Changes in cell differentiation and proliferation lead to production of abzymes in EAE mice treated with DNA–Histone complexes

Abstract

Experimental autoimmune encephalomyelitis (EAE)‐prone C57BL/6 mice are used as a model of human multiple sclerosis. We immunize mice with myelin oligodendrocyte glycoprotein (MOG), DNA–histone and DNA‐methylated bovine serum albumin (met‐BSA) complexes to reveal different characteristics of EAE development including bone marrow lymphocyte proliferation and differentiation profiles of hematopoietic stem cells. Immunization of C57BL/6 mice with MOG35‐55 results in the acceleration of EAE development. Anti‐DNA antibodies are usually directed against DNA–histone complexes resulting from cell apoptosis. During the acute EAE phase (7‐20 days after immunization), catalytic antibodies efficiently hydrolysing myelin basic protein (MBP), MOG and DNA are produced with parallel suppression of antibodies hydrolysing histones. We could show that in contrast to MOG, immunization with histone‐DNA results in a reduction of proteinuria, a significant increase in anti‐DNA, anti‐MBP and anti‐MOG antibody titres, as well as an increase in their catalytic activities for antigen hydrolysis, but slightly changes the concentration of cytokines. Contrary to MOG, DNA–histone and DNA‐met‐BSA only stimulated the formation of anti‐DNA antibodies hydrolysing DNA with a long delay (15‐20 days after immunization). Our data indicate that for C57BL/6 mice immunization with DNA‐met‐BSA and DNA–histone complexes may have opposing effects compared to MOG. DNA–histone stimulates the appearance of histone‐hydrolysing abzymes in the acute EAE phase, while abzymes with DNase activity appear at significantly later time‐points. We conclude that MOG, DNA–histone and DNA‐met‐BSA have different effects on numerous bone marrow, cellular, immunological and biochemical parameters of immunized mice, but all antigens finally significantly stimulate the development of the EAE.

Production of Abzymes in Th, CBA, and C57BL/6 Mice before and after MOG Treatment: Comparing Changes in Cell Differentiation and Proliferation

“…Untreated control non-autoimmune CBA mice were characterized by low levels of proteinuria at three months of age (1.6 ± 0.08 mg/mL) and levels did not change remarkably over the next 45 days ( Figure 1C). Interestingly, C57BL/6 mice showed significantly higher proteinuria (up to 7.22 ± 0.9 mg/mL) at three months of age even before treatment with MOG [17,18,38,41,42]. Upon spontaneous development of EAE, levels of proteinuria almost did not change in untreated control C57BL/6 mice before day 20, and then gradually increased to 17.0 mg/mL by day 63.…”

“…We compared the development of EAE over time using previously obtained data from C57BL/6 mice and two new experimental groups: Th untreated control/Th MOG-treated mice and CBA untreated control/CBA MOG-treated mice. The same experiments were performed earlier and well-reproducible data on the analysis of all parameters for untreated control and MOG-treated C57BL/6 mice were available [17,18,41,42] for comparison with the new results.…”

“…Spontaneous and MOG-induced development of EAE in C57BL/6 mice leads to significant changes in the differentiation profile of hematopoietic progenitors: BFU-E (erythroid burst-forming unit, early erythroid colonies), CFU-E (erythroid burst-forming unit, late erythroid colonies), CFU-GM (granulocytic-macrophagic colony-forming unit), CFU-GEMM (granulocytic, erythroid, myeloid colony-forming unit), and lymphocyte proliferation levels [17,18,41,42].…”

Extreme Diversity of IgGs Against Histones, DNA, and Myelin Basic Protein in the Cerebrospinal Fluid and Blood of Patients with Multiple Sclerosis

“…It is known that anti-DNA Abs are mostly directed against histone-DNA complexes appearing in blood during cell apoptosis [29]. IgGs purified from blood sera of HIV-infected [27] and MS [30] patients as well as EAE-prone mice [28] efficiently hydrolyze from one to five human histones (H1, H2a, H2b, H3, and H4). However, proteolytic activity auto-IgGs against histones from CSFs of patients with MS in the hydrolysis of five histones has not been previously studied.…”

“…It was recently shown that in contract to healthy humans, 100% of IgGs purified from the sera of 32 HIV-infected patients efficiently hydrolyze from one to five human histones (H1, H2a, H2b, H3, and H4) [27]. In addition, the blood and brain of experimental autoimmune encephalomyelitis (EAE)-prone C57BL/6 mice contain auto-Abs against histones effectively hydrolyzing these proteins [28]. Many anti-DNA Abs are directed against nucleosomal histone-DNA complexes appearing during cell apoptosis [29].…”