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 rod and ring structures (RRs) 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 anti-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.
Keppeke GD, Calise SJ, Chan EKL, and Andrade LEC. Ribavirin induces widespread accumulation of IMP dehydrogenase into rods/rings structures in multiple major mouse organs. Antiviral Res. 162:130-135.
Calise SJ, Abboud G, Kasahara H, Morel L, and Chan EKL. Immune response-dependent assembly of IMP dehydrogenase filaments. Front Immunol. 9:2789.
Calise SJ, Zheng B, Hasegawa T, Satoh M, Isailovic N, Ceribelli A, Andrade LEC, Boylan K, Cavazzana I, Fritzler MJ, Garcia de la Torre I, Hiepe F, Kohl K, Selmi C, Shoenfeld Y, Tincani A, Chan EKL. Reference standards for the detection of anti-mitochondrial and anti-rods/rings autoantibodies. Clin Chem Lab Med. 56(10):1789-1798.
Calise SJ and Chan EKL. Advances in the immunobiology of autoantigenic rods/rings structures. In Immunodeficiency, Infection and Autoimmune Diseases – Report on the 13th Dresden Symposium on Autoantibodies (Conrad K, Andrade LEC, Chan EKL, Fritzler MJ, Pruijn GJM, Shoenfeld Y, and Steiner G, Eds.), pp. 71-80. Pabst Science Publishers, Lengerich, Germany. Review.
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. 173:149-156.
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.
Calise SJ, Carcamo WC, and Chan EK. Clinical implications of anti-rods and rings autoantibodies in hepatitis C patients treated with interferon/ribavirin therapy. In Infection, Tumors and Autoimmunity – Report on the 11th Dresden Symposium on Autoantibodies (Conrad K, Chan EKL, Fritzler MJ, Humbel RL, Meroni PL, Steiner G, Shoenfeld Y, Eds.), Pabst Science Publishers, Lengerich, Germany. 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.