Immune Response and Production of Abzymes in Patients with Autoimmune and Neurodegenerative Diseases

Abstract

The mechanisms of development of autoimmune, neurological, and viral diseases and the possibilities of immune response to various antigens in these pathologies still pose many questions. Human immune system is theoretically capable of synthesizing about a million antibodies with very different properties against the same antigen. It remains unclear how many antibodies and with what properties can form in healthy people and patients with autoimmune diseases (AIDs). The capabilities of traditional approaches, such as enzyme immunoassay or affinity chromatography of Abs on specific sorbents, in answering these questions and analyzing the diversity of antibodies formed against external and internal antigens, as well as their role in the pathogenesis of various diseases, are very limited. Analysis of monoclonal antibodies in the blood of patients with systemic lupus erythematosus (SLE) using phage display revealed that the number of autoantibodies against DNA and myelin basic protein (MBP) can exceed 3-4 thousand, and approximately 30-40% of them are abzymes capable of hydrolyzing DNA and MBP. However, this approach does not allow to investigate the variety of properties of such antibodies, in particular their catalytic activity. Abzymes can play either positive or negative role in the development of various diseases. For example, in HIV-infected patients, abzymes against viral polymerase and integrase cleave these proteins, thus slowing down the development of immunodeficiency syndrome. Other antibodies play a negative role in the pathogenesis of viral, neurological, and autoimmune diseases. Thus, antibodies capable of hydrolyzing DNA and histones can penetrate through the cellular and nuclear membranes, stimulate cell apoptosis, and, as a result, trigger autoimmune processes in many pathologies. Antibodies against MBP cleave this protein in the membranes of cells in nerve tissues, leading to the development of multiple sclerosis (MS). In this case, abzymes against individual histones were able to hydrolyze each of these histones, as well as MBP, while Abs against MBP hydrolyzed MBP and all five histones. It has also been established that the substrate specificity of abzymes in the hydrolysis of histones and MBP varied greatly depending on the stage of MS or SLE development. Here, we used this example to analyze in detail the role that abzymes against various antigens play in their expanded involvement in the pathogenesis of some AIDs. The review also describes the impact of defects in the bone marrow stem cell differentiation characteristic of AIDs in the formation of B lymphocytes producing harmful abzymes and summarizes for the first time the data on the exceptional diversity of autoantibodies and abzymes, their unusual biological functions, and involvement in the pathogenesis of autoimmune pathologies.