Development of rheumatoid factor research through 50 years

The discovery of Waaler in 1937 initiated fruitful research on RFs. It was not until the early 1960s that investigators in the field agreed that RFs are antibodies to Fc fragment of IgG. Separate factors combining with human and rabbit IgG and a factor combining with both these IgGs were at first demonstrated by mixed agglutination and then by separation through IgG-conjugated columns. Only RF combining with native autologous IgG should be considered an autoantibody. Other RFs are allo- or heteroantibodies. Cross-reacting RFs that combine with IgG of various species or with IgG and antigens of cell nuclei are of considerable interest. This cross-reactivity may be due to a combining site interacting with shared epitopes or otherwise to multispecificity of the RF molecule in that it has separate or partially overlapping combining sites acting on different epitopes. Experimental studies conducted since the mid-1950s showed that formation of RFs may be elicited by altered autologous IgG. Under natural conditions such alteration was shown to result from interaction of IgG antibody with its corresponding antigen and RF in many infectious diseases and possibly also in rheumatoid arthritis appeared to result from stimulation by immune complexes. More recently alterations of IgG by its reaction with microbial Fc receptors as well as non-specific polyclonal stimulation of B cells were shown to play a role in RF formation. RFs have been implemented in the pathogenicity of rheumatoid arthritis. Recent studies on dispersion of immune complexes in tissue sections by aggregated IgG showed that self-polymerization of IgG RFs results in formation of glomerular deposits in various nephropathies.