In silico Identification of the HLA-DRB1*15:01 Restricted B-cell and T-cell Epitopes of the Autoantigens MOG and AQP4 Associated with Autoimmune Neuropathy
Main Article Content
Abstract
Immunogenicity plays a crucial role in the pathogenesis of autoimmune neuropathy associated with MOG and AQP4 proteins. Hence, we employed computational tools, including MHC-II Binding Prediction and B Cell Epitope Prediction tools from IEDB, Clustal Omega, SWISS-MODEL, AbodyBuilder, HDOCK, AlphaFold Protein Structure Database, and Protein Data Bank, to identify potential HLA-DRB1*15:01 restricted T-cell and B-cell epitopes of the autoantigens MOG and AQP4 and their structural characteristics. Subsequently, the peptide sequences of bacterial proteins identical to the epitopes of MOG and AQP4 proteins were analyzed using BLASTp, MoRFchibi SYSTEM, IUPred3, SEG, miPepBase, and NCBI databases to detect the presence of MoRF, SliM, and LCR. Our findings revealed that MOG22-LQVSSSY-28, MOG80-YRNGKD-85, MOG179-QYRLRGKL-186 and AQP475-CTRKIS-80 were common sequences of the HLA-DRB1*15:01 restricted T-cell and B-cell epitopes of the autoantigens MOG and AQP4. While MoRFs and LCRs were found in some bacteria, the prevalence was low (10.81% and 5.40%, respectively). This suggests that these bacteria may not use the identical peptides to regulate protein-protein interactions and host cell activities.
Keywords:
Epitope, MOG, AQP4, HLA-DRB1*15:01, autoimmune neuropathy
References
[1] A. Davidson, B. Diamond, Autoimmune diseases. The New England journal of medicine, 345(5), 2001, 340–350. (https://doi.org/10.1056/NEJM 200108023450506)
[2] D. Whittam, M. Wilson, S. Hamid, G. Keir, M. Bhojak, A. Jacob, What’s new in neuromyelitis optica? A short review for the clinical neurologist, Journal of neurology, 264(11), 2017, pp. 2330–2344. (https://doi.org/10.1007/s00415-017-8445-8)
[3] E. Wallstrom, M. Khademi, M. Andersson, R. Weissert, C. Linington, T. Olsson, Increased reactivity to myelin oligodendrocyte glycoprotein peptides and epitope mapping in HLA DR2(15)+ multiple sclerosis, European journal of immunology, 28(10), 1998, pp. 3329–3335.
(https://doi.org/10.1002/(SICI)1521-4141(199810) 28:10<3329::AID-IMMU3329>3.0.CO;2-B)
[4] M. Khare, M. Rodriguez, C. S. David, HLA class II transgenic mice authenticate restriction of myelin oligodendrocyte glycoprotein-specific immune response implicated in multiple sclerosis pathogenesis, International immunology, 15(4), 2003, pp. 535–546, 2003. (https://doi.org/10.1093/ intimm/dxg053)
[5] M. Varrin-Doyer, C.M. Spencer, U. Schulze-Topphoff, P.A. Nelson, R. M. Stroud, B.A. Cree, B. A., S.S. Zamvil, Aquaporin 4-specific T cells in neuromyelitis optica exhibit a Th17 bias and recognize Clostridium ABC transporter, Annals of neurology, 72(1), 2012, pp. 53–64. (https://doi.org/ 10.1002/ana.23651)
[6] S. V. Alves-Leon, M.L. Veluttini-Pimentel, M. E. Gouveia, F. R. Malfetano, E. L. Gaspareto, M. P. Alvarenga, I. Frugulhetti, T. Quirico-Santos, Acute disseminated encephalomyelitis: Clinical features, HLA DRB1*1501, HLA DRB1*1503, HLA DQA1*0102, HLA DQB1*0602, and HLA DPA1*0301 allelic association study, Arquivos de neuro-psiquiatria, 67(3A), 2009, pp. 643–651. (https://doi.org/10.1590/s0004-282x20090004000 13)
[7] M. Matiello, J. Schaefer-Klein, D. G. Brum, E. J. Atkinson, O. H. Kantarci, B. G. Weinshenker, NMO genetics collaborators, HLA-DRB1*1501 tagging rs3135388 polymorphism is not associated with neuromyelitis optica, Multiple sclerosis (Houndmills, Basingstoke, England), 16(8), 2010, pp. 981–984. (https://doi.org/10.1177/1352458510 374340)
[8] D. G. Brum, A. A. Barreira, A. C. dos Santos, D. R. Kaimen-Maciel, M. Matiello, R. M. Costa, N. H. Deghaide, L. S. Costa, P.L ouzada-Junior, P. R. Diniz, E. R. Comini-Frota, C. T. Mendes-Junior, E. A. Donadi, HLA-DRB association in neuromyelitis optica is different from that observed in multiple sclerosis. HLA-DRB association in neuromyelitis optica is different from that observed in multiple sclerosis, Multiple sclerosis (Houndmills, Basingstoke, England), 16(1), 2010, pp. 21–29. (https://doi.org/10.1177/1352458509350741)
[9] R. Kogay, C. Schönbach, Epitope Predictions, in Encyclopedia of Bioinformatics and Computational Biology, Elsevier, 2019, pp. 952–971. (https://doi.org/10.1016/B978-0-12-809633-8.20248-3)
[10] M. Rojas, P. Restrepo-Jiménez, D. M. Monsalve, Y. Pacheco, Y. Acosta-Ampudia, C. Ramírez-Santana, P. S. C. Leung, A. A. Ansari, M. E. Gershwin, J. M. Anaya, Molecular mimicry and autoimmunity, Journal of autoimmunity, 95, 2018, pp. 100–123. (https://doi.org/10.1016/j.jaut.2018. 10.012)
[11] R. van der Lee, M. Buljan, B. Lang, , R. J. Weatheritt, G. W. Daughdrill, A. K. Dunker, M. Fuxreiter, J. Gough, J. Gsponer, D. T. Jones, P. M. Kim, R. W. Kriwacki, C. J. Oldfield, R. V. Pappu, P. Tompa, V. N. Uversky, P. E. Wright, M. M. Babu, Classification of intrinsically disordered regions and proteins, Chemical reviews, 114(13), 2014, pp. 6589–6631. (https://doi.org/10.1021/ cr400525m)
[12] A. Mohan, C. J. Oldfield, P. Radivojac, V. Vacic, M. S. Cortese, A. K. Dunker, V. N. Uversky, Analysis of molecular recognition features (MoRFs), Journal of molecular biology, 362(5), 2006, pp. 1043–1059. (https://doi.org/10.1016/ j.jmb.2006.07.087)
[13] N.E. Davey, K. Van Roey, R. J. Weatheritt, G. Toedt, B. Uyar, B. Altenberg, A. Budd, F. Diella, H. Dinkel, T. J. Gibson, Attributes of short linear motifs, Molecular bioSystems, 8(1), 2012, pp. 268–281. (https://doi.org/10.1039/c1mb05231d)
[14] N. E. Davey, G. Travé, T. J. Gibson, How viruses hijack cell regulation, Trends in biochemical sciences, 36(3), 2011, pp. 159–169, (https://doi.org/10.1016/j.tibs.2010.10.002)
[15] T. D. Goddard, C. C. Huang, E. C. Meng, E.F. Pettersen, G. S. Couch, J. H. Morris, Thomas E. Ferrin, UCSF ChimeraX : Meeting modern challenges in visualization and analysis, Protein Science, 27, 2018, pp. 14–25. (https://doi.org/10. 1002/pro.3235)
[16] J. Neefjes, M. L. M. Jongsma, P. Paul, and O. Bakke, Towards a systems understanding of MHC class I and MHC class II antigen presentation, Nature reviews. Immunology, 11(12), 2011, pp. 823–836. (https://doi.org/10.1038/nri3084)
[17] N. Kerlero De Rosb, M. Hoffman, I. Mendel, I. Yust, J. Kaye, R. Bakimer, S. Flechter, O. Abramsky, R. Milo, A. Karni, A. Ben-Nun, “Predominance of the autoimmune response to myelin oligodendrocyte glycoprotein (MOG) in multiple sclerosis: Reactivity to the extracellular domain of MOG is directed against three main regions, European journal of immunology, 27(11), 1997, pp. 3059–3069. (https://doi.org/10.1002/eji. 1830271144)
[18] R. Weissert, J. Kuhle, K. L. de Graaf, W. Wienhold, M. M. Herrmann, C. Müller, T. G. Forsthuber, K. H. Wiesmüller, A. Melms, High Immunogenicity of Intracellular Myelin Oligodendrocyte Glycoprotein Epitopes, Journal of immunology (Baltimore, Md. : 1950), 169(1), 2002, pp. 548–556. (https://doi.org/10.4049/ jimmunol.169.1.548)
[19] L. S. Hofer, M. Ramberger, V. Gredler, A. S. Pescoller, K. Rostásy, M. Sospedra, H. Hegen, T. Berger, A. Lutterotti, M. Reindl, Comparative Analysis of T-Cell Responses to Aquaporin-4 and Myelin Oligodendrocyte Glycoprotein in Inflammatory Demyelinating Central Nervous System Diseases. Frontiers in immunology, 11, 2020. (https://doi.org/10.3389/fimmu.2020.01188)
[20] N. Matsuya, M. Komori, K. Nomura, S. Nakane, T. Fukudome, H. Goto, H. Shiraishi, K. P. Wandinger, H. Matsuo, T. Kondo, Increased T-cell immunity against aquaporin-4 and proteolipid protein in neuromyelitis optica, International immunology, 23(9), 2011, pp. 565–573. (https:// doi.org/10.1093/intimm/dxr056)
[2] D. Whittam, M. Wilson, S. Hamid, G. Keir, M. Bhojak, A. Jacob, What’s new in neuromyelitis optica? A short review for the clinical neurologist, Journal of neurology, 264(11), 2017, pp. 2330–2344. (https://doi.org/10.1007/s00415-017-8445-8)
[3] E. Wallstrom, M. Khademi, M. Andersson, R. Weissert, C. Linington, T. Olsson, Increased reactivity to myelin oligodendrocyte glycoprotein peptides and epitope mapping in HLA DR2(15)+ multiple sclerosis, European journal of immunology, 28(10), 1998, pp. 3329–3335.
(https://doi.org/10.1002/(SICI)1521-4141(199810) 28:10<3329::AID-IMMU3329>3.0.CO;2-B)
[4] M. Khare, M. Rodriguez, C. S. David, HLA class II transgenic mice authenticate restriction of myelin oligodendrocyte glycoprotein-specific immune response implicated in multiple sclerosis pathogenesis, International immunology, 15(4), 2003, pp. 535–546, 2003. (https://doi.org/10.1093/ intimm/dxg053)
[5] M. Varrin-Doyer, C.M. Spencer, U. Schulze-Topphoff, P.A. Nelson, R. M. Stroud, B.A. Cree, B. A., S.S. Zamvil, Aquaporin 4-specific T cells in neuromyelitis optica exhibit a Th17 bias and recognize Clostridium ABC transporter, Annals of neurology, 72(1), 2012, pp. 53–64. (https://doi.org/ 10.1002/ana.23651)
[6] S. V. Alves-Leon, M.L. Veluttini-Pimentel, M. E. Gouveia, F. R. Malfetano, E. L. Gaspareto, M. P. Alvarenga, I. Frugulhetti, T. Quirico-Santos, Acute disseminated encephalomyelitis: Clinical features, HLA DRB1*1501, HLA DRB1*1503, HLA DQA1*0102, HLA DQB1*0602, and HLA DPA1*0301 allelic association study, Arquivos de neuro-psiquiatria, 67(3A), 2009, pp. 643–651. (https://doi.org/10.1590/s0004-282x20090004000 13)
[7] M. Matiello, J. Schaefer-Klein, D. G. Brum, E. J. Atkinson, O. H. Kantarci, B. G. Weinshenker, NMO genetics collaborators, HLA-DRB1*1501 tagging rs3135388 polymorphism is not associated with neuromyelitis optica, Multiple sclerosis (Houndmills, Basingstoke, England), 16(8), 2010, pp. 981–984. (https://doi.org/10.1177/1352458510 374340)
[8] D. G. Brum, A. A. Barreira, A. C. dos Santos, D. R. Kaimen-Maciel, M. Matiello, R. M. Costa, N. H. Deghaide, L. S. Costa, P.L ouzada-Junior, P. R. Diniz, E. R. Comini-Frota, C. T. Mendes-Junior, E. A. Donadi, HLA-DRB association in neuromyelitis optica is different from that observed in multiple sclerosis. HLA-DRB association in neuromyelitis optica is different from that observed in multiple sclerosis, Multiple sclerosis (Houndmills, Basingstoke, England), 16(1), 2010, pp. 21–29. (https://doi.org/10.1177/1352458509350741)
[9] R. Kogay, C. Schönbach, Epitope Predictions, in Encyclopedia of Bioinformatics and Computational Biology, Elsevier, 2019, pp. 952–971. (https://doi.org/10.1016/B978-0-12-809633-8.20248-3)
[10] M. Rojas, P. Restrepo-Jiménez, D. M. Monsalve, Y. Pacheco, Y. Acosta-Ampudia, C. Ramírez-Santana, P. S. C. Leung, A. A. Ansari, M. E. Gershwin, J. M. Anaya, Molecular mimicry and autoimmunity, Journal of autoimmunity, 95, 2018, pp. 100–123. (https://doi.org/10.1016/j.jaut.2018. 10.012)
[11] R. van der Lee, M. Buljan, B. Lang, , R. J. Weatheritt, G. W. Daughdrill, A. K. Dunker, M. Fuxreiter, J. Gough, J. Gsponer, D. T. Jones, P. M. Kim, R. W. Kriwacki, C. J. Oldfield, R. V. Pappu, P. Tompa, V. N. Uversky, P. E. Wright, M. M. Babu, Classification of intrinsically disordered regions and proteins, Chemical reviews, 114(13), 2014, pp. 6589–6631. (https://doi.org/10.1021/ cr400525m)
[12] A. Mohan, C. J. Oldfield, P. Radivojac, V. Vacic, M. S. Cortese, A. K. Dunker, V. N. Uversky, Analysis of molecular recognition features (MoRFs), Journal of molecular biology, 362(5), 2006, pp. 1043–1059. (https://doi.org/10.1016/ j.jmb.2006.07.087)
[13] N.E. Davey, K. Van Roey, R. J. Weatheritt, G. Toedt, B. Uyar, B. Altenberg, A. Budd, F. Diella, H. Dinkel, T. J. Gibson, Attributes of short linear motifs, Molecular bioSystems, 8(1), 2012, pp. 268–281. (https://doi.org/10.1039/c1mb05231d)
[14] N. E. Davey, G. Travé, T. J. Gibson, How viruses hijack cell regulation, Trends in biochemical sciences, 36(3), 2011, pp. 159–169, (https://doi.org/10.1016/j.tibs.2010.10.002)
[15] T. D. Goddard, C. C. Huang, E. C. Meng, E.F. Pettersen, G. S. Couch, J. H. Morris, Thomas E. Ferrin, UCSF ChimeraX : Meeting modern challenges in visualization and analysis, Protein Science, 27, 2018, pp. 14–25. (https://doi.org/10. 1002/pro.3235)
[16] J. Neefjes, M. L. M. Jongsma, P. Paul, and O. Bakke, Towards a systems understanding of MHC class I and MHC class II antigen presentation, Nature reviews. Immunology, 11(12), 2011, pp. 823–836. (https://doi.org/10.1038/nri3084)
[17] N. Kerlero De Rosb, M. Hoffman, I. Mendel, I. Yust, J. Kaye, R. Bakimer, S. Flechter, O. Abramsky, R. Milo, A. Karni, A. Ben-Nun, “Predominance of the autoimmune response to myelin oligodendrocyte glycoprotein (MOG) in multiple sclerosis: Reactivity to the extracellular domain of MOG is directed against three main regions, European journal of immunology, 27(11), 1997, pp. 3059–3069. (https://doi.org/10.1002/eji. 1830271144)
[18] R. Weissert, J. Kuhle, K. L. de Graaf, W. Wienhold, M. M. Herrmann, C. Müller, T. G. Forsthuber, K. H. Wiesmüller, A. Melms, High Immunogenicity of Intracellular Myelin Oligodendrocyte Glycoprotein Epitopes, Journal of immunology (Baltimore, Md. : 1950), 169(1), 2002, pp. 548–556. (https://doi.org/10.4049/ jimmunol.169.1.548)
[19] L. S. Hofer, M. Ramberger, V. Gredler, A. S. Pescoller, K. Rostásy, M. Sospedra, H. Hegen, T. Berger, A. Lutterotti, M. Reindl, Comparative Analysis of T-Cell Responses to Aquaporin-4 and Myelin Oligodendrocyte Glycoprotein in Inflammatory Demyelinating Central Nervous System Diseases. Frontiers in immunology, 11, 2020. (https://doi.org/10.3389/fimmu.2020.01188)
[20] N. Matsuya, M. Komori, K. Nomura, S. Nakane, T. Fukudome, H. Goto, H. Shiraishi, K. P. Wandinger, H. Matsuo, T. Kondo, Increased T-cell immunity against aquaporin-4 and proteolipid protein in neuromyelitis optica, International immunology, 23(9), 2011, pp. 565–573. (https:// doi.org/10.1093/intimm/dxr056)