The 85th Meeting of the Israel Chemical Society

Invited
From a synthetic N-glucosylated peptide probe to a hyper-glucosylated adhesin protein antigen, and beyond: A bacterial infection triggering an antibody mediated form of multiple sclerosis?

Anna Maria Papini 1,2 Rina Aharoni 3 Ruth Arnon 3 Raya Eilam 4 Antonio Mazzoleni 1,5 Hendrik Rusche 1,2 Feliciana Real-Fernandez 1 Francesco Lolli 6 Elisa Peroni 2 Francesca Nuti 1 Barbara Imperiali 7 Jean-Maurice Mallet 5 Paolo Rovero 8
1Interdepartmental Laboratory of Peptide and Protein Chemistry and Biology, Department of Chemistry "Ugo Schiff", University of Florence, Sesto Fiorentino, Firenze, Italy
2LCB and PeptLab@UCP, Université Paris-Seine, Cergy-Pontoise, France
3Department of Immunology, Weizmann Institute of Sciences, Rehovot, Israel
4Department of Veterinary Resources, Weizmann Institute of Sciences, Rehovot, Israel
5Department of Chemistry, Ecole Normale Superieure, Paris, France
6Dipartimento di Scienze Biomediche, Sperimentali e Cliniche "Mario Serio", University of Florence, Firenze, Italy
7Department of Chemistry, MIT, Cambridge, MA, USA
8Interdepartmental Laboratory of Peptide and Protein Chemistry and Biology, Department NeuroFarBa, University of Florence, Sesto Fiorentino, Firenze, Italy

Gycopeptides mimicking glycan and/or protein interactions with the immune system components are valuable to diagnostics, therapeutics and mechanistic studies in autoimmunity. We demonstrated that a family of structure-based designed glucoasparagine (N-Glc) b-turn glycopeptides, specifically identify serum Abs in a Multiple Sclerosis (MS) disease form. This was the first evidence involving an aberrant N-Glc relevant for Ab detection in MS. Turning our attention to bacterial glycoconjugates of human pathogens, we proved that hyperglucosylated adhesin HMW1 derived from the opportunistic pathogen NTHi Haemophilus influenzae shares a common glucosylation-dependent epitope with b-turn structures. Immunohistochemistry experiments showed that anti-hyperglucosylated adhesin Abs from MS selectively stained spinal cord sections of naïve healthy and EAE model mice. HMW1-Glc7/8/9 is the first example of an N-Glc antigen to be considered a relevant candidate for triggering pathogenic Abs and specific bacterial N-glucosyltransferases can trigger an immune-mediated early response correlating with neurodegeneration. With these results the foundation was laid to determine the exact molecular mimicry mechanism and to elucidate the human protein target(s) (cryptic mimics), by mass spectrometry after an epitope excision and extraction strategy. Considering that IgMs can be reminiscent of an early triggering infection and that IgGs could be prognostic, we developed an octopus-like dextran modified with multiple copies of a di-glucosylated adhesin epitope. This novel polymeric structure, containing ca. 100 N-Glc moieties/octopus, was proven to dramatically increase binding potency of IgGs and IgMs and was instrumental to purify specific Abs from representative MS sera. This promising proof-of-concept can lead for the first time to selective depletion of circulating IgMs, possibly perpetuating nonself recognition. In conclusion, the clinical impact of glycopeptide-based probes for autoimmune diseases is emerging only recently as just the tip of the iceberg of an overlooked potential. Their mimicry effect in autoimmunity can have promising applications in diagnostics and therapeutics.









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