Identification of novel non-myelin biomarkers in multiple sclerosis using an improved phage-display approach
Autoři:
Andrea Cortini aff001; Sara Bembich aff001; Lorena Marson aff001; Eleonora Cocco aff002; Paolo Edomi aff001
Působiště autorů:
Department of Life Sciences, University of Trieste, Trieste, Italy
aff001; Multiple Sclerosis Center, University of Cagliari/ATS Sardegna, Cagliari, Italy
aff002
Vyšlo v časopise:
PLoS ONE 14(12)
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pone.0226162
Souhrn
Although the etiology of multiple sclerosis is not yet understood, it is accepted that its pathogenesis involves both autoimmune and neurodegenerative processes, in which the role of autoreactive T-cells has been elucidated. Instead, the contribution of humoral response is still unclear, even if the presence of intrathecal antibodies and B-cells follicle-like structures in meninges of patients has been demonstrated. Several myelin and non-myelin antigens have been identified, but none has been validated as humoral biomarker. In particular autoantibodies against myelin proteins have been found also in healthy individuals, whereas non-myelin antigens have been implicated in neurodegenerative phase of the disease.
To provide further putative autoantigens of multiple sclerosis, we investigated the antigen specificity of immunoglobulins present both in sera and in cerebrospinal fluid of patients using phage display technology in a new improved format. A human brain cDNA phage display library was constructed and enriched for open-read-frame fragments. This library was selected against pooled and purified immunoglobulins from cerebrospinal fluid and sera of multiple sclerosis patients. The antigen library was also screened against an antibody scFv library obtained from RNA of B cells purified from the cerebrospinal fluid of two relapsing remitting patients. From all biopanning a complex of 14 antigens were identified; in particular, one of these antigens, corresponding to DDX24 protein, was present in all selections. The ability of more frequently isolated antigens to discriminate between sera from patients with multiple sclerosis or other neurological diseases was investigated. The more promising novel candidate autoantigens were DDX24 and TCERG1. Both are implicated in RNA modification and regulation which can be altered in neurodegenerative processes. Therefore, we propose that they could be a marker of a particular disease activity state.
Klíčová slova:
B cells – Bacteriophages – Cerebrospinal fluid – DNA libraries – DNA sequence analysis – Multiple sclerosis – Phage display
Zdroje
1. Compston A, Coles A. Multiple sclerosis. Lancet. 2008; 372(9648): 1502–1517. doi: 10.1016/S0140-6736(08)61620-7 18970977
2. Dendrou CA, Fugger L, Friese MA. Immunopathology of multiple sclerosis. Nat Rev Immunol. 2015; 15: 545–558. doi: 10.1038/nri3871 26250739
3. Hauser SL, Waubant E, Arnold DL, Vollmer T, Antel J, Fox RJ, et al. B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med. 2008; 358(7): 676–688. doi: 10.1056/NEJMoa0706383 18272891
4. Barr TA, Shen P, Brown S, Lampropoulou V, Roch T, Lawrie S, et al. B cell depletion therapy ameliorates autoimmune disease through ablation of IL-6-producing B cells. J Exp Med. 2012; 209: 1001–1010. doi: 10.1084/jem.20111675 22547654
5. Frischer JM, Bramow S, Dal-Bianco A, Lucchinetti CF, Rauschka H, Schmidbauer M, et al. The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain. 2009; 132: 1175–89. doi: 10.1093/brain/awp070 19339255
6. Stern JNH, Yaari G, Vander Heiden JA, Church G, Donahue WF, Hintzen RQ, et al. B cells populating the multiple sclerosis brain mature in the draining cervical lymph nodes. Sci Transl Med. 2014; 6(248): 248ra107. doi: 10.1126/scitranslmed.3008879 25100741
7. Qin Y, Duquette P, Zhang Y, Talbot P, Poole R, Antel J. Clonal expansion and somatic hypermutation of V(H) genes of B cells from cerebrospinal fluid in multiple sclerosis. J Clin Invest. 1998; 102: 1045–1050. doi: 10.1172/JCI3568 9727074
8. Colombo M, Dono M, Gazzola P, Roncella S, Valetto A, Chiorazzi N, et al. Accumulation of clonally related B lymphocytes in the cerebrospinal fluid of multiple sclerosis patients. J Immunol. 2000; 164: 2782–2789. doi: 10.4049/jimmunol.164.5.2782 10679121
9. Owens GP, Bennett JL, Lassmann H, O’Connor KC, Ritchie AM, Shearer A, et al. Antibodies produced by clonally expanded plasma cells in multiple sclerosis cerebrospinal fluid. Ann Neurol. 2009; 65: 639–649. doi: 10.1002/ana.21641 19557869
10. Serafini B, Rosicarelli B, Magliozzi R, Stigliano E, Aloisi F. Detection of ectopic B-cell follicles with germinal centers in the meninges of patients with secondary progressive multiple sclerosis. Brain Pathol. 2004; 14: 164–174. Available from: https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1750-3639.2004.tb00049.x 15193029
11. Pikor NB, Prat A, Bar-Or A, Gommerman JL. Meningeal tertiary lymphoid tissues and multiple sclerosis: a gathering place for diverse types of immune cells during CNS autoimmunity. Front Immunol. 2015; 6: 657. doi: 10.3389/fimmu.2015.00657 26793195
12. Levin MC, Lee S, Gardner LA, Shin Y, Douglas JN, Cooper C. Autoantibodies to non-myelin antigens as contributors to the pathogenesis of multiple sclerosis. J Clin Cell Immunol. 2013; 4. doi: 10.4172/2155-9899.1000148 24363960
13. Salapa H, Lee S, Shin Y, Levin M. Contribution of the Degeneration of the Neuro-Axonal Unit to the Pathogenesis of Multiple Sclerosis. Brain Sci. 2017; 7: 69. doi: 10.3390/brainsci7060069 28629158
14. Trapp BD, Nave K-A. Multiple Sclerosis: An Immune or Neurodegenerative Disorder? Annu Rev Neurosci. 2008; 31: 247–269. doi: 10.1146/annurev.neuro.30.051606.094313 18558855
15. Lassmann H, van Horssen J, Mahad D. Progressive multiple sclerosis: pathology and pathogenesis. Nat Rev Neurol. 2012;8: 647–656. doi: 10.1038/nrneurol.2012.168 23007702
16. Lee S, Xu L, Shin Y, Gardner L, Hartzes A, Dohan FC, et al. A potential link between autoimmunity and neurodegeneration in immune-mediated neurological disease. J Neuroimmunol. 2011; 235: 56–69. doi: 10.1016/j.jneuroim.2011.02.007 21570130
17. Eikelenboom MJ, Petzold A, Lazeron RHC, Silber E, Sharief M, Thompson EJ, et al. Multiple sclerosis: Neurofilament light chain antibodies are correlated to cerebral atrophy. Neurology. 2003; 60: 219–223. doi: 10.1212/01.wnl.0000041496.58127.e3 12552034
18. Silber E, Semra YK, Gregson NA, Sharief MK. Patients with progressive multiple sclerosis have elevated antibodies to neurofilament subunit. Neurology. 2002; 58: 1372–1381. doi: 10.1212/wnl.58.9.1372 12011283
19. Mathey EK, Derfuss T, Storch MK, Williams KR, Hales K, Woolley DR, et al. Neurofascin as a novel target for autoantibody-mediated axonal injury. 2007; 204: 2363–2372. doi: 10.1084/jem.20071053 17846150
20. N Douglas J, Gardner LA, Levin MC. Antibodies to an intracellular antigen penetrate neuronal cells and cause deleterious effects. J Clin Cell Immunol. 2013; 4. doi: 10.4172/2155-9899.1000134
21. Srivastava R, Aslam M, Kalluri R, Schirmer L, Buck D, Tackenberg B, et al. Potassium channel KIR4.1 as an immune target in multiple sclerosis. N Engl J Med. 2012; 367: 115–123. doi: 10.1056/NEJMoa1110740 22784115
22. Teunissen CE, Malekzadeh A, Leurs C, Bridel C, Killestein J. Body fluid biomarkers for multiple sclerosis—the long road to clinical application. Nat Rev Neurol. 2015; 11: 585–596. doi: 10.1038/nrneurol.2015.173 26392381
23. Housley WJ, Pitt D, Hafler DA. Biomarkers in multiple sclerosis. Clin Immunol. 2015; 161: 51–58. doi: 10.1016/j.clim.2015.06.015 26143623
24. Malini E, Maurizio E, Bembich S, Sgarra R, Edomi P, Manfioletti G. HMGA interactome: new insights from phage display technology. Biochemistry. 2011; 50: 3462–3468. doi: 10.1021/bi200101f 21417337
25. Sblattero D, Bradbury A. Exploiting recombination in single bacteria to make large phage antibody libraries. Nat Biotechnol. 2000; 18(1): 75–80. doi: 10.1038/71958 10625396
26. Sblattero D, Bradbury A. A definitive set of oligonucleotide primers for amplifying human V regions. Immunotechnology. 1998; 3: 271–278. doi: 10.1016/s1380-2933(97)10004-5 9530560
27. Owens GP, Ritchie AM, Burgoon MP, Williamson RA, Corboy JR, Gilden DH. Single-cell repertoire analysis demonstrates that clonal expansion is a prominent feature of the B cell response in multiple sclerosis cerebrospinal fluid. J Immunol. 2003; 171: 2725–2733. doi: 10.4049/jimmunol.171.5.2725 12928426
28. Cortese I, Tafit R, Grimaldit LME, Martinot G, Nicosiat A, Corteset R. Identification of peptides specific for cerebrospinal fluid antibodies in multiple sclerosis by using phage libraries. Med Sci. 1996; 93: 11063–11067. doi: 10.1073/pnas.93.20.11063 8855309
29. Owens G, Burgoon M, Devlin M, Gilden D. Strategies to identify sequences or antigens unique to multiple sclerosis. Mult Scler J. 1996; 2: 184–194. doi: 10.1177/135245859600200404 9345372
30. Yu X, Gilden DH, Ritchie AM, Burgoon MP, Keays KM, Owens GP. Specificity of recombinant antibodies generated from multiple sclerosis cerebrospinal fluid probed with a random peptide library. J Neuroimmunol. 2006; 172: 121–131. doi: 10.1016/j.jneuroim.2005.11.010 16371235
31. Cortese I, Capone S, Tafi R, Grimaldi LM, Nicosia A, Cortese R. Identification of peptides binding to IgG in the CSF of Multiple Sclerosis patients. Mult Scler J. 1998; 4: 31–36. doi: 10.1177/135245859800400108 9532590
32. Cortese I, Capone S, Luchetti S, Grimaldi LM, Nicosia A, Cortese R. CSF-enriched antibodies do not share specificities among MS patients. Mult Scler J. 1998; 4: 118–123. doi: 10.1177/135245859800400305 9762658
33. Somers V, Govarts C, Somers K, Hupperts R, Medaer R, Stinissen P. Autoantibody profiling in multiple sclerosis reveals novel antigenic candidates. J Immunol. 2008; 180: 3957–3963. doi: 10.4049/jimmunol.180.6.3957 18322204
34. Yu X, Gilden D, Schambers L, Barmina O, Burgoon M, Bennett J, et al. Peptide reactivity between multiple sclerosis (MS) CSF IgG and recombinant antibodies generated from clonally expanded plasma cells in MS CSF. J Neuroimmunol. 2011; 233: 192–203. doi: 10.1016/j.jneuroim.2010.11.007 21176973
35. Renoux AJ, Todd PK. Neurodegeneration the RNA way. Prog Neurobiol. 2012; 97: 173–189. doi: 10.1016/j.pneurobio.2011.10.006 22079416
36. Gallo J-M, Jin P, Thornton CA, Lin H, Robertson J, D’Souza I, et al. The role of RNA and RNA processing in neurodegeneration. J Neurosci. 2005; 25: 10372–10375. doi: 10.1523/JNEUROSCI.3453-05.2005 16280575
37. Wolozin B, Apicco D. RNA binding proteins and the genesis of neurodegenerative diseases. Adv Exp Med Biol. 2015; 822:11–15. doi: 10.1007/978-3-319-08927-0_3 25416971
38. Montes M, Coiras M, Becerra S, Moreno-Castro C, Mateos E, Majuelos J, et al. Functional consequences for apoptosis by Transcription Elongation Regulator 1 (TCERG1)-mediated Bcl-x and Fas/CD95 alternative splicing. PLoS One. 2015; 10(10):e0139812. doi: 10.1371/journal.pone.0139812 26462236
39. Muñoz-Cobo JP, Sánchez-Hernández N, Gutiérrez S, El Yousfi Y, Montes M, Gallego C, et al. Transcriptional Elongation Regulator 1 affects transcription and splicing of genes associated with cellular morphology and cytoskeleton dynamics and is required for neurite outgrowth in neuroblastoma cells and primary neuronal cultures. Mol Neurobiol. 2017; 54(10): 7808–7823. doi: 10.1007/s12035-016-0284-6 27844289
40. Arango M, Holbert S, Zala D, Brouillet E, Pearson J, Régulier E, et al. CA150 expression delays striatal cell death in overexpression and knock-in conditions for mutant huntingtin neurotoxicity. J Neurosci. 2006; 26: 4649–4659. doi: 10.1523/JNEUROSCI.5409-05.2006 16641246
41. Pons M, Prieto S, Miguel L, Frebourg T, Campion D, Suñé C, Lecourtois M. Identification of TCERG1 as a new genetic modulator of TDP-43 production in Drosophila. Acta Neuropathol Commun. 2018; 6: 138. doi: 10.1186/s40478-018-0639-5 30541625
42. Ma Z, Moore R, Xu X, Barber GN. DDX24 negatively regulates cytosolic RNA-mediated innate immune signaling. PLoS Pathog. 2013; 9:e1003721. doi: 10.1371/journal.ppat.1003721 24204270
43. Shi D, Dai C, Qin J, Gu W. Negative regulation of the p300-p53 interplay by DDX24. Oncogene. 2016; 35: 528–536. doi: 10.1038/onc.2015.77 25867071
44. Durocher M, Ander BP, Jickling G, Hamade F, Hull H, Knepp B, et al. Inflammatory, regulatory, and autophagy co-expression modules and hub genes underlie the peripheral immune response to human intracerebral hemorrhage. J Neuroinflammation. 2019; 16(1): 56. doi: 10.1186/s12974-019-1433-4 30836997
45. Douglas JN, Gardner LA, Salapa HE, Lalor SJ, Lee S, Segal BM, et al. Antibodies to the RNA-binding protein hnRNP A1 contribute to neurodegeneration in a model of central nervous system autoimmune inflammatory disease. J Neuroinflammation. 2016; 13(1): 178. doi: 10.1186/s12974-016-0647-y 27391474
46. Douglas JN, Gardner LA, Salapa HE, Levin MC. Antibodies to the RNA binding protein heterogeneous nuclear ribonucleoprotein A1 colocalize to stress granules resulting in altered RNA and protein Levels in a model of neurodegeneration in Multiple Sclerosis. J Clin Cell Immunol. 2016; 7: 402. doi: 10.4172/2155-9899.1000402 27375925
Článek vyšel v časopise
PLOS One
2019 Číslo 12
- S diagnostikou Parkinsonovy nemoci může nově pomoci AI nástroj pro hodnocení mrkacího reflexu
- Je libo čepici místo mozkového implantátu?
- Pomůže v budoucnu s triáží na pohotovostech umělá inteligence?
- AI může chirurgům poskytnout cenná data i zpětnou vazbu v reálném čase
- Nová metoda odlišení nádorové tkáně může zpřesnit resekci glioblastomů
Nejčtenější v tomto čísle
- Methylsulfonylmethane increases osteogenesis and regulates the mineralization of the matrix by transglutaminase 2 in SHED cells
- Oregano powder reduces Streptococcus and increases SCFA concentration in a mixed bacterial culture assay
- The characteristic of patulous eustachian tube patients diagnosed by the JOS diagnostic criteria
- Parametric CAD modeling for open source scientific hardware: Comparing OpenSCAD and FreeCAD Python scripts
Zvyšte si kvalifikaci online z pohodlí domova
Všechny kurzy