**5. Specific reorganization of immune system of SLE prone MRL-lpr/lpr mice**

According to our data, the catalytic activity of nuclease and protease Abzs in sera of autoim‐ mune patients is usually very easily detectable at the beginning of autoimmune diseases, when concentrations of Abs to DNA or other autoantigens are not yet significantly increased, and correspond to levels in healthy donors [13–21]. It was shown that detection of Abzs with different activities in human serum may be considered a good indicator of the onset or a significant progression of autoimmune reactions associated with several pathologies [13–21]. In this regard, is of great interest to understand what mechanisms underlie the development of autoimmune processes and how they associated with the production of catalytic antibodies. Some observations suggest that autoimmune diseases can be originated from defects in the hematopoietic stem cells (HSCs) [107]. Therefore, one can assume that in the development of different Ads, there may be some common objective laws. Taking this into account, it seems reasonable first to consider what regularities were found by us in the development of SLE in MRL-lpr/lpr mice. First, it was shown that IgGs from the sera of 2-month-old to 7-month-old control non-autoimmune BALB/c and (CBAxC57BL)F1 mice and conditionally healthy 2 month-old to3-month-old autoimmune prone MRL-lpr/lpr mice are catalytically inactive [22– 24].

It is known that MRL-lpr/lpr mice spontaneously developing a lupus-like AI disorder are characterized by visual symptoms of the pathology (pink spots, baldness of head, and parts of the back, general health deterioration, etc.). The sera of these mice contain Abzs with DNase, amylase and ATPase activities [22–24, 108]. Appearance of proteinuria (≥3-mg/ml concentra‐ tion of protein in urine) correlated well with pronounced visual symptoms [22–24]. The highest levels of anti-DNA Abs, catalytic activities of Abzs, visible markers of SLE and proteinuria were observed usually at 5–12 months of age, which agrees with previously reported data for typical period of signs of pathology appearance in MRL-lpr/lpr mice [109]. We have analyzed spontaneously diseased mice with all visible symptoms no older than 7 months. Although the state of "health" in the case of AI-prone mice should be considered very provisional, the mouse SLE pathology is nevertheless spontaneous and autoimmune reactions, leading to deep pathology develop gradually. To distinguish various levels of the pathology development, MRL-lpr/lpr mice demonstrating no typical SLE indices and Abzs activities (similar to healthy control non-autoimmune mice) were conditionally designated (independently of age) as healthy MRL-lpr/lpr mice, whereas the animals demonstrating no visual or biochemical SLE indices but having detectable abzyme activities were conditionally designated as pre-diseased mice.

A specific reorganization of immune system of these mice after spontaneous development of deep SLE-like pathology results in conditions associated with a production of Abs hydrolyzing Autoimmune Processes in Multiple Sclerosis: Production of Harmful Catalytic Antibodies Associated with Significant Changes in the Hematopoietic Stem Cell Differentiation and Proliferation http://dx.doi.org/10.5772/63824 121

DNA, ATP, and polysaccharides with low catalytic activities (conditionally pre-diseased mice). A significant increase in amylase and especially DNase, ATPase relative activities was associated with a transition from pre-diseased to deep diseased mice correlating with addi‐ tional changes in differentiation and proliferation of mouse bone marrow hematopoietic stem cells and lymphocyte proliferation in different organs. The highest increase in activities of all Abzs was revealed in 3-month healthy mice immunized with DNA, which are characterized by a different profile of HSC differentiation and by a significant suppression of cell apoptosis in comparison with pre-diseased and diseased mice. Overall, all mouse groups investigated were characterized by a specific relationship between abzyme activities, HSC differentiation profiles, levels of lymphocyte proliferation, and cell apoptosis in different organs [22–24]. We came to the conclusion that the appearance of ATPase and DNase activities in diseased mice [22–24] similarly to SLE and MS patients [13–21] may be considered as the earliest statistically significant marker of spontaneous SLE and a further significant increase in catalytic activities correlates with the appearance of SLE visible markers and with an increase in proteinuria and concentrations of anti-DNA Abs. Some differences in immune system reorganizations at predisease and deep disease leading to the production of different autoantibodies and Abzs comparing with healthy mice were revealed [22–24].
