Rheumatoid factor (RF) was described by Waaler in 1940 and by Rose and his associates in 1948. It was found in sera of a majority of patients with rheumatic arthritis; it combined with rabbit antibodies sensitizing sheep erythrocytes and caused agglutination of these erythrocytes. In the second part of the 1950s, a general consensus was reached among workers in the field that RF detected in sera of patients with rheumatoid arthritis is an antibody of the immunoglobulin M (IgM) class combining with the Fc fragment of IgG originating from a variety of species; the most frequently studied IgGs were of rabbit and human origin. It was shown that RF reacting with rabbit IgG is different from RF reacting with human IgG and that there also exists a cross-reacting RF, presumably a multispecific antibody combining with IgG of both of these species. Later, in addition to IgM, RF was shown in the IgG and IgA classes. The heterogeneity of RF justified the use of the plural - RFs.
Some investigators have referred to all RFs as autoantibodies. This does not seem justified at all with reference to the RFs combining with IgG of foreign species. Furthermore, RFs combining with human IgG frequently react only with aggregated IgG or, otherwise, with IgG of the allotypic specificity other than that of the patient. Again, neither of these RFs should be called an autoantibody. The term autoantibody should be reserved for those RFs that react with the patient's own native IgG; some evidence for the existence of such RFs has been presented.
An important observation concerning specificity of RFs was made by Hannestad and his associates in the 1970s. They demonstrated RFs which in addition to IgG reacted with other unrelated antigens such as nuclear antigens or cardiolipin. Significantly, the same molecule of RF could react with IgG and these unrelated antigens. It has been proposed that such a cross-reacting RF molecule recognizes shared epitopes on these antigens; alternatively, it has been suggested that the cross-reacting RF is a multispecific antibody with separate or overlapping combining sites for different epitopes.
Another type of serum factor was described by Milgrom, Dubiski and Wozniczko in a few samples (less than 1%) of human sera in 1956. Similar to RFs, it is an IgM antibody combining with IgG antibodies, however this factor reacts only with human antibodies and only if they appear in the form of immune complexes; it does not react with free antibodies. Accordingly, this factor provided evidence for the long disputed thesis about molecular transformation of an antibody molecule in the course of its reaction with the antigen. Furthermore, the characteristics of this factor encouraged the hypothesis that this factor as well as RFs are formed in response to a stimulus exerted by the individual's own IgG antibodies altered during in vivo reactions with their antigens. According to this hypothesis, RFs as well as other AAs in human sera would represent stereotypes of reactions of subjects exposed to prolonged immunizing stimuli. This was consistent with the demonstration of RFs in several pathologic conditions other than rheumatoid arthritis, primarily in subacute bacterial endocarditis. This hypothesis was further supported by studies on experimental animals, which showed that immunization with partially denatured autologous IgG as well as prolonged exposure to any strong antigen resulted in formation of RF-like antibodies. Alternatively, several investigators postulated that RF may be formed as a result of polyclonal stimulation of B cells by mitogens released or created under various pathologic conditions.
The pathological role of RFs in rheumatoid arthritis has been repeatedly suggested but never substantiated convincingly. In recent years, more and more studies have been conducted on IgG RFs. It has been shown that these RFs have a propensity for self-aggregation in that each RF molecule may act as an antigen through its Fc fragment and as an antibody through its Fab fragment. Evidence has been obtained that such aggregates may form immune deposits responsible for or contributing to glomer-ulonephritides.
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