Formation of different abzymes in autoimmune‐prone MRL‐lpr/lpr mice is associated with changes in colony formation of haematopoietic progenitors

Abstract

It was shown that IgGs from the sera of 2–7-month-old control non-autoimmune (CBA x C57BL)F1 and BALB/c mice and 2–3-month-old autoimmune prone MRL-lpr/lpr mice (conditionally healthy mice) are catalytically inactive. During spontaneous development of deep systemic lupus erythematosus (SLE)-like pathology a specific reorganization of immune system of these mice leads to conditions associated with a production of IgGs hydrolyzing DNA, ATP and polysaccharides with low catalytic activities (conditionally pre-diseased mice).A significant increase in DNase, ATPase and amylase IgG relative activities associated with a transition from pre-diseased to deep diseased mice is correlated with additional changes in differentiation and proliferation of mice bone marrow haematopoietic stem cells (HSCs) and lymphocyte proliferation in different organs.The highest increase in all abzyme activities was found in mice immunized with DNA, which in comparison with pre-diseased and diseased mice are characterized by a different profile of HSC differentiation and by a suppression of cell apoptosis. Abzyme activities in the serum of pregnant females were comparable with those for pre-diseased mice, but the profile of HSC differentiation and cell apoptosis levels in pregnant and pre-diseased mice were quite different. Right after the beginning of lactation (4 days after delivery) and in a late time of lactation (14 days after delivery) there was an observed increase in cell apoptosis and two different stages of significant change in the HSC differentiation profiles; the first stage was accompanied with a significant increase and the second with a remarkable decrease in abzyme activities. Overall, all mouse groups investigated are characterized by a specific relationship between abzyme activities, HSC differentiation profiles, levels of lymphocyte proliferation, and cell apoptosis in different organs. From our point of view, the appearance of ATPase, DNase activities may be considered the earliest statistically significant marker of mouse spontaneous SLE and a further significant increase in their activities correlates with the appearance of SLE visible markers and with an increase in concentrations of anti-DNA Abs and urine protein. However, development of autoimmune (AI)-reactions and the increase in the sera anti-DNA antibodies (Abs) and in the abzyme activities in pregnant and lactating mice do not associate with SLE visible markers and proteinuria. The possible differences in immune system reorganizations during pre-disease, disease, pregnancy and lactation leading to production of different auto-antibodies and abzymes are discussed.

Catalytic Antibodies in Norm and Systemic Lupus Erythematosus

“…The average anti-DNA Abs concentration in the case of (CBAxC57BL)F1 and BALB/c nonautoimmune control mice was estimated to be approximately 0.03-0.04 A 450 units and was comparable with that for healthy autoimmune-prone MRL-lpr/lpr mice (0.032 A 450 units) [29][30][31]. After spontaneous development of SLE in MRL-lpr/lpr mice (depending of individual mice during 4-7 months), it increases to 0.2 A 450 units, but there were no remarkable change in the anti-DNA Abs titers in the case of control nonautoimmune mice during 7-8 months of the experiment [29][30][31].…”

“…It was shown that abzymes with different activities may be obtained with a significantly higher incidence in autoimmune mouse strains comparing to conventionally used control nonautoimmune mice [51,52]. Immunization of autoimmune-prone MRL-lpr/lpr mice with DNA-protein complexes also results in significantly higher production of anti-DNA Abs and abzymes with DNase activity comparing with nonautoimmune CBA and BALB/c healthy mice [29][30][31]. At the same time, artificial antiidiotypic abzymes can be induced by immunization of animals with different enzymes [23][24][25][26][27][28].…”

“…After spontaneous development of SLE in MRL-lpr/lpr mice (depending of individual mice during 4-7 months), it increases to 0.2 A 450 units, but there were no remarkable change in the anti-DNA Abs titers in the case of control nonautoimmune mice during 7-8 months of the experiment [29][30][31]. After MRL-lpr/lpr mice immunization with complex of methylated-BSA with DNA (further marked as DNA), the average concentration of anti-DNA Abs increased to approximately 0.6 A 450 units [29][30][31]. It should be mentioned that IgG antibodies from the sera of control 2-7 month-old nonautoimmune CBA and BALB mice and conditionally healthy 2-3 months old MRL-lpr/lpr mice were shown to be catalytically inactive [29][30][31].…”

“…Mice demonstrating all visual symptoms and biochemical indexes of SLE were designated as diseased animals. We have compared healthy (2-3 months of age) and spontaneously diseased MRLlpr/lpr mice with all visible symptoms no older than 7 months [29][30][31]. For a more precise characterization of the various states of these mice, we have evaluated a variety of medical, biochemical, and immunological characteristics of their status including the relative levels of Abs to various autoantigens of abzymes demonstrating different catalytic activities.…”

“…However, specific positive roles have been also proposed for several abzymes. Increase in Abzs activities is associated with a specific reorganization of the immune system including change in differentiation profile and level of proliferation of hematopoietic stem cells of bone marrow as well as lymphocyte proliferation in different organs of SLE and experimental autoimmune encephalomyelitis (EAE) in mice [29][30][31][32]. Different mechanisms of abzymes production were revealed in healthy animals after external immunization and in autoimmune mice during their spontaneous or antigen-induced development of autoimmune processes [29][30][31][32].…”