Suppression of experimental autoimmune encephalomyelitis by IgG Fc fragments bearing regRF epitopes.

Previously we identified a rheumatoid factor, the production of which provides rats with resistance to experimental autoimmune diseases. It has been named regulatory rheumatoid factor (regRF). Immunization with conformers of IgG Fc fragments carrying epitopes specific to regRF reduces rat collagen-induced arthritis. The aim of this study was to determine whether IgG Fc fragments bearing regRF epitopes suppress experimental autoimmune encephalomyelitis, and to evaluate the potential of a strategy of stimulating production of regRF to treat multiple sclerosis. Two days after myelin basic protein injection, rats were immunized with Fc fragments exhibiting regRF epitopes, as well as with Fc fragments without those epitopes. The effect of Fc immunization on clinical signs of EAE and immunological parameters was evaluated. Stimulation of regRF production by IgG Fc fragments bearing regRF epitopes diminished EAE symptoms in rats, while immunization with Fc fragments without those epitopes worsened EAE. The improvement of EAE symptoms in rats treated with Fc fragments bearing regRF epitopes was associated with regRF production and with the relatively low number of blood CD4 T lymphocytes during disease development. In experiments involving immunizing intact rats and lymph node mononuclear cell cultures, Fc fragments bearing regRF epitopes decreased the CD4 T lymphocyte population indirectly, via regRF production. RegRF is a promising biotarget in MS, and Fc fragments bearing regRF epitopes are a potential therapeutic agent for MS.

Аtherosclerosis-like changes in the rabbit aortic wall induced by immunization with native high-density lipoproteins.

INTRODUCTION: A high level of total cholesterol or low-density lipoprotein (LDL) cholesterol is considered the main cause of atherosclerosis and cardiovascular disease. For this reason, experimental atherosclerosis is induced by creating high blood cholesterol in animals. However, the hypothesis that atherosclerotic processes are mostly caused by immune (autoimmune) mechanisms has recently been gaining traction. At the same time, no experimental model has been developed that clearly demonstrates the autoimmune mechanism by which atherosclerosis develops and reproduces the full picture of atherosclerosis solely by means of an immune response, without resorting to additional interventions such as a high-cholesterol diet or the use of genetic models of hyperlipidemia. Previously, we were able to induce atherosclerosis-like lesions in the aorta and the development of pericardial fat in rats by immunizing them with human native lipoproteins. The purpose of this study was to test whether atherosclerosis can be induced in normocholesterolaemic rabbits by immunizing them with human native high-density lipoproteins (hnHDL). METHODS: Rabbits were immunized with hnHDL. Aortic wall structure, plasma cholesterol level, and antibodies against HDL were studied. RESULTS: Immunization with hnHDL was found to cause atherosclerosis-like lesions in the rabbit aorta such as adipocytic and chondrocytic metaplasia, proteoglycan deposits, leukocytic infiltration. Atherosclerosis-like lesions developed in the aorta of hnHDL-immunized rabbits against a background of normal blood LDL-cholesterol level. Therefore, a high plasma cholesterol level is not the sole cause of atherosclerosis. The immune response against HDL is an independent cause of atherogenesis. CONCLUSIONS: A rabbit model of atherosclerosis caused by immunization with hnHDL can be widely used to examine the mechanisms occurring during atherogenesis.

Immunoglobulin G amplifies the production of regulatory rheumatoid factor in vitro through idiotype-anti-idiotype interactions.

Immunoglobulin G can inhibit antibody response. The mechanism of immunosuppression by immunoglobulins remains unknown. Recently, we found a new factor of immunoregulation referred to as regulatory rheumatoid factor (regRF). RegRF prevents autoimmunity and reduces experimental autoimmune reactions. RegRF comprises a population of anti-idiotypic antibodies that have a unique paratope specific to the antigen-binding sites of the antibodies, and a shared paratope specific to neoepitopes of IgG Fc fragments. Given the specificity of regRF, we can anticipate that IgG would be able to induce regRF production, and consequently that the immunosuppressive effect of IgG may be mediated by regRF. We found that IgG induces regRF production in a culture of B lymphocytes obtained from the red bone marrow of intact rats. IgG does not expose neoepitopes recognized by the shared paratope of regRF, and does not acquire them in culture. Therefore, the stimulation of regRF production induced by IgG is not a result of the interaction between the shared paratope of regRF and the neoepitopes of IgG. Fc fragments of IgG are unable to stimulate regRF production. Fab fragments inhibit spontaneous regRF production. F(ab´)2 fragments stimulate regRF production in lymphocyte culture. We theorize that IgG activates regRF-producing lymphocytes through idiotype-anti-idiotype interactions.

Fc fragments of immunoglobulin G are an inductor of regulatory rheumatoid factor and a promising therapeutic agent for rheumatic diseases.

We recently identified rheumatoid factor, the production of which neither predicts nor exacerbates experimental autoimmune disease, but the opposite, namely it is associated with autoimmune disease resistance and remission. We have named it regulatory rheumatoid factor (regRF). The aim of this study was to determine whether rat Fc fragments and human Fc fragments are an antigen for regRF, and to determine the conditions for obtaining them. The presence of an antigenic determinant for regRF on IgG fragments was inferred from the fragments' ability to inhibit the agglutination caused by regRF and to induce regRF production in vivo. It was found that antigenic determinants for both human regRF and rat regRF are absent from native IgG and can be induced in the hinge region of Fc fragments of homologous IgG by papain digestion. The rat Fc fragments are susceptible to spontaneous reconfiguration, which results in loss of the antigenic determinants for regRF. Reconfiguration can be observed by SDS-PAGE. Immunization of arthritic rats with Fc fragments of rat IgG that carry antigenic determinants for rat regRF reduces the symptoms of collagen-induced arthritis. The Fc fragments can be viewed as the basis for a therapeutic vaccine to suppress autoimmune responses.

The idiotypic network in the regulation of autoimmunity: Theoretical and experimental studies.

The regulation of autoimmunity is a key issue in fundamental immunology. Despite outstanding achievements on this front, we currently have more questions than answers. The idea of an immune network as a regulatory mechanism is quite attractive, since it enables us to explain the selectivity (specificity), and moreover the clonality, of the regulation. Nevertheless it remains unclear how this mysterious network of immune cells is organized, how it operates, and how it exerts control over autoimmunity. This article presents an attempt to understand how the immune network functions and how it controls autoreactivity. We present a mathematical model of the immune network that is based on principles of immune network organization and function that we arrived at from a survey of the available literature. To test the principles on which the mathematical model is based, we studied the model and compared the different responses to antigen that it generated with the results obtained from experimental studies of immune response. The modeled kinetics of idiotype and anti-idiotype in response to the administration of antigen are in good agreement with the experimental kinetics of idiotypic and anti-idiotypic antibodies. To obtain evidence of the existence of idiotypic mechanisms for regulating autoimmunity, we studied a mathematical model containing autoclones and compared the model results with data from experimental studies in a model of autoimmune hemolytic anemia in mice. Because the results from the theoretical and the experimental studies coincide, there is justification to conclude that autoreactive lymphocytes are normal components of the immune network within which they are regulated. We discuss a possible molecular/cellular mechanism for negative control of autoreactive cells as affected by anti-idiotypic antibodies.