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RF detected by agglutination of tanned IgG-loaded erythrocytes is involved in negative idiotypic regulation of lymphocytes specific to autoimmunity-inducing antigens.

Previously, we showed that immunoglobulin G (IgG) Fc fragments can expose neoepitopes specific to antibodies that were named regulatory rheumatoid factor (regRF). RegRF confers resistance to experimental autoimmune diseases. Immunization of rats with rat Fc fragments exposing neoepitopes recognized by regRF reduces the symptoms of collagen‐induced arthritis. Therefore, IgG Fc fragments that expose neoepitopes recognized by regRF are promising antirheumatic agents and regRF‐producing lymphocytes are potential therapeutic biotargets. The purpose of this study was to elucidate the physicochemical features of human IgG Fc fragments that are associated with the presence of immunosuppressive neoepitopes recognized by regRF. It was found that the acquisition of neoepitopes recognized by regRF is associated with a reduction of the hinge disulfide bonds and conformational changes in the Fc fragment domains. Alkylation of thiol groups in the hinge leads to loss of the epitopes. Therefore, the neoepitopes recognized by regRF may form directly in the hinge when interchain disulfide bonds are reduced or in the region of the CH2 domain as part of the conformational changes caused by the reduction of the interchain disulfide bonds in the hinge. Species‐specificity studies of neoepitopes recognized by regRF revealed that human and rat neoepitopes recognized by regRF are cross‐reactive.

Formation dynamics of antibodies to rat erythrocytes (REs) and auto-antibodies to mouse erythrocytes were studied in an experimental model of autoimmune hemolytic anemia (AHA) in mice. The experimental conditions of AHA were simulated in a mathematical model of an immune network. It was found that maximal production of auto-antibodies and antibodies to REs do not synchronize. Antiserum, obtained at the peak of auto-antibodies formation, competed with REs for bounding with antibodies. This represents proof that auto-antibodies to erythrocytes and antibodies to REs are an idiotype-anti-idiotypic pair. In the autoimmune reaction, the autoreactive clone, being anti-idiotypic, responded earlier than the clone reacting to the injected antigen. Comparison of autoimmune reaction kinetics in the mathematical model of an immune network with experimental dynamics of AHA shows them to be similar. So activation of the autoreactive clone to erythrocytes during experimental AHA in mice is mediated by idiotype-anti-idiotypic interactions with the clone reacting to REs.

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