Immunoglobulin G structure and rheumatoid factor epitopes

Abstract

Antibodies are important for immunity and exist in several classes (IgM, IgD, IgA, IgG, IgE). They are composed of symmetric dimeric molecules with two antigen binding regions (Fab) and a constant part (Fc), usually depicted as Y-shaped molecules. Rheumatoid factors found in patients with rheumatoid arthritis are autoantibodies binding to IgG and paradoxically appear to circulate in blood alongside with their antigen (IgG) without reacting with it. Here, it is shown that rheumatoid factors do not react with native IgG in solution, and that their epitopes only become accessible upon certain physico-chemical treatments (e.g. heat treatment at 57 °C), by physical adsorption on a hydrophobic surface or by antigen binding. Moreover, chemical cross-linking in combination with mass spectrometry showed that the native state of IgG is a compact (closed) form and that the Fab parts of IgG shield the Fc region and thereby control access of rheumatoid factors and presumably also some effector functions. It can be inferred that antibody binding to pathogen surfaces induces a conformational change, which exposes the Fc part with its effector sites and rheumatoid factor epitopes. This has strong implications for understanding antibody structure and physiology and necessitates a conceptual reformulation of IgG models.

Comparison of the specificity of rheumatoid factor detected by latex fixation with that of regulatory rheumatoid factor

“…In the presence of residual moisture, freeze‐dried proteins can undergo disulfide interchange and other reactions 13 . Therefore, the data we obtained on the specificity of RF detected in the blood of rheumatoid arthritis patients are consistent with the data that the pathological RF is specific to epitopes that are hidden in the IgG structure (cryptic epitopes) and only become exposed by conformational changes, which may occur upon antigen binding in vivo or in vitro, upon immobilization on surfaces (eg, the hydrophobic polystyrene surface used in routine ELISA for RFs), or under certain physico‐chemical conditions (eg, elevated temperature) 9 …”

“…13 Therefore, the data we obtained on the specificity of RF detected in the blood of rheumatoid arthritis patients are consistent with the data that the pathological RF is specific to epitopes that are hidden in the IgG structure (cryptic epitopes) and only become exposed by conformational changes, which may occur upon antigen binding in vivo or in vitro, upon immobilization on surfaces (eg, the hydrophobic polystyrene surface used in routine ELISA for RFs), or under certain physico-chemical conditions (eg, elevated temperature). 9 Thus, the regulatory rheumatoid factor detected in the blood of healthy donors by agglutination of tanned IgG-loaded erythrocytes and the pathology-associated rheumatoid factor detected by latex fixation differ in their specificity.…”

Peptides, Antibodies, Peptide Antibodies and More

“…X-ray structures of Abs have mainly been limited to isolated Fab and Fc parts, even though a few structures of whole Abs have been published [60,61]. However, recent results using ion exchange-purified IgGs and chemical cross-linking in combination with MS have shown that native IgGs have a compact ("closed") structure [62].…”

Novel and known periodontal pathogens residing in gingival crevicular fluid are associated with rheumatoid arthritis

“…45,46 Besides, recent evidence indicates that RFs recognize cryptic epitopes on the Fc fragment, different for IgM's or IgA's, that seem exposed only after a conformational change of the IgG induced upon antigen binding. 47 This may somewhat afford an explanation to why only RF isotype IgA correlated with P. gingivalis.…”