After incubation for 1.0C4.5 h at 37 C, 2.5 L of loading buffer containing 1% SDS, 50 mM EDTA, pH 8.0, 30% glycerol, and 0.005% bromophenol blue was added to the reaction mixture. of pernicious humans IgGs against five histones, MBP, and DNA have been shown for the first time. The data obtained indicate that the formation of such polyspecific-polyreactive abzymes, whose single active center can recognize and hydrolyze different substrates, can occur due to the formation of antibodies against hybrid antigenic determinants consisting of several histone protein sequences. IgGs with high affinity for DNA with DNase and protease activities may be antibodies against DNA-histone complex antigenic determinants, including protein and DNA sequences. Polyreactive IgGs-abzymes against MBP, five histones, and DNA with extended cytotoxicity can play a very negative role in the pathogenesis of multiple sclerosis and probably other different diseases. Keywords: human blood sera antibodies-abzymes, multiple sclerosis patients, catalytic abzymes, hydrolysis of H2A histone, IgGs against H2B, H1, H2A, H3, H4 histones, myelin basic protein, DNA, enzymatic cross recognition and hydrolysis 1. Introduction Antibodies (Abs) to chemically stable analogues of reaction transition states and natural autoantibodies with enzymatic activities are called abzymes (ABZs), and they are well described in the literature [1,2,3,4,5,6]. The spontaneous and stimulated by different antigens development of various autoimmune diseases (ADs) results in the synthesis of ABZs Galactose 1-phosphate Potassium salt by B-cells ROBO1 against polysaccharides, lipids, peptides, proteins, DNAs, and RNAs and their complexes. In the blood sera of AD patients, many different ABZs were discovered directly against many specific antigens, mimicking chemical reaction transition states. Secondary anti-idiotypic auto-ABZs to active sites of several classical enzymes were also detected; their formation may account for using Jernes model of the anti-idiotypic network [7]. The appearance of Abs-ABZs in the blood sera of mammals is very reliable and the earliest indicator of the onset of the autoimmune (AI) diseases in humans and mammals [1,2,3,4,5,6]. To date, different abzymes (IgGs, IgA, and IgMs) splitting DNAs, RNAs [8,9,10,11,12], poly and oligosaccharides [13,14,15], various peptides, and proteins [16,17,18,19,20,21,22,23] have been found in the blood sera of patients with different ADs and several viral pathologies [1,2,3,4,5,6]. Some healthy humans sometimes produce antibody-abzymes having very low vasoactive intestinal peptide [16], thyroglobulin [18], and polysaccharide-hydrolyzing [13,14,15] activities. At the same time, the blood of healthy humans and patients suffering from specific pathologies demonstrating insignificant AI reactions usually lack ABZs [1,2,3,4,5,6]. Nonetheless, germline antibodies of some healthy humans and mammals could possess amyloid- and superantigen-directed enzymatic activities [24,25]. Myelin basic protein (MBP) is the major and vital protein of the myelin-proteolipid sheath of axons. It is believed that the development of multiple sclerosis is associated with the hydrolysis of proteins, including MBP of the myelin sheath of nerve tissues. The specific abzymes against MBP can hydrolyze the axon myelin sheath MBP, having an essential negative role in MS pathogenesis due to infringement of nerve impulse conduction [1,2,3,4,5,6,21,22]. Histones and their different modified forms hold a vital role in the functioning of chromatin. Free extracellular histones in the blood are detrimental Galactose 1-phosphate Potassium salt proteins causing toxic impacts through inflammatory pathways and teamwork with Toll-like receptors [26]. ABZs hydrolyzing five histones (H1CH4) and MBP were detected in the blood of HIV-infected [21,22,27,28,29,30,31,32,33,34], SLE [35], and MS [36] patients, as well as mice with autoimmune experimental encephalomyelitis [37]. In AD patients, many antibodies to histones and DNA are directed against histone-DNA complexes emerging in Galactose 1-phosphate Potassium salt the blood due to cell apoptosis [38]. Antibodies that hydrolyze DNA are cytotoxic. They penetrate through membranes of cells and nuclei, hydrolyze DNA of chromatin and induce cell apoptosis [2,3,4,5,6]. The catalytic cross-reactivity of ABZs against MBP, histones, and DNA is dangerous to humans and mammals because all five histones, due to Galactose 1-phosphate Potassium salt apoptosis of cells, occur in human blood. Considering this, the analysis of possible enzymatic cross-reactivity of abs-abzymes against MBP, histones, and DNA is critical for analyzing the beginning and progress of multiple sclerosis. For canonical enzymes, the situation is simple: one gene-one enzyme. Classical enzymes specific for various substrates usually catalyze only one chemical reaction [39,40,41]. From theoretical estimation, due to the V (D) J recombination, regions of unique DNA encoding variable domains of the Abs human immune system can create about 106 B-lymphocytes against one antigen, producing antibodies to the same antigen with very different properties.