Back

Sergey Suchkov

Sergey Suchkov

I.M.Sechenov First Moscow State Medical University, Russia

Title: Antibody-proteases as novel biomarkers and highly informative molecular tools to predict and to prevent demyelination

Biography

Sergey Suchkov graduated from Astrakhan State Medical University and was awarded with MD.In 1985, Suchkov obtained his Ph.D. As a Ph.D. student of the I.M. Sechenov Moscow Medical Academy and Institute of Medical Enzymology, USSR Academy of Medical Sciences, Moscow, Russia. In 2001, Suchkov finished the PostDoc Research Fellowship Program and maintained his Doctor Degree at the National Institute of Immunology, Russia. From 1987 through 1989, Dr. Suchkov was a senior Researcher, Lab of Developmental Immunology, Koltzov Institute of Developmental Biology, USSR Academy of Sciences to deal to developmental immunology. From 1989 through 1995, Dr. Suchkov was being a Head of the Lab of Clinical Immunology and Im-munobiotechnology, Helmholtz Eye Research Institute in Moscow. From 1995 through 2004, Dr. Suchkov was being a Chairman of the Department for Clinical Immunology, Moscow Clinical Research Institute (MONIKI) and the Immunologist-in-Chief of the Moscow Regional Ministry of Health. At present, Dr Sergey Suchkov, M, Ph.D., is Professor in Immunology, Department of Pathology, School for Pharmacy, I.M. Sechenov First Moscow State Medical University, Dean of the Department (Faculty) of The PPPM Development, and the First Vice-President of the University of World Business, Politics and Law and Secretary General, United Cultural Convention (UCC), Cambridge, UK.

Abstract

The methodological bricks of subclinical diagnostic protocols should include basic algorithms to differ essentially from those employed in traditional clinical practice, i.e., (i) to confirm a diagnosis of subclinical stage of the disease course and (ii) to select a mode for preventive treatment to quench the autoimmune inflammation. In this sense, among the best-validated proteome-related biomarkers, antibodies (Abs) are the best known ones to represent one of the principal immune effectors and thus key mediators of inflammatory responses to generate the events. Most of autoimmune disorders including multiple sclerosis (MS) are preceded by a symptom-free subclinical stage in which the patients can be identified by specific autoAbs. The sequence-specificity of Ab-proteases demonstrates five sites of preferential proteolysis to be located within the immunodominant regions of MBP confirmed by the structural databanks. Cleavage at those sites occurred at a similar rate as determined by 32P-MBP degradation assay. Those sites are located within the immuno dominant regions of MBP; and two of them falling inside the sequence covering a 81-103 peptide segment and its 82-98 subsegment as well, with the highest encephalitogenic properties both to act as a specific inducer of EAE in SJL mice and to be attacked by the MBP-targeted Ab-proteases very often in MS patients with the most severe (progradient) clinical courses. Meanwhile, sites localized within the frame of 43-68 and 146-170 peptide subsegments whilst being less immunogenic happened to be EAE inducers very rare but were shown to be attacked by Ab-proteases very often in MS patients with moderate (remission-type) clinical courses. To test the Ab-proteses specificity toward distinct MBP fragments, recombinant fusion proteins of Trx with the C-terminally fused MBP peptides were designed, and in all cases, recombinant substrates were cleaved only at preferential sites inside the MBP fragment, leaving the Trx part undegraded. These data further confirmed the substrate specificity of the Ab and its profound difference from trypsin, a common protease that cleaves at basic residues. Finally, in moderate (remission-type) courses, Ab-proteases focuse its proteolytic effect on low-immunogenic and low-encephalitogenic 43-68 и 146-170 sites but in aggressive cases (progradient courses), the Ab-mediated proteolysis was prevailed on highly-immunogenic and highly-encephalitogenic 81-103 and 82-98 sites. And registration in the evolution of highly immunogenic Ab-proteases to attack 81-103 and 82-98 sites predominantly would illustrate either risks of transformation of subclinical stahes into clinical ones, or risks of exacerbations to develop. The traditional applications of assays for canonical antimyeline Abs for diagnostic and prognostic purposes in patients with a clinically isolated syndrome (CIS), a frequent precursor to clinically definite MS (CDMS), has yielded conflicting results. Meanwhile, the activity of Ab-proteases in combination with the sequence-specificity would confirm a high subclinical and predictive value of the tools as applicable for personalized monitoring protocols. It is so important to stress that the close association between the proteolytic sensitivity of MBP and post-translational modifications of the latter may represent one of the key regulatory mechanisms in the epitope generation. For sure, a combinative (enzyme- and Ab-mediated) proteolysis may illustrate a crucial pathway to exert a concerted attack on MBP, although mechanisms responsible for the activation of these potential activities are not known yet. Ab-proteases can be programmed and re-programmed to suit the needs of the body metabolism or could be designed for the development of principally new catalysts with no natural counterparts. Of tremendous value are Ab-proteases directly affecting the physiologic remodeling of tissues with multilevel architectonics (for instance, myelin). By changing sequence specificity of the Ab-mediated proteolysis one may reach reduction of a density of points of the negative proteolytic effects within the myelin sheath and minimizing scales of demyelination. And, autoAb-mediated proteolysis could thus be applied to isolate from Ig molecules the efficient catalytic domains directed against particular autoimmune epitopes pathogenically and clinically relevant (encephalitogenic epitopes). Further studies on targeted Ab-mediated proteolysis may provide a supplementary tool for predicting demyelination and thus the disability of the MS patients.

Speaker Presentations

Speaker PDFs

Speaker PPTs

Download PPT