Autoimmune Processes in Multiple Sclerosis: Production of Harmful Catalytic Antibodies Associated with Significant Changes in the Hematopoietic Stem Cell Differentiation and Proliferation

Abstract

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system. MS pathogenesis is not clear. Destruction of myelin by inflammation caused by autoimmune reactions has been proposed. Interestingly, healthy humans usually do not develop abzymes (Abzs). It was shown that DNase and MBP-hydrolyzing Abzs are easily detectable at the beginning of autoimmune diseases (ADs) including MS, when concentrations of antibodies to autoantigens are not yet significantly increased and correspond to levels in healthy donors. In addition, the relative enzymatic activity of antibodies from cerebrospinal fluid (CSF) is ~50-fold higher than that from the sera of the same MS patients. Experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice, a model mimicking relevant aspects of human MS was used. During develop‐ ment of spontaneous and MOG35-55-induced EAE in C57BL/6 mice, a specific reorganization of the immune system of mice was observed. It leads to a condition which was associated with the generation of catalytically active IgGs-hydrolyzing DNA, myelin basic protein (MBP), and MOG. Production of Abzs was associated with increased proteinuria, leading changes in differentiation of mice bone marrow hematopoietic stem cells (HSCs) and an increase in proliferation of lymphocytes in bone marrow, spleen, and thymus as well as a significant suppression of cell apoptosis in these organs. Treatment of control non-autoimmune CBA mice with MOG led to the different differentiation and proliferation of HSCs comparing with EAE C57BL/6 mice. The treatment of EAE mice with cuprizone inducing demyelination lead to a signifi‐ cant decrease in the size of the brain corpus callosum, but do not significantly change the differentiation profile of HSCs differentiation when compared with untreated mice. It indicates that cuprizone treatment is associated with demyelination, but not autoimmune reactivity. The possible differences in immune system reorganizations during preclinical phases of the disease, acute and late EAE, leading to production of different autoantibodies and Abzs as well other changes are discussed.