**8. Conclusion**

to various autoantigens are constantly expanding. This is indicative of the fact that the basis

C57BL/6 and MRL-lpr–lpr are two various mouse models spontaneously developing two different autoimmune diseases, EAE and SLE, respectively. Stimulation of EAE pathology development usually occurs after immunization of C57BL/6 mice with MOG [112, 113], while SLE after treatment of MRL-lpr–lpr mice with DNA [22–24]. It was interesting to understand a possible difference or similarity in the changing of the differentiation profiles of stem cells of the bone marrow in the case of these models comparing with those for the control CBA mice before and after their treatment with MOG and with DNA. **Figure 16** demonstrates the relative levels BFU-E, CFU-E, CFU-GM, and CFU-GEMM units (%) at the beginning (zero time), spontaneous changes and after mice treatment with MOG (57BL/6) and DNA (MRL-lpr–lpr) at 40 days of the experiments. One can see that the relative content of BFU-E colonies (%) constantly decrease in autoimmune EAE and SLE mice at transition from zero time to spon‐ taneous development of these diseases (40 days) and acceleration of their development by

**Figure 16.** Change in the relative percent (sum of four types of colonies was taken for 100%) of BFU-E (A), CFU-E (B), CFU-GM (C), and BFU-GEMM (D) types of colonies in comparison with zero time of the experiments (first group of values) in the case of spontaneous development of EAE and SLE by respectively C57BL/6 and MRL-lpr–lpr mice after 40 days and changes of differentiation profile of HSCs in CBA mice after 40 days (second group of values); third group of values corresponds to relative amount of the colonies after 40 days in the case C57BL/6 and CBA mice treated with

**7. Comparison of stem cell differentiation in SLE and EAE mice**

of all autoimmune diseases may be to some extent similar.

134 Trending Topics in Multiple Sclerosis

treatment with MOG and DNA at 40 days (**Figure 16A**).

MOG [110, 111] and MRL-lpr–lpr mice immunized with DNA [22–24].

It is obvious that in MS patients auto-Abs directed to nucleic acids, proteins, and polysacchar‐ ides with different catalytic functions may be induced by primary antigens. During the development of spontaneous and MOG-induced EAE in C57BL/6 mice, a specific reorganiza‐ tion of the immune system of mice takes place. This causes the generation of harmful catalyt‐ ically active IgGs-hydrolyzing MOG, MBP, and DNA, as well as changes in differentiation of HSCs and to the increase in proliferation of lymphocytes and apoptosis in different organs [110]. Treatment of control non-autoimmune CBA mice with MOG led to different differen‐ tiation and proliferation of HSCs comparing with EAE C57BL/6 mice [111].

It was shown that DNA-, RNA-, oligosaccharide-, and MBP-hydrolyzing IgGs and/or IgAs and IgMs from patients with Ms are catalytically very heterogeneous; these Abzs can contain kappa- and lambda-types of light chains, demonstrate different affinity for substrates, different pH optima, may be metal-dependent or independent, and catalyze the hydrolysis of MBP as serine-like or metalloproteases. IgGs of four subclasses (IgG1–IgG4) are catalytically active in the hydrolysis of DNA and MBP, with their different contribution to the total activity of these Abzs in the hydrolysis of these substrates.

MS patients demonstrate some similarity with SLE patients in the development of the same medical, biochemical, immunological indexes including specific plaques in the brain, which appear on late stages of these diseases. Anti-DNA Abs is known as the main important diagnostic index for SLE, but these Abs were also identified as a major component of the intrathecal IgGs in brain and CNS cells of MS patients [40].

It is known that demyelinating plaques appear at relatively late stages in the development of MS, and their presence detected by brain MRI are essential for the diagnosis according to Mc Donald's criteria. At the same time, the detection of Abzs with DNase- and MBP-hydrolyzing activities was shown to be the earliest indicator of development of MS. Catalytic activities of nuclease and protease Abzs are usually very easily detectable at the onset of MS and other autoimmune diseases when the total concentrations of Abs to DNA, MBP, or other autoantigens are still low and correspond to their ranges in healthy donors. Although Abzs with low activity can sometimes be detected in conventionally healthy people, the RAs of Abzs from MS and SLE patients are usually 1–3 orders of magnitude higher. Therefore, an appearance of some Abzs or a 10- to 100-fold increase in the activity of others over the average Abzs indices for healthy donors may be used as the earliest markers of autoimmune reactions in patients with MS and other autoimmune diseases.

Recognition and degradation of MBP peptides by serum auto-Abs was stated as a novel biomarker for MS [82]. But IgGs from SLE patients also efficiently hydrolyze MBP and oligopeptides corresponding to different AGDs of MBP [84, 85]. Thus, it is clear that early diagnostics of MS requires the use of all known independent methods to exclude SLE and probably other possible diseases leading to a formation of DNA- and MBP-hydrolyzing Abzs. Nevertheless, even revealing of DNase and RNase Abzs on early stages of MS may be very useful. For example, in the case of three patients, we have suggested the possibility of initial stages of MS, but the symptoms did not meet all Poser's and Mc Donald´s criteria. However, Abs found in the sera of these patients demonstrated a high DNase activity speaking in favor of a possibility of an early stage of MS. One and a half years later, these patients met Poser's and Mc Donald´ criteria, and after 2–3 consecutive years, brain plaques were also found in these patients.

The immune systems of individual MS patients generate Abzs, which can attack MBP of myelin-proteolipid shell of axons, while an established MS therapeutic Copaxone inhibits specific MBP-hydrolyzing activity of Abzs [82]. It means that the development of MS and probably SLE or other diseases associated with demyelination can be suppressed by specific inhibitors of MBP-hydrolyzing IgGs, IgAs, and IgMs.

All data indicative of the fact that CFU-E cells can be precursors of cells producing Abzs in different organs. In this connection, it should be mentioned that IgGs from CSF of patients with MS 30- to 50-fold more active in the hydrolysis of MBP, DNA, and oligosaccharides, then Abs from sera of the same patients [110, 111]. It means that even CSFs of patients with MS contain specific cells producing these catalytically active Abs. Moreover, DNase Abzs form SLE and MS patients are cytotoxic and induce apoptotic cell death. SLE and MS Abzs efficiently hydrolyzed polysaccharides. Therefore, it is very possible that abzymes with DNase, amylase, and MBP-hydrolyzing activities may in addition to other different factors cooperatively promote important neuropathological mechanisms in MS and SLE pathogenesis development.
