Title : Antibodies with functionality as a new generation of translational tools designed to monitor autoimmune myocarditis at clinical and subclinical stages
Abstract:
Catalytic Abs (catAbs) are multivalent Immunoglobulins (Igs) with a capacity to hydrolyze the Antigenic (Ag) substrate. In this sense, proteolytic Abs (Ab-proteases) represent Abs to pro-vide proteolytic effects. Abs against Cardiac Myosin (CM) with proteolytic activity exhibiting targeted cleavage of CM molecule are of great value to monitor stages of autoimmune in-flammation in patients with Autoimmune Myocarditis (AIM) and persons-at-risk. Meanwhile, AIM can be defined as the autoimmune inflammatory process affecting the muscular tissues of the heart (myocardium), which is being transformed in a stepwise man-ner into dilated cardiomyopathy (DCM). New targeted therapies for autoimmune and inflammatory diseases (including AIM) would require greater understanding of a patient or a person-at-risk to get the therapy personalized for those subsets, for specific biomarkers and the targets. In this sense, the identification and implementation of diagnostic, predictive and prognostic biomarkers remain the Holy Grail of platforms and protocols which are the crucial for Personalized & Precision Medicine (PPM).
AIM is just one of the chronic organ-specific autoimmune diseases resulting in a destruction of cardiac tissue by different tools, including highly aggressive and destructive autoAbs. A grand role in the development of autoimmunity in AIM, in particular, is the exposure of self-Ags, which are encrypted and unavailable to the immune system under physiologic condi-tions. Meanwhile, CM is one of the most important self-targets in AIM. The primary damage in AIM progression is mediated by anti-CM autoAbs to trigger a release of separate and pathogenically valuable cardiac-associated epitopes into the bloodstream. A subset of patients with AIM and of their symptom-free relatives has circulating heart-reactive autoAbs, which, in turn, are directed against multiple Ags, some of which are strictly expressed in the myocardium (e.g. specific for the heart), others are expressed in heart and skeletal muscle (e.g. muscle-specific). Abs of IgG class, which are shown to be cardiac and disease-specific for AIM, can be used as reliable markers of autoimmune pathogenesis for identifying patients in whom immunosuppression and/or immunomodulation therapy may be beneficial and their relatives at risk.
Along with canonical Abs, some of the families proven to occur are Abs with catalytic (prote-olytic) activity (catAbs or abzymes) and thus to belong to Abs with a feature of functionality! Such Ab-proteases have been found in a series of autoimmune disorders, including multiple sclerosis, autoimmune thyroiditis, etc. The unique clinical case is a family of Ab-proteases detectable in AIM to cleave CM. Of great interest is the evolution of Ab-associated proteolytic activity at different stages of the disease progression. The activity of Ab-proteases was first registered at the subclinical stages 4-12 months prior to the clinical illness. And the activity of the Ab-proteases revealed significant correlation with scales of autoaggression and the disability of the patients with AIM as well. Therefore, the activity of Ab-proteases and its dynamics tested would confirm a high subclin-ical and predictive value of the tools as applicable for monitoring protocols.
The translational potential of this knowledge is in the rational design of new diagnostic tools and targeted therapeutics based on principles of artificial biocatalysts and biodesign. Ab-proteases can be programmed and re-programmed to suit the needs of the body metabo-lism. Or could be designed for the development of new catalysts with no natural counter-parts. Ab-protease engineering would offer the ability to enhance or alter their sequence-specific activity to expand the clinical utility of those new tools. Therefore, further studies on Ab-mediated CM degradation and other targeted Ab-mediated proteolysis may provide bi-omarkers of newer generations to diagnose, to monitor, to control and to treat and rehabili-tate AIM patients at clinical stages. Or to prevent the disorder at subclinical stages in per-sons-at-risks to secure the efficacy of regenerative manipulations and for assessing the dis-ease progression and predicting disability of the AIM patients and persons-at-risks.
