Identification and characterization of antibodies elicited by human cystatin C fragment
Izabela Behrendt
Faculty of Chemistry, University of Gdańsk, Gdańsk, Poland
Search for more papers by this authorMartyna Prądzińska
Faculty of Chemistry, University of Gdańsk, Gdańsk, Poland
Search for more papers by this authorMarta Spodzieja
Faculty of Chemistry, University of Gdańsk, Gdańsk, Poland
Search for more papers by this authorPaulina Czaplewska
Intercollegiate Faculty of Biotechnology, University of Gdańsk and Medical University of Gdańsk, Gdańsk, Poland
Search for more papers by this authorAleksandra S. Kołodziejczyk
Faculty of Chemistry, University of Gdańsk, Gdańsk, Poland
Search for more papers by this authorAneta Szymańska
Faculty of Chemistry, University of Gdańsk, Gdańsk, Poland
Search for more papers by this authorFranciszek Kasprzykowski
Faculty of Chemistry, University of Gdańsk, Gdańsk, Poland
Search for more papers by this authorSusanna L. Lundström
Department of Medical Biochemistry and Biophysics, Division of Physiological Chemistry, Karolinska Institutet, Stockholm, Sweden
Search for more papers by this authorRoman A. Zubarev
Department of Medical Biochemistry and Biophysics, Division of Physiological Chemistry, Karolinska Institutet, Stockholm, Sweden
Search for more papers by this authorCorresponding Author
Sylwia Rodziewicz-Motowidło
Faculty of Chemistry, University of Gdańsk, Gdańsk, Poland
Correspondence
Sylwia Rodziewicz-Motowidło, Faculty of Chemistry of the University of Gdańsk, Wita Stwosza 63, 80-308, Gdańsk, Poland.
Email: [email protected]
Search for more papers by this authorIzabela Behrendt
Faculty of Chemistry, University of Gdańsk, Gdańsk, Poland
Search for more papers by this authorMartyna Prądzińska
Faculty of Chemistry, University of Gdańsk, Gdańsk, Poland
Search for more papers by this authorMarta Spodzieja
Faculty of Chemistry, University of Gdańsk, Gdańsk, Poland
Search for more papers by this authorPaulina Czaplewska
Intercollegiate Faculty of Biotechnology, University of Gdańsk and Medical University of Gdańsk, Gdańsk, Poland
Search for more papers by this authorAleksandra S. Kołodziejczyk
Faculty of Chemistry, University of Gdańsk, Gdańsk, Poland
Search for more papers by this authorAneta Szymańska
Faculty of Chemistry, University of Gdańsk, Gdańsk, Poland
Search for more papers by this authorFranciszek Kasprzykowski
Faculty of Chemistry, University of Gdańsk, Gdańsk, Poland
Search for more papers by this authorSusanna L. Lundström
Department of Medical Biochemistry and Biophysics, Division of Physiological Chemistry, Karolinska Institutet, Stockholm, Sweden
Search for more papers by this authorRoman A. Zubarev
Department of Medical Biochemistry and Biophysics, Division of Physiological Chemistry, Karolinska Institutet, Stockholm, Sweden
Search for more papers by this authorCorresponding Author
Sylwia Rodziewicz-Motowidło
Faculty of Chemistry, University of Gdańsk, Gdańsk, Poland
Correspondence
Sylwia Rodziewicz-Motowidło, Faculty of Chemistry of the University of Gdańsk, Wita Stwosza 63, 80-308, Gdańsk, Poland.
Email: [email protected]
Search for more papers by this authorAbstract
Amyloid formation is associated with a number of neurodegenerative diseases that affect the independence and quality of life of aging populations. One of rather atypical, occurring at a young age amyloidosis is hereditary cystatin C amyloid angiopathy (HCCAA) related to aggregation of L68Q variant of human cystatin C (hCC). Human cystatin C plays a very important role in many aspects of human health; however, its amyloidogenic properties manifested in HCCAA present a real, lethal threat to some populations and any work on factors that can affect possible influencing hCC aggregation is not to overestimate. It was proved that interaction of hCC with monoclonal antibodies suppresses significantly hCC dimerization process. Therefore, immunotherapy seems to be the right approach toward possible HCCAA treatment. In this work, the hCC fragment encompassing residue 60-70 (in 2 variants: linear peptide and multiple antigenic peptide) was used as an immunogen in rabbit immunization. As a result, specific anti-hCC antibodies were found in both rabbit sera. Surprisingly, rabbit antibodies were obtained after immunization with only a short peptide. The obtained antibodies were characterized, and their influence on the aggregation propensity of the hCC molecules was evaluated. The antibodies turned out not to have any significant influence on the cystatin C dimerization process. Nevertheless, we hope that antibodies elicited in rabbits by other hCC fragments could lead to elaboration of effective treatment against HCCAA.
REFERENCES
- 1Tan SY, Pepys MB. Amyloidosis. Histopathology. 1994; 25(5): 403-414.
- 2Thomas PJ, Qu B, Pedersen PL. Defective protein folding as a basis of human disease. Trends Biochem Sci. 1995; 20(11): 456-459.
- 3Koo EH, Lansbury PT, Kelly JW. Amyloid diseases: abnormal protein aggregation in neurodegeneration. Proc Natl Acad Sci U S A. 1999; 96(18): 9989-9990.
- 4Dobson CM. Principles of protein folding, misfolding and aggregation. Semin Cell Dev Biol. 2004; 15(1): 3-16.
- 5Pepys MB. Amyloidosis. Annu Rev Med. 2006; 57(1): 223-241.
- 6Chiti F, Dobson CM. Protein misfolding, functional amyloid, and human disease. Annu Rev Biochem. 2006; 75(1): 333-366.
- 7Knowles TP, Vendruscolo M, Dobson CM. The amyloid state and its association with protein misfolding diseases. Nat Rev Mol Cell Biol. 2014; 15(6): 384-396. https://doi.org/10.1038/nrm3810
- 8Trojanowski JQ, Goedert M, Iwatsubo T, Lee VM. Fatal attractions: abnormal protein aggregation and neuron death in Parkinson's disease and Lewy body dementia. Cell Death Differ. 1998; 5(10): 832-837.
- 9Śladewska A, Szymańska A, Kordalska M, et al. Identification of the epitope for the anti-cystatin C antibody. J Mol Recognit. 2011; 24(4): 687-699. https://doi.org/10.1002/jmr.1100
- 10Spodzieja M, Szymańska A, Kołodziejczyk A, et al. Interaction of serum amyloid A with human cystatin C-identification of binding sites. J Mol Recognit. 2012; 25(10): 513-524. https://doi.org/10.1002/jmr.2220
- 11Behrendt I, Prądzińska M, Spodzieja M, et al. Epitope location for two monoclonal antibodies against human cystatin C, representing opposite aggregation inhibitory properties. Amino Acids. 2016; 48(7): 1717-1729. https://doi.org/10.1007/s00726-016-2242-z
- 12Prądzińska M, Behrendt I, Spodzieja M, et al. Isolation and characterization of autoantibodies against human cystatin C. Amino Acids. 2016; 48(11): 2501-2518. https://doi.org/10.1007/s00726-016-2271-7
- 13Prądzińska M, Behrendt I, Astorga-Wells J, et al. Application of amide hydrogen/deuterium exchange mass spectrometry for epitope mapping in human cystatin C. Amino Acids. 2016; 48(12): 2809-2820. https://doi.org/10.1007/s00726-016-2316-y
- 14Abrahamson M, Jonsdottir S, Olafsson I, Jensson O, Grubb A. Hereditary cystatin C amyloid angiopathy: identification of the disease-causing mutation and specific diagnosis by polymerase chain reaction based analysis. Hum Genet. 1992; 89(4): 377-380.
- 15Mussap M, Plebani M. Biochemistry and clinical role of human cystatin C. Crit Rev Clin Lab Sci. 2004; 41(5–6): 467-550. https://doi.org/10.1080/10408360490504934
- 16Palsdottir A, Snorradottir AO, Thorsteinsson L. Hereditary cystatin C amyloid angiopathy: genetic, clinical, and pathological aspects. Brain Pathol. 2006; 16(1): 55-59.
- 17Rawlings ND, Barrett AJ, Finn R. Twenty years of the MEROPS database of proteolytic enzymes, their substrates and inhibitors. Nucleic Acids Res. 2016; 44(Database issue): D343-D350. https://doi.org/10.1093/nar/gkv1118
- 18Abrahamson M, Ritonja A, Brown MA, Grubb A, Machleidt W, Barrett AJ. Identification of the probable inhibitory reactive sites of the cysteine proteinase inhibitors human cystatin C and chicken cystatin. J Biol Chem. 1987; 262(20): 9688-9694.
- 19Turk V, Bode W. The cystatins: protein inhibitors of cysteine proteinases. FEBS Lett. 1991; 285(2): 213-219.
- 20Hall A, Håkansson K, Mason RW, Grubb A, Abrahamson M. Structural basis for the biological specificity of cystatin C. Identification of leucine 9 in the N-terminal binding region as a selectivity-conferring residue in the inhibition of mammalian cysteine peptidases. J Biol Chem. 1995; 270(10): 5115-5121.
- 21Janowski R, Kozak M, Jankowska E, et al. Human cystatin C, an amyloidogenic protein, dimerizes through three-dimensional domain swapping. Nat Struct Mol Biol. 2001; 8(4): 316-320. https://doi.org/10.1038/86188
- 22Abrahamson M, Grubb A. Increased body temperature accelerates aggregation of the Leu-68-->Gln mutant cystatin C, the amyloid-forming protein in hereditary cystatin C amyloid angiopathy. Proc Natl Acad Sci U S A. 1994; 91(4): 1416-1420.
- 23Rodziewicz-Motowidło S, Wahlbom M, Wang X, et al. Checking the conformational stability of cystatin C and its L68Q variant by molecular dynamics studies: why is the L68Q variant amyloidogenic? J Struct Biol. 2006; 154(1): 68-78. https://doi.org/10.1016/j.jsb.2005.11.015
- 24Wahlbom M, Wang X, Lindström V, Carlemalm E, Jaskólski M, Grubb A. Fibrillogenic oligomers of human cystatin C are formed by propagated domain swapping. J Biol Chem. 2007; 282(25): 18318-18326. https://doi.org/10.1074/jbc.M611368200
- 25Nilsson M, Wang X, Rodziewicz-Motowidło S, et al. Prevention of domain swapping inhibits dimerization and amyloid fibril formation of cystatin C: use of engineered disulfide bridges, antibodies, and carboxymethylpapain to stabilize the monomeric form of cystatin C. J Biol Chem. 2004; 279(23): 24236-24245. https://doi.org/10.1074/jbc.M402621200
- 26Östner G, Lindström V, Postnikov AB, Solovyeva TI, Emilsson ÖI, Grubb A. High throughput testing of drug library substances and monoclonal antibodies for capacity to reduce formation of cystatin C dimers to identify candidates for treatment of hereditary cystatin C amyloid angiopathy. Scand J Clin Lab Invest. 2011; 71(8): 676-682. https://doi.org/10.3109/00365513.2011.621026
- 27Olafsson I, Löfberg H, Abrahamson M, Grubb A. Production, characterization and use of monoclonal antibodies against the major extracellular human cysteine proteinase inhibitors cystatin C and kininogen. Scand J Clin Lab Invest. 1988; 48(6): 573-582.
- 28Juszczyk P, Paraschiv G, Szymańska A, et al. Binding epitopes and interaction structure of the neuroprotective protease inhibitor cystatin C with beta-amyloid revealed by proteolytic excision mass spectrometry and molecular docking simulation. J Med Chem. 2009; 52(8): 2420-2428.
- 29Östner G, Lindström V, Hjort Christensen P, Kozak M, Abrahamson M, Grubb A. Stabilization, characterization, and selective removal of cystatin C amyloid oligomers. J Biol Chem. 2013; 288(23): 16438-16450. https://doi.org/10.1074/jbc.M113.469593
- 30Solomon B, Koppel R, Hanan E, Katzav T. Monoclonal antibodies inhibit in vitro fibrillar aggregation of the Alzheimer beta-amyloid peptide. Proc Natl Acad Sci U S A. 1996; 93(1): 452-455.
- 31Solomon B, Koppel R, Frankel D, Hanan-Aharon E. Disaggregation of Alzheimer beta-amyloid by site-directed mAb. Proc Natl Acad Sci U S A. 1997; 94(8): 4109-4112.
- 32Davtyan H, Ghochikyan A, Petrushina I, et al. Immunogenicity, efficacy, safety, and mechanism of action of epitope vaccine (Lu AF20513) for Alzheimer's disease: prelude to a clinical trial. J Neurosci. 2013; 33(11): 4923-4934. https://doi.org/10.1523/JNEUROSCI.4672-12.2013
- 33Davtyan H, Ghochikyan A, Hovakimyan A, et al. A dual vaccine against influenza & Alzheimer's disease failed to enhance anti-β-amyloid antibody responses in mice with pre-existing virus specific memory. J Neuroimmunol 2014; 277(0): 77–84. https://doi.org/10.1016/j.jneuroim.2014.10.002, 1-2.
- 34Mandler M, Valera E, Rockenstein E, et al. Next-generation active immunization approach for synucleinopathies: implications for Parkinson's disease clinical trials. Acta Neuropathol. 2014; 127(6): 861-879. https://doi.org/10.1007/s00401-014-1256-4
- 35Mandler M, Valera E, Rockenstein E, et al. Active immunization against alpha-synuclein ameliorates the degenerative pathology and prevents demyelination in a model of multiple system atrophy. Mol Neurodegener. 2015; 10(1): 1-15. https://doi.org/10.1186/s13024-015-0008-9
- 36Correia BE, Bates JT, Loomis RJ, et al. Proof of principle for epitope-focused vaccine design. Nature. 2014; 507(7491): 201-206. https://doi.org/10.1038/nature12966
- 37Ponomarenko J, Bui HH, Li W, et al. ElliPro: a new structure-based tool for the prediction of antibody epitopes. BMC Bioinformatics. 2008; 9(1): 514. https://doi.org/10.1186/1471-2105-9-514
- 38Parker JM, Guo D, Hodges RS. New hydrophilicity scale derived from high-performance liquid chromatography peptide retention data: correlation of predicted surface residues with antigenicity and X-ray-derived accessible sites. Biochemistry. 1986; 25(19): 5425-5432.
- 39Tam JP. Synthetic peptide vaccine design: synthesis and properties of a high-density multiple antigenic peptide system. Proc Natl Acad Sci U S A. 1988; 85(15): 5409-5413.
- 40Davtyan H, Petrushina I, Ghochikyan A. Immunotherapy for Alzheimer's disease: DNA- and protein-based epitope vaccines. Methods Mol Biol. 2014; 1143: 259-281. https://doi.org/10.1007/978-1-4939-0410-5_16
- 41Szymańska A, Radulska A, Czaplewska P, Grubb A, Grzonka Z, Rodziewicz-Motowidło S. Governing the monomer-dimer ratio of human cystatin C by single amino acid substitution in the hinge region. Acta Biochim Pol. 2009; 56(3): 455-463.
- 42Laemmli UK. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970; 227(5259): 680-685.
- 43Lundström SL, Yang H, Lyutvinskiy Y, et al. Blood plasma IgG Fc glycans are significantly altered in Alzheimer's disease and progressive mild cognitive impairment. J Alzheimers Dis. 2014; 38(3): 567-579. https://doi.org/10.3233/JAD-131088
- 44Lundström SL, Fernandes-Cerqueira C, Ytterberg AJ, et al. IgG antibodies to cyclic citrullinated peptides exhibit profiles specific in terms of IgG subclasses, Fc-glycans and a Fab-peptide sequence. PLoS One. 2014; 9(11): e113924. Doi: https://doi.org/10.1371/journal.pone.0113924): e113924
- 45Martens CL, Moore KW, Steinmetz M, Hood L, Knight KL. Heavy chain genes of rabbit IgG: isolation of a cDNA encoding gamma heavy chain and identification of two genomic C gamma genes. Proc Natl Acad Sci U S A. 1982; 79(19): 6018-6022.
- 46Raju TS, Briggs JB, Borge SM, Jones AJ. Species-specific variation in glycosylation of IgG: evidence for the species-specific sialylation and branch-specific galactosylation and importance for engineering recombinant glycoprotein therapeutics. Glycobiology. 2000; 10(5): 477-486.
- 47Rayner LE, Kadkhodayi-Kholghi N, Heenan RK, Gor J, Dalby PA, Perkins SJ. The solution structure of rabbit IgG accounts for its interactions with the Fc receptor and complement C1q and its conformational stability. J Mol Biol. 2013; 425(3): 506-523.
- 48Schneiderman RD, Hanly WC, Knight KL. Expression of 12 rabbit IgA C alpha genes as chimeric rabbit-mouse IgA antibodies. Proc Natl Acad Sci U S A. 1989; 86(19): 7561-7565.
- 49Murzin AG. Sweet-tasting protein monellin is related to the cystatin family of thiol proteinase inhibitors. J Mol Biol. 1993; 230(2): 689-694. https://doi.org/10.1006/jmbi.1993.1186
- 50Jemmerson R, Paterson Y. Mapping epitopes on a protein antigen by the proteolysis of antigen-antibody complexes. Science. 1986; 232(4753): 1001-1004.
- 51Hager-Braun C, Tomer KB. Determination of protein-derived epitopes by mass spectrometry. Expert Rev Proteomics. 2005; 2(5): 745-756. https://doi.org/10.1586/14789450.2.5.745
- 52Olafsson I, Grubb A. Hereditary cystatin C amyloid angiopathy. Amyloid. 2000; 7(1): 70-79.
- 53Zhang J, Yang J, Wang H, Ru G, Fan D. Synthesized multiple antigenic polypeptide vaccine based on B-cell epitopes of human Heparanase could elicit a potent Antimetastatic effect on human hepatocellular carcinoma in vivo. PLoS One. 2013; 8(1):e52940. https://doi.org/10.1371/journal.pone.0052940): e52940
- 54Sompayrac LM. How the Immune System Works. 4th ed. Oxford: Wiley-Blackwell; 2012.
- 55Joshi VG, Dighe VD, Thakuria D, Malik YS, Kumar S. Multiple antigenic peptide (MAP): a synthetic peptide dendrimer for diagnostic, antiviral and vaccine strategies for emerging and re-emerging viral diseases. Indian J Virol. 2013; 24(3): 312-320. https://doi.org/10.1007/s13337-013-0162-z
- 56Li W, Joshi M, Singhania S, Ramsey K, Murthy A. Peptide vaccine: progress and challenges. Vaccines (Basel). 2014; 2(3): 515-536. https://doi.org/10.3390/vaccines2030515
