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.
Highlights
ImmunoglobulinsImmunoglobulins (Igs) constitute an important part of the immune defence against pathogens and help to recognize and remove foreign antigens [1,2,3,4]
Rheumatoid factors (RFs) IgM and RF IgA were measurable in the fractions from the RF-positive sample (whereas no RF activity was present in a healthy donor (HD) pool)
This clearly illustrates the paradoxical situation with RFs being present in rheumatoid arthritis (RA) sera without reacting with their antigen, in blood alongside with their antigen (IgG), since no IgG was present in the IgM peak and since the RFs in the peak were capable of reacting with IgG in the RF enzyme-linked immunoassay (ELISA)
Summary
Immunoglobulins (Igs) constitute an important part of the immune defence against pathogens and help to recognize and remove foreign antigens [1,2,3,4]. Igs are called antibodies and occur in several classes (IgM, IgD, IgA, IgG, IgE) and subclasses (IgG1-4, IgA1,2) with different structures and effector functions. All Igs/antibodies share the same basic unit design of two identical heavy chains with an N-terminal variable domain, and three or four constant domains (CH1-CH4) and two identical light chains with an N-terminal variable. IgG structure and RF epitopes and analysis, decision to publish, or preparation of the manuscript
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