Anti-α-glucose–based glycan IgM antibodies predict relapse activity in multiple sclerosis after the first neurological event

Abstract

Background

There is no specific serum-based biomarker for the diagnosis or prognosis of relapsing-remitting multiple sclerosis (RRMS).

Objective

We investigated whether levels of IgM antibodies to Glc(α1,4)Glc(α) (GAGA4) or to a panel of four glucose-based glycans could differentiate MS from other neurological diseases (OND) or predict risk of early relapse following first presentation (FP) of RRMS.

Methods

Retrospective analysis of 440 sera samples of three cohorts: A) FP-RRMS (n = 44), OND (n = 44); B) FP-RRMS (n = 167), OND (n = 85); and C) FP (n = 100). Anti-GAGA4 IgM levels were measured by enzyme immunoassay in cohort-A and cohort-B. Cohort-C IgM antibodies to glucose-based glycan panel were measured by immunofluorescence.

Results

FP-RRMS had higher levels of anti-GAGA4 IgM than OND patients (cohort-A, P = 0.01; cohort-B, P = 0.0001). Sensitivity and specificity were 27% and 97% for cohort-A; and 26% and 90% for cohort-B, respectively. In cohort-C, 58 patients experienced early relapse (<24 months), 31 had late relapse (≥24 months), and 11 did not experience second attack during follow-up. Kaplan–Meier curves demonstrated decrease in time to next relapse for patients positive for the antibody panel (P = 0.02, log rank).

Conclusions

Serum anti-GAGA4 IgM discerns FP-RRMS patients from OND patients. Higher levels of serum anti-α-glucose IgM in FP patients predict imminent early relapse.

Keywords

antibodies anti-glucose antibodies anti-glycan antibodies biomarker diagnosis enzyme immunoassay IgM multiple sclerosis prognosis

References

1 Freedman MS Thompson EJ Deisenhammer F . Recommended standard of cerebrospinal fluid analysis in the diagnosis of multiple sclerosis: a consensus statement. Arch Neurol 2005; 62: 865–870.

2 Lolli F Mulinacci B Carotenuto A . An N-glucosylated peptide detecting disease-specific autoantibodies, biomarkers of multiple sclerosis. Proc Natl Acad Sci USA 2005; 102: 10273–10278.

3 Lolli F Mazzanti B Pazzagli M . The glycopeptide CSF114(Glc) detects serum antibodies in multiple sclerosis. J Neuroimmunol 2005; 167: 131–137.

4 Berger T Rubner P Schautzer F . Antimyelin antibodies as a predictor of clinically definite multiple sclerosis after a first demyelinating event. N Engl J Med 2003; 349: 139–145.

5 Kuhle J Pohl C Mehling M . Lack of association between antimyelin antibodies and progression to multiple sclerosis. N Engl J Med 2007; 356: 371–378.

6 Schwarz M Spector L Gortler M . Serum anti-Glc(alpha1,4)Glc(alpha) antibodies as a biomarker for relapsing-remitting multiple sclerosis. J Neurol Sci 2006; 244: 59–68.

7 Poser CM Paty DW Scheinberg L . New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 1983; 13: 227–231.

8 Schwarz M Spector L Gargir A . A new kind of carbohydrate array, its use for profiling antiglycan antibodies, and the discovery of a novel human cellulose-binding antibody. Glycobiology 2003; 13: 749–754.

9 Thomas DC Clayton DG . Betting odds and genetic associations. J Natl Cancer Inst 2004; 96: 421–423.

10.

10 Menge T Lalive PH von Budingen HC Cree B Hauser SL Genain CP . Antibody responses against galactocerebroside are potential stage-specific biomarkers in multiple sclerosis. J Allergy Clin Immunol 2005; 116: 453–459.

11.

11 Goldsby RA Kindt TJ Osborne BA . Kuby Immunology. 4th ed. New York, NY, W.H. Freeman and Company; 2000.

12.

12 Binder CJ Shaw PX Chang MK . The role of natural antibodies in atherogenesis. J Lipid Res 2005; 46: 1353–1363.

13.

13 DeFranco, AL, Locksley, RM, Robertson, M. Immunity: the immune response to infectious and inflammatory disease. New Science Press, London; 2007.

14.

14 Pirko I Ciric B Gamez J . A human antibody that promotes remyelination enters the CNS and decreases lesion load as detected by T2-weighted spinal cord MRI in a virus-induced murine model of MS. FASEB J 2004; 18: 1577–1579.

15.

15 Warrington AE Bieber AJ Ciric B Pease LR Van Keulen V Rodriguez M . A recombinant human IgM promotes myelin repair after a single, very low dose. J Neurosci Res 2007; 85: 967–976.

16.

16 Mandrioli J Sola P Bedin R Gambini M Merelli E . A multifactorial prognostic index in multiple sclerosis. Cerebrospinal fluid IgM oligoclonal bands and clinical features to predict the evolution of the disease. J Neurol 2008; 255: 1023–1031.

17.

17 Steinman L . Multiple sclerosis: a two-stage disease. Nat Immunol 2001; 2: 762–764.

18.

18 Spiro RG . Characterization and quantitative determination of the hydroxylysine-linked carbohydrate units of several collagens. J Biol Chem 1969; 244: 602–612.

19.

19 Mahieu PM Lambert PH Maghuin-Rogister GR . Primary structure of a small glycopeptide isolated from human glomerular basement membrane and carrying a major antigenic site. Eur J Biochem 1973; 40: 599–606.

20.

20 van Horssen J Bö L Dijkstra CD de Vries HE . Extensive extracellular matrix depositions in active multiple sclerosis lesions. Neurobiol Dis 2006; 24: 484–491.

21.

21 Gyorgy B Tothfalusi L Nagy G . Natural autoantibodies reactive with glycosaminoglycans in rheumatoid arthritis. Arthritis Res Ther 2008; 10: R110.

22.

22 Masuoka J . Surface glycans of Candida albicans and other pathogenic fungi: physiological roles, clinical uses, and experimental challenges. Clin Microbiol Rev 2004; 17: 281–310.

23.

23 Hellerqvist CG Lindberg B Sigfrid S Holme T Lindberg AA . Structural studies on the O-specific sidechains of the cell-wall lipopolysaccharide from Salmonella typhimurium 395 ms. Carbohydr Res 1968; 8: 43–55.

24.

24 Lind S Lindberg AA . Epitope size, specificity and equilibrium constant for four monoclonal antibodies binding to the O:4 polysaccharide antigen of Salmonella serogroup B bacteria. Mol Immunol 1992; 29: 1013–1023.

25.

25 Bach JF . Infections and autoimmune diseases. J Autoimmun 2005; 25(Suppl.): 74–80.

26.

26 McDonald WI Compston A Edan G . Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001; 50: 121–127.

27.

27 Polman CP Reingold SC Edan G . Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”. Ann Neurol 2005; 58: 840–846.

28.

28 Barkhof F Rocca M Francis G . Validation of diagnostic magnetic resonance imaging criteria for multiple sclerosis and response to interferon beta1a. Ann Neurol 2003; 53: 718–724.

29.

29 Barkhof F Filippi M Miller DH . Comparison of MRI criteria at first presentation to predict conversion to clinically definite multiple sclerosis. Brain 1997; 120: 2059–2069.

30.

30 Tintoré M Rovira A Martínez MJ . Isolated demyelinating syndromes: comparison of different MR imaging criteria to predict conversion to clinically definite multiple sclerosis. AJNR Am J Neuroradiol 2000; 21: 702–706.