke, G.D., Calise, S.J., Chan, E.K., and Andrade, L.E. Anti-rods/rings autoantibody generation in hepatitis C patients during interferon-α/ribavirin therapy. World J Gastroenterol. 22(6):1966-74. Review.
Keppeke, G.D., Calise, S.J., Chan, E.K., and Andrade, L.E. Assembly of IMPDH2-based, CTPS-based, and mixed rod/ring structures is dependent on cell type and conditions of induction. J Genet Genomics 42(6):287-299.
Calise, S.J., Keppeke, G.D., Andrade, L.E., and Chan, E.K. Anti-rods/rings: a human model of drug-induced autoantibody generation. Front Immunol. 6:41. Review.
Keppeke, G.D., Andrade, L.E., Grieshaber, S.S., and Chan, E.K. Microinjection of specific anti-IMPDH2 antibodies induces disassembly of cytoplasmic rods/rings that are primarily stationary and stable structures. Cell Biosci. 5:1.
Keppeke, G.D., Satoh, M., Ferraz, M.L., Chan, E.K., and Andrade, L.E. Temporal evolution of human autoantibody response to cytoplasmic rods and rings structure during anti-HCV therapy with ribavirin and interferon-α. Immunol Res. 60:38-49.
Calise, S.J., Carcamo, W.C., Ceribelli, A., Dominguez, Y., Satoh, M., and Chan, E.K. Antibodies to rods and rings. In Autoantibodies (Shoenfeld, Y., Meroni, P.L., Gershwin, M.E., Eds.), pp. 161-168. Elsevier Science, Third Edition. Book Chapter.
Calise, S.J., Carcamo, W.C., Krueger, C., Yin, J.D., Purich, D.L., and Chan, E.K. Glutamine deprivation initiates reversible assembly of mammalian rods and rings. Cell Mol Life Sci. 71:2963-73.
Carcamo, W.C., Calise, S.J., von Mühlen, C.A., Satoh, M., and Chan, E.K. Molecular cell biology and immunobiology of mammalian rod/ring structures. Int Rev Cell Mol Biol. 308:35-74. Review.
Carcamo, W.C., Ceribelli, A., Calise, S.J., Krueger, C., Liu, C., Daves, M., Villalta, D., Bizzaro, N., Satoh, M., and Chan, E.K. Differential reactivity to IMPDH2 by anti-rods/rings autoantibodies and unresponsiveness to pegylated interferon-alpha/ribavirin therapy in US and Italian HCV patients. J Clin Immunol. 33:420-6.
Keppeke, G.D., Nunes, E., Ferraz, M.L., Silva, E.A., Granato, C., Chan, E.K., and Andrade, L.E. Longitudinal Study of a Human Drug-Induced Model of Autoantibody to Cytoplasmic Rods/Rings following HCV Therapy with Ribavirin and Interferon-α. PLoS One 7:e45392.
Covini, G., Carcamo, W.C., Bredi, E., von Mühlen, C.A., Colombo, M., and Chan, E.K. Cytoplasmic rods and rings autoantibodies developed during pegylated interferon and ribavirin therapy in patients with chronic hepatitis C. Antiviral Therapy 17:805-11.
Carcamo, W.C., Satoh, M., Kasahara, H., Terada, N., Hamazaki, T., Chan, J.Y., Yao, B., Tamayo, S., Covini, G., von Mühlen, C.A., and Chan, E.K. Induction of cytoplasmic rods and rings structures by inhibition of the CTP and GTP synthetic pathway in mammalian cells. PLoS One 6:e29690.