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Use of the VH6-1 gene segment to code for anti-interleukin-18 autoantibodies in multiple sclerosis

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Abstract

We investigated whether levels and repertoires of anti-interleukin-18 (IL-18) autoantibodies (auto-Abs) differ in multiple sclerosis (MS) patients and healthy donors (HDs). IL-18 concentration in MS patients’ sera was higher than in HD, but the level of anti-IL-18 auto-Abs was lower in MS patients. Correlation patterns of IL-18/anti-IL-18 auto-Abs system differed in HD and MS patients, so we have compared segment composition of the anti-IL-18 single-chain variable fragments (scFvs) selected from MS and naïve phage display libraries. Considerable differences between anti-IL-18 auto-Abs of these libraries were found. MS panel contained auto-Abs displaying both signs of “fetal” and somatically hypermutated repertoires. Naïve panel mainly contained the naïve antibodies. These variations from the norm are possible results of abnormal regulation of the repertoire perhaps determined by remodeling of the molecular mechanisms involved in the V(D)J recombination and/or abnormal selection by antigen in MS pathogenesis.

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References

  • Altschul SF, Madden TL, Schäffer AA, Zhang J, Zhang Z, Miller W, Lipman DJ (1997) Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res 25:3389–3402

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Anderson G, Rodriguez M (2011) Multiple sclerosis, seizures, and antiepileptics: role of IL-18, IDO, and melatonin. Eur J Neurol 18:680–685

    Article  CAS  PubMed  Google Scholar 

  • Aringer M, Smolen JS (2004) Tumour necrosis factor and other proinflammatory cytokines in systemic lupus erythematosus: a rationale for therapeutic intervention. Lupus 13:344–347

    Article  CAS  PubMed  Google Scholar 

  • Arnaout R, Lee W, Cahill P, Honan T, Sparrow T, Weiand M, Nusbaum C, Rajewsky K, Koralov SB (2011) High-resolution description of antibody heavy-chain repertoires in humans. PLoS One 6, e22365

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Baer R, Bankier AT, Biggin MD, Deininger PL, Farrell PJ, Gibson TJ, Hatfull G, Hudson GS, Satchwell SC, Séguin C et al (1984) DNA sequence and expression of the B95-8 Epstein-Barr virus genome. Nature 310:207–211

    Article  CAS  PubMed  Google Scholar 

  • Batanova TA, Ulitin AB, Morozova VV, Laman AG, Zhirakovskaia EV, Dubrovskaia VV, Brovko FA, Tikunova NV (2006) Construction and characterization of combinatorial naive phage library of human scFvs. Mol Gen Mikrobiol Virusol 3:35–41

    PubMed  Google Scholar 

  • Benoit S, Toksoy A, Bröcker EB, Gillitzer R, Goebeler M (2004) Treatment of recalcitrant pustular psoriasis with infliximab: effective reduction of chemokine expression. Br J Dermatol 150:1009–1012

    Article  CAS  PubMed  Google Scholar 

  • Berman JE, Nickerson KG, Pollock RR, Barth JE, Schuurman RK, Knowles DM, Chess L, Alt FW (1991) VH gene usage in humans: biased usage of the VH6 gene in immature B lymphoid cells. Eur J Immunol 21:1311–1314

    Article  CAS  PubMed  Google Scholar 

  • Bossù P, Ciaramella A, Salani F, Vanni D, Palladino I, Caltagirone C, Scapigliati G (2010) Interleukin-18, from neuroinflammation to Alzheimer’s disease. Curr Pharm Des 16:4213–4224

    Article  PubMed  Google Scholar 

  • Brezinschek HP, Brezinschek RI, Lipsky PE (1995) Analysis of the heavy chain repertoire of human peripheral B cells using single-cell polymerase chain reaction. J Immunol 155:190–202

    CAS  PubMed  Google Scholar 

  • Brochet X, Lefranc MP, Giudicelli V (2008) IMGT/V-QUEST: the highly customized and integrated system for IG and TR standardized V-J and V-D-J sequence analysis. Nucleic Acids Res 36:W503–W508

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Calvani N, Richards HB, Tucci M, Pannarale G, Silvestris F (2004) Up-regulation of IL-18 and predominance of a Th1 immune response is a hallmark of lupus nephritis. Clin Exp Immunol 138:171–178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Caminero A, Comabella M, Montalban X (2011) Tumor necrosis factor alpha (TNF-α), anti-TNF-α and demyelination revisited: an ongoing story. J Neuroimmunol 234:1–6

    Article  CAS  PubMed  Google Scholar 

  • Clark LA, Ganesan S, Papp S, van Vlijmen HW (2006) Trends in antibody sequence changes during the somatic hypermutation process. J Immunol 177:333–340

    Article  CAS  PubMed  Google Scholar 

  • Cuisinier AM, Guigou V, Boubli L, Fougereau M, Tonnelle C (1989) Preferential expression of VH5 and VH6 immunoglobulin genes in early human B-cell ontogeny. Scand J Immunol 30:493–497

    Article  CAS  PubMed  Google Scholar 

  • de Kruif J, Kramer A, Visser T, Clements C, Nijhuis R, Cox F, van der Zande V, Smit R, Pinto D, Throsby M, Logtenberg T (2009) Human immunoglobulin repertoires against tetanus toxoid contain a large and diverse fraction of high-affinity promiscuous V(H) genes. J Mol Biol 387:548–558

    Article  PubMed  Google Scholar 

  • Dinarello CA (1999) IL-18: a TH1-inducing, proinflammatory cytokine and new member of the IL-1 family. J Allergy Clin Immunol 103:11–24

    Article  CAS  PubMed  Google Scholar 

  • Dinarello CA (2006) Interleukin 1 and interleukin 18 as mediators of inflammation and the aging process. Am J Clin Nutr 83:447S–455S

    CAS  PubMed  Google Scholar 

  • Disanto G, Morahan JM, Barnett MH, Giovannoni G, Ramagopalan SV (2012) The evidence for a role of B cells in multiple sclerosis. Neurology 78:823–832

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dotto GP, Horiuchi K, Zinder ND (1984) The functional origin of bacteriophage f1 DNA replication. Its signals and domains. J Mol Biol 172:507–521

    Article  CAS  PubMed  Google Scholar 

  • Ehrenmann F, Kaas Q, Lefranc MP (2010) IMGT/3Dstructure-DB and IMGT/DomainGapAlign: a database and a tool for immunoglobulins or antibodies, T cell receptors, MHC, IgSF and MhcSF. Nucleic Acids Res 38:D301–D307

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Elkarim RA, Mustafa M, Kivisäkk P, Link H, Bakhiet M (1998) Cytokine autoantibodies in multiple sclerosis, aseptic meningitis and stroke. Eur J Clin Investig 28:295–299

    Article  CAS  Google Scholar 

  • Foreman AL, Van de Water J, Gougeon ML, Gershwin ME (2007) B cells in autoimmune diseases: insights from analyses of immunoglobulin variable (Ig V) gene usage. Autoimmun Rev 6:387–401

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gabibov AG, Belogurov AA Jr, Lomakin YA, Zakharova MY, Avakyan ME, Dubrovskaya VV, Smirnov IV, Ivanov AS, Molnar AA, Gurtsevitch VE, Diduk SV, Smirnova KV, Avalle B, Sharanova SN, Tramontano A, Friboulet A, Boyko AN, Ponomarenko NA, Tikunova NV (2011) Combinatorial antibody library from multiple sclerosis patients reveals antibodies that cross-react with myelin basic protein and EBV antigen. FASEB J 25:4211–4221

    Article  CAS  PubMed  Google Scholar 

  • Gavilondo JV, Larrick JW (2000) Antibody engineering at the millennium. Biotechniques 29:128–132

    CAS  PubMed  Google Scholar 

  • Hamasaki T, Hashiguchi S, Ito Y, Kato Z, Nakanishi K, Nakashima T, Sugimura K (2005) Human anti-human IL-18 antibody recognizing the IL-18-binding site 3 with IL-18 signaling blocking activity. J Biochem 138:433–442

    Article  CAS  PubMed  Google Scholar 

  • Hershberg U, Uduman M, Shlomchik MJ, Kleinstein SH (2008) Improved methods for detecting selection by mutation analysis of Ig V region sequences. Int Immunol 20:683–694

    Article  CAS  PubMed  Google Scholar 

  • Hillörn V, Söderström I, Feld S, Cilio C, Forsgren S, Hägg E, Lundkvist I, Holmberg D (1997) Aberrant V(H) gene utilization in patients with established insulin dependent diabetes mellitus. J Autoimmun 10:157–163

    Article  PubMed  Google Scholar 

  • Holtmann MH, Douni E, Schütz M, Zeller G, Mudter J, Lehr HA, Gerspach J, Scheurich P, Galle PR, Kollias G, Neurath MF (2002) Tumor necrosis factor-receptor 2 is up-regulated on lamina propria T cells in Crohn’s disease and promotes experimental colitis in vivo. Eur J Immunol 32:3142–3151

    Article  CAS  PubMed  Google Scholar 

  • Kawanokuchi J, Mizuno T, Takeuchi H, Kato H, Wang J, Mitsuma N, Suzumura A (2006) Production of interferon-gamma by microglia. Mult Scler 12:558–564

    Article  CAS  PubMed  Google Scholar 

  • Kramer RA, Marissen WE, Goudsmit J, Visser TJ, Clijsters-Van der Horst M, Bakker AQ, de Jong M, Jongeneelen M, Thijsse S, Backus HH, Rice AB, Weldon WC, Rupprecht CE, Dietzschold B, Bakker AB, de Kruif J (2005) The human antibody repertoire specific for rabies virus glycoprotein as selected from immune libraries. Eur J Immunol 35:2131–2145

    Article  CAS  PubMed  Google Scholar 

  • Lomakin YA, Zakharova MY, Stepanov AV, Dronina MA, Smirnov IV, Bobik TV, Pyrkov AY, Tikunova NV, Sharanova SN, Boitsov VM, Vyazmin SY, Kabilov MR, Tupikin AE, Krasnov AN, Bykova NA, Medvedeva YA, Fridman MV, Favorov AV, Ponomarenko NA, Dubina MV, Boyko AN, Vlassov VV, Belogurov AA Jr, Gabibov AG (2014) Heavy-light chain interrelations of MS-associated immunoglobulins probed by deep sequencing and rational variation. Mol Immunol 62:305–314

    Article  CAS  PubMed  Google Scholar 

  • Lossos IS, Tibshirani R, Narasimhan B, Levy R (2000) The inference of antigen selection on Ig genes. J Immunol 165:5122–5126

    Article  CAS  PubMed  Google Scholar 

  • Maher SG, Romero-Weaver AL, Scarzello AJ, Gamero AM (2007) Interferon: cellular executioner or white knight? Curr Med Chem 14:1279–1289

    Article  CAS  PubMed  Google Scholar 

  • Manheimer-Lory A, Katz JB, Pillinger M, Ghossein C, Smith A, Diamond B (1991) Molecular characteristics of antibodies bearing an anti-DNA-associated idiotype. J Exp Med 174:1639–1652

    Article  CAS  PubMed  Google Scholar 

  • McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD, McFarland HF, Paty DW, Polman CH, Reingold SC, Sandberg-Wollheim M, Sibley W, Thompson A, van den Noort S, Weinshenker BY, Wolinsky JS (2001) Recommended diagnostic criteria for multiple sclerosis: guidelines from the international panel on the diagnosis of multiple sclerosis. Ann Neurol 50:121–127

    Article  CAS  PubMed  Google Scholar 

  • Meager A, Wadhwa M, Dilger P, Bird C, Thorpe R, Newsom-Davis J, Willcox N (2003) Anti-cytokine autoantibodies in autoimmunity: preponderance of neutralizing autoantibodies against interferon-alpha, interferon-omega and interleukin-12 in patients with thymoma and/or myasthenia gravis. Clin Exp Immunol 132:128–136

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mockridge CI, Chapman CJ, Spellerberg MB, Sheth B, Fleming TP, Isenberg DA, Stevenson FK (1998) Sequence analysis of V(4–34)-encoded antibodies from single B cells of two patients with systemic lupus erythematosus (SLE). Clin Exp Immunol 114:129–136

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Näsman I, Lundkvist I (1996) Evidence for oligoclonal diversification of the VH6-containing immunoglobulin repertoire during reconstitution after bone marrow transplantation. Blood 87:2795–2804

    PubMed  Google Scholar 

  • Nicoletti F, Di Marco R, Mangano K, Patti F, Reggio E, Nicoletti A, Bendtzen K, Reggio A (2001) Increased serum levels of interleukin-18 in patients with multiple sclerosis. Neurology 57:342–344

    Article  CAS  PubMed  Google Scholar 

  • Nissim A, Hoogenboom HR, Tomlinson IM, Flynn G, Midgley C, Lane D, Winter G (1994) Antibody fragments from a “single pot” phage display library as immunochemical reagents. EMBO J 13:692–698

    CAS  PubMed  PubMed Central  Google Scholar 

  • Novick D, Kim SH, Fantuzzi G, Reznikov LL, Dinarello CA, Rubinstein M (1999) Interleukin-18 binding protein: a novel modulator of the Th1 cytokine response. Immunity 10:127–136

    Article  CAS  PubMed  Google Scholar 

  • Okamura H, Tsutsi H, Komatsu T, Yutsudo M, Hakura A, Tanimoto T, Torigoe K, Okura T, Nukada Y, Hattori K et al (1995) Cloning of a new cytokine that induces IFN-gamma production by T cells. Nature 378:88–91

    Article  CAS  PubMed  Google Scholar 

  • Owens GP, Ritchie AM, Burgoon MP, Williamson RA, Corboy JR, Gilden DH (2003) Single-cell repertoire analysis demonstrates that clonal expansion is a prominent feature of the B cell response in multiple sclerosis cerebrospinal fluid. J Immunol 171:2725–2733

    Article  CAS  PubMed  Google Scholar 

  • Perera WS, Moss MT, Urbaniak SJ (2000) Comparison between hybridoma and Fab/phage anti-RhD: their V gene usage and pairings. Dis Markers 16:15–19

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Roark JH, Bussel JB, Cines DB, Siegel DL (2002) Genetic analysis of autoantibodies in idiopathic thrombocytopenic purpura reveals evidence of clonal expansion and somatic mutation. Blood 100:1388–1398

    CAS  PubMed  Google Scholar 

  • Shajarian M, Alsahebfosoul F, Etemadifar M, Sedaghat N, Shahbazi M, Firouzabadi FP, Dezashibi HM (2015) IL-23 plasma level measurement in relapsing remitting multiple sclerosis (RRMS) patients compared to healthy subjects. Immunol Investig 44:36–44

    Article  CAS  Google Scholar 

  • Sivalingam SP, Thumboo J, Vasoo S, Thio ST, Tse C, Fong KY (2007) In vivo pro- and anti-inflammatory cytokines in normal and patients with rheumatoid arthritis. Ann Acad Med Singap 36:96–99

    PubMed  Google Scholar 

  • Sospedra M, Martin R (2005) Immunology of multiple sclerosis. Annu Rev Immunol 23:683–747

    Article  CAS  PubMed  Google Scholar 

  • Souto-Carneiro MM, Sims GP, Girschik H, Lee J, Lipsky PE (2005) Developmental changes in the human heavy chain CDR3. J Immunol 175:7425–7436

    Article  CAS  PubMed  Google Scholar 

  • Takeda K, Tsutsui H, Yoshimoto T, Adachi O, Yoshida N, Kishimoto T, Okamura H, Nakanishi K, Akira S (1998) Defective NK cell activity and Th1 response in IL-18-deficient mice. Immunity 8:383–390

    Article  CAS  PubMed  Google Scholar 

  • Tamura K, Peterson D, Peterson N, Stecher G, Nei M, Kumar S (2011) MEGA5: molecular evolutionary genetics analysis using maximum likelihood, evolutionary distance, and maximum parsimony methods. Mol Biol Evol 28:2731–2739

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tyumentseva MA, Morozova VV, Lebedev LR, Babkin IV, Tikunova NV (2013) Presence of aberrant VH6 domains in anti-interferon-γ autoantibodies in multiple sclerosis. Hum Antibodies 22:31–49

    CAS  PubMed  Google Scholar 

  • Uduman M, Yaari G, Hershberg U, Stern JA, Shlomchik MJ, Kleinstein SH (2011) Detecting selection in immunoglobulin sequences. Nucleic Acids Res 39:W499–W504

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • van de Loo FA (2011) Soluble IL-18 receptor complex: a new star in the firmament of rheumatoid arthritis diagnosis? Arthritis Res Ther 13:111

    Article  PubMed  PubMed Central  Google Scholar 

  • van Dijk-Härd I, Feld S, Holmberg D, Lundkvist I (1999) Increased utilization of the VH6 gene family in patients with autoimmune idiopathic thrombocytopenic purpura. J Autoimmun 12:57–63

    Article  PubMed  Google Scholar 

  • Vikhrova MA, Shveygert MV, Khrapov EA, Filipenko ML, Gileva IP, Morozova VV, Tikunova NV (2010) Selection of naturally occurring autoantibodies to interleukin-18 from phage display library. Hum Antibodies 19:71–78

    CAS  PubMed  Google Scholar 

  • Watanabe M, Uchida K, Nakagaki K, Trapnell BC, Nakata K (2010) High avidity cytokine autoantibodies in health and disease: pathogenesis and mechanisms. Cytokine Growth Factor Rev 21:263–273

    Article  CAS  PubMed  Google Scholar 

  • Yakushenko EV, Lopatnikova JA, Khrapov EA, Voronina EN, Filipenko ML, Kozlova JN, Pustoshilova NM, Shurligina AV et al (2007) Preparation of recombinant interleukin-18 and study of its antitumoral activity. Bulletin SB RAMN 2:23–26

    Google Scholar 

  • Yousfi Monod M, Giudicelli V, Chaume D, Lefranc MP (2004) IMGT/JunctionAnalysis: the first tool for the analysis of the immunoglobulin and T cell receptor complex V-J and V-D-J junctions. Bioinformatics 20:i379–i385

    Article  PubMed  Google Scholar 

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Acknowledgments

The authors thank Professor Aleksandr G. Gabibov, corresponding member of Russian Academy of Sciences, for the fruitful discussion during this study. This work was supported in part by the Interdisciplinary Integration of the Siberian Branch of the Russian Academy of Sciences grant no. 139 and grant no. 5.38 of the program “Fundamental sciences to medicine” of the Siberian Branch of the Russian Academy of Sciences.

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Authors and Affiliations

  1. Siberian Division of Russian Academy of Sciences, Institute of Chemical Biology and Fundamental Medicine, Novosibirsk, 630090, Russia

    Marina Tiumentseva, Vera Morozova, Aleksandr Zakabunin, Maksim Filipenko & Nina Tikunova

  2. Regional Centre of MS and Other Autoimmune Diseases of the Nervous System, State Novosibirsk Regional Clinical Hospital, Novosibirsk, 630087, Russia

    Denis Korobko & Nadezhda Malkova

  3. Novosibirsk State Medical University, Novosibirsk, 630091, Russia

    Nadezhda Malkova

  4. The International Biotechnology Center (IBC) “Generium”, Volginsky Village, Petushinski District, 601125, Russia

    Marina Tiumentseva

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  1. Marina Tiumentseva
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  2. Vera Morozova
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  3. Aleksandr Zakabunin
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Correspondence to Marina Tiumentseva.

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The study was approved by the Ethics Committee of State Novosibirsk Regional Clinical Hospital, and informed consents were obtained from all participants.

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Tiumentseva, M., Morozova, V., Zakabunin, A. et al. Use of the VH6-1 gene segment to code for anti-interleukin-18 autoantibodies in multiple sclerosis. Immunogenetics 68, 237–246 (2016). https://doi.org/10.1007/s00251-015-0895-5

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