Title : Antibody-proteases as the upgraded translational tools of the next-step generation in personalized and precision neurology practice to monitor multiple sclerosis at clinical and subclinical stages
Abstract:
Biomarkers enable pre-early diagnosis, guide targeted therapy and monitor the active ty and therapeutic responses across the diseases. Among the best-validated predictive biomarkers are autoimmunity-related ones to predict and prognosticate risks of the chronification, complications and thus disabling. The latter is so much valuable and important since chronic autoimmune inflammation course is structured to consist from different stages including subclinical and clinical ones. Multiple sclerosis (MS) is just one of the chronic tissue-specific autoimmune diseases resulting in a destruction of myelin by different tools, including autoAbs of very broad specificity. Along with canonical Abs, some of the families proven to occur are Abs possessing with catalytic activity (abzymes), and thus to belong to Abs with functionality! Abs against myelin basic protein/MBP endowing with proteolytic activity (Ab-proteases with functionality) are of great value to monitor demyelination to illustrate the evolution of MS. Anti-MBP autoAbs from MS patients and mice with EAE exhibited specific proteolytic cleavage of MBP which, in turn, markedly differed between: (i) MS patients and healthy controls; (ii) different clinical MS courses; (iii) EDSS scales of demyelination to correlate with the disability of MS patients to predict the transformation prior to changes of the clinical course. Ab-mediated proteolysis of MBP was shown to be sequence-specific whilst demonstrating five sites of preferential proteolysis to be located within the immunodominant regions of MBP and to fall inside into 5 sequences fixed. Some of the latter (with the highest encephalitogenic properties) were proved to act as a specific inducer of EAE and to be attacked by the MBP-targeted Ab-proteases in MS patients with the most severe (progradient) clinical courses. The other ones whilst being less immunogenic happened to be EAE inducers very rare but were shown to be attacked by Ab-proteases in MS patients with moderate (remission-type) courses. The activity of Ab-proteases was first registered at the subclinical stages 1-2 years prior to the clinical illness. About 24% of the direct MS-related relatives were seropositive for low-active Ab-proteases from which 22% of the seropositive relatives established were being monitored for 2 years whilst demonstrating a stable growth of the Ab-associated proteolytic activity. Moreover, some of the low-active Ab-proteases in persons at MS-related risks (at subclinical stages of MS), and primary clinical and MRT manifestations observed were coincided with the activity to have its mid-level reached. Registration in the evolution of highly immunogenic Ab-proteases would illustrate either risks of transformation of subclinical stages into clinical ones, or risks of exacerbations to develop. And the “escalation” illustrating re-orientation of the sequence specificity to focus on the more important targeted sites for proteolysis might be an early prognostic and/or predictive sign to monitor demyelination progressing and thus the clinical illness to come. The activity of Ab-proteases in combination with the sequence-specificity would confirm a high subclinical and predictive (translational) value of the tools as applicable for personalized monitoring protocols. Sequence-specific Ab-proteases have proved to be greatly informative and thus valuable biomarkers to monitor MS at both subclinical and clinical stages! And the translational potential of this knowledge is in the rational design of new diagnostic tools and new therapeutics based on principles of artificial biocatalysts and Biodesign. 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. Therefore, the proposed predictive value of MBP-targeted Ab-proteases for the development of MS is being challenged! Of tremendous value in this sense are Ab-proteases directly affecting the physiologic remodelling of tissues with multilevel architectonics (for instance, myelin)., whilst securing the requests and standards of regeneration and remyelination. So, further studies on Ab-mediated MBP degradation and other targeted Ab-mediated proteolysis may provide biomarkers of newer generations and thus a supplementary tool for assessing the disease progression and predicting disability of the patients and persons-at-risks.
