Abstract:Proteolytic activity of polyclonal IgG antibodies (Abs) from the blood of AIDS patients was analyzed for the first time. These Abs were shown to display higher activity in hydrolysis of beta-casein than in hydrolysis of human immunodeficiency virus (HIV)-1 reverse transcriptase (RT) or human serum albumin (HSA). Several abzymatic criteria were applied and it was shown that RT, HSA, and beta-casein hydrolyzing activities are an intrinsic property of polyclonal Abs from AIDS patients. Casein-hydrolyzing Abs were… Show more
“…It was recently shown that pIgGs and/or pIgMs of HIV‐infected patients catalyze hydrolysis of DNA, HIV‐1 reverse transcriptase, and integrase . Human casein and serum albumin were the first examples of protease Abs against human proteins appearing in humans after viral infection.…”
Histones and their posttranslational modifications have key roles in chromatin remodeling and gene transcription. Besides intranuclear functions, histones act as damage-associated molecules when they are released into the extracellular space. Administration of histones to animals leads to systemic inflammatory and toxic responses. Autoantibodies with enzymatic activities (abzymes) are distinctive feature of some autoimmune and viral diseases. Electrophoretically and immunologically homogeneous IgGs containing no canonical enzymes were isolated from sera of human immunodeficiency virus-infected patients by chromatography on several affinity sorbents. In contrast to canonical proteases (trypsin, chymotrypsin, and proteinase K), IgGs from human immunodeficiency virus-infected patients purified by affinity chromatography on Sepharose containing immobilized histones specifically recognized and hydrolyzed only histones but not many other tested globular proteins. Using matrix-assisted laser desorption/ionization mass spectrometry, the sites of H1 histone (193 amino acids [AAs]) cleavage by anti-H1 histone IgGs were determined for the first time. It was shown that 1 cluster of 2 major and 4 moderate sites of cleavage is located at the beginning (106-112 AAs) of the known antigenic determinants disposed at the long C-terminal sequence of H1. Two clusters of minor and very weak sites of the protein cleavage correspond to middle (8 sites, 138-158 AAs) and terminal (5 sites, 166-176 AAs) parts of the antigenic determinants. It was shown that in contrast to canonical proteases, N-terminal part of H1 histone (1-136 AAs) containing no antigenic determinants is an unpredictably very resistant against hydrolysis by abzymes, while it can be easily cleavage by canonical proteases. Because histones act as damage-associated molecules, abzymes against H1 and other histones can play important role in pathogenesis of acquired immune deficiency syndrome and probably other different diseases.
“…It was recently shown that pIgGs and/or pIgMs of HIV‐infected patients catalyze hydrolysis of DNA, HIV‐1 reverse transcriptase, and integrase . Human casein and serum albumin were the first examples of protease Abs against human proteins appearing in humans after viral infection.…”
Histones and their posttranslational modifications have key roles in chromatin remodeling and gene transcription. Besides intranuclear functions, histones act as damage-associated molecules when they are released into the extracellular space. Administration of histones to animals leads to systemic inflammatory and toxic responses. Autoantibodies with enzymatic activities (abzymes) are distinctive feature of some autoimmune and viral diseases. Electrophoretically and immunologically homogeneous IgGs containing no canonical enzymes were isolated from sera of human immunodeficiency virus-infected patients by chromatography on several affinity sorbents. In contrast to canonical proteases (trypsin, chymotrypsin, and proteinase K), IgGs from human immunodeficiency virus-infected patients purified by affinity chromatography on Sepharose containing immobilized histones specifically recognized and hydrolyzed only histones but not many other tested globular proteins. Using matrix-assisted laser desorption/ionization mass spectrometry, the sites of H1 histone (193 amino acids [AAs]) cleavage by anti-H1 histone IgGs were determined for the first time. It was shown that 1 cluster of 2 major and 4 moderate sites of cleavage is located at the beginning (106-112 AAs) of the known antigenic determinants disposed at the long C-terminal sequence of H1. Two clusters of minor and very weak sites of the protein cleavage correspond to middle (8 sites, 138-158 AAs) and terminal (5 sites, 166-176 AAs) parts of the antigenic determinants. It was shown that in contrast to canonical proteases, N-terminal part of H1 histone (1-136 AAs) containing no antigenic determinants is an unpredictably very resistant against hydrolysis by abzymes, while it can be easily cleavage by canonical proteases. Because histones act as damage-associated molecules, abzymes against H1 and other histones can play important role in pathogenesis of acquired immune deficiency syndrome and probably other different diseases.
“…Since 1995, Ravetch et al and other groups 50,54,55 have published a series of papers indicating that glycosylation of IgGs in rheumatoid arthritis (RA) is one of the crucial underlying molecular mechanisms causing inflammation. IgG antibodies are potent inducers of proinflammatory responses.…”
Section: Figure 11mentioning
confidence: 99%
“…Other hypotheses implicate viral DNA, 7,18,47,50 microbial DNA, and/or unmethylated CpG motifs within the DNA of any species 56 all of which may be interesting to the innate immune system. Could a new mechanism of antigen recognition be taking place, omitting the classical antigen-presentation loop to the T-cells and their helper response?…”
Section: Figure 11mentioning
confidence: 99%
“…7,18,47,50 Furthermore, all of the same questions that we have about anti-ssDNA antibodies can also be applied to the dsDNA category.…”
Purpose: We have compared a two-step affinity purification method, previously developed in house, which utilizes biotinylated oligo-deoxythymidine (dT) bound streptavidin (SA) M-280 magnetic beads and protein G Dynabeads®, with Melon™ Gel, another two step commercial method, for the isolation and purification of human anti-DNA autoantibodies reactive with single stranded DNA (ssDNA), in order to determine which method is more applicable for analysis of antibody subclasses and, potentially subclass functional activities.Results: Although Melon Gel allowed for faster anti-ssDNA autoantibody purification and higher recovery rate, its final product was of lower purity than that of the magnetic bead method, as confirmed with nanogram silver staining method following PhastGelTM non-reducing SDS-PAGE. The polyclonal nature of anti-ssDNA autoantibodies produced by patients with Systemic Lupus Erythematosus (SLE) has been determined and compared with normal human, and B-Chronic Lymphocytic Leucosis-(B-CLL) anti-ssDNA autoantibodies. Characterization of isolated antibodies by isoelectric focusing, western blot analysis and ELISA confirmed them to be human IgGs and detected the presence of all four IgG antibody subclasses with different participation. Additionally, Lab-on chip (Agilent 2100) method, revealed the presence of different MW patterns within lupus IgG subclasses, not detectable by SDS PAGE, which were not consistent with patterns seen in sera of control or in individuals with B-CLL.
Conclusions:The results obtained suggest incomparably better purity of antibodies isolated via the magnetic bead method vs. Melon-gel. SDS-PAGE and Lab-on-chip analyses of antibodies revealed the presence of different IgG patterns within human lupus anti-ssDNA autoantibody subclasses than those observed in healthy individuals and B-CLL patients. These patterns may be associated with SLE disease pathogenesis and highlight the importance of further molecular, structural, and functional studies of lupus anti-ssDNA antibodies.
“…It was demonstrated with HIV patients that in case of viral infections with subsequent development of autoimmune reactions, generation of Abs against viral proteins that also have catalytic activity occurs. These abzymes hydrolyze specifically only reverse transcriptase [214] and HIV integrase [215 217].…”
Blood of healthy donors contains low concentrations of autoantibodies to its own components, including DNA and RNA. Increased concentrations of antibodies to DNA and RNA have been found in blood of people and animals with autoimmune diseases and viral and bacterial infections. Detection of different antibodies with catalytic activities, including abzymes with DNase and RNase activities, is the earliest indicator of the development of some autoimmune diseases. This review reveals possible mechanisms of generation of anti-DNA and anti-RNA antibodies without catalytic activities and abzymes in normal organisms and in organisms with different pathologies. A possible role of these autoantibodies and the reasons of their exceptional diversity in normal organisms and in organisms with different autoimmune diseases are discussed.
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