Arthritis and Rheumatism VOL. IV, NO. 6 DECEMBER, 1961 HISTORICAL ESSAY The History of the Rheumatoid Factor By CHARLES RAGAN T HE SIGNIFICANCE of the rheumatoid factor in the pathogenesis of rheumatoid arthritis remains conjectural. This contribution on its historical aspects will add nothing to the solution of the problem but will relate chronologically the development of the factor. Part of the information is first-hand, part second-hand, but none is farther from the source than second-hand. In the dark past of the study of rheumatoid arthritis-less than thirty years ago-investigators were struck by those clinical characteristics of the disease which pointed to an infectious etiology: it was often called infectious arthritis. Cecil, Nichols and, Stainsby described a particular streptococcus they were able to isolate from the blood and joints of patients with rheumatoid arthritis. In retrospect, it should be said that one of the members of the husband-andwife team of Nichols and Stainsby had a series of quinsy sore throats that winter. As confirmation of the etiological role of this particular streptococcus, the sera of patients with rheumatoid arthritis agglutinated the organism. This caused, understandably, a furore in rheumatism circles m d numerous attempts were made to confirm or refute the observation. Among the more complete and detailed of these attempts was the series of papers by M. H. Dawson. In carefully controlled microbiological studies, he was unable to isolate the organism from patients with rheumatoid arthritis, but did confirm that a number of such patients possessed an agglutinin for the organism. He then showed that the agglutinin reacted with all group A hemolytic streptococci and, in some instances, with pneumococci and staphylococci. The general feeling through the 1930's was that the streptococcus agglutination reaction was a nonspecific one, but lurking in everyone's mind was the possibility that the streptococcus might play an etiological role. The procedure could be trusted only in one or two laboratories in the world and was quite unwieldy. As an example, the author attempted to recover the agglutinin and From the Department of Medicine, Columbia Unicersitv CoUege of Physicians and S w geonr, and the Edward Daniels Faulkner Arthritis Clinic of the Presbyterian Ho@al, New Ymk, N. Y. 571 572 CHARLFS RACAN exposed 100 cc. of high-titered serum repeatedly to grcup A streptococci until almost all the material had been removed from the supernatant. Alter gentle washing, the factor was removed with barium chloride. Finally, after pressure dialysis, a fairly pure material was obtained which would agglutinate group A streptococci. Only microgram amounts of nitrogen were present and the project was finally abandoned. Subsequently. Lamont-Havers was able to show that the streptococci were sensitized by an antistreptococcal antibody present in most sera after the neonatal period. The rheumatoid factor then reacted with the antibody, the streptococcus serving only as a particulate carrier. The next phase was related to the sensitized sheep cell agglutination. A technician working under Professor Harry Rose, (of Columbia University) in microbiology-Miss Elizabeth Pearce-had rheumatoid arthritis and was being followed in the Arthritis Clinic. Dr. Rose at that time was interested in rickettsia1 pox, which had recently been described in New York City. Miss P e a r c e a s seems to happen to investigators of Rickettsia--contracted the disease. Following her recovery, she attempted to set up complement fixations with her serum against the Rickettsia, and her serum agglutinated the sensitized cells. Dr. Rose suggested that the observed agglutination might be due to her primary disease and we found that a significant number of patients with rheumatoid arthritis would agglutinate, in high titer, sheep red cells sensitized with antisheep cell rabbit serum. A comparison with the streptococcus agglutination was attempted and the correlation was good but not complete. Mrs. Miriam 0. Lipman, who had been working with the streptococcus agglutination for over 15 years, carried out this part of the investigation. Shortly after the paper describing these results was published, she recalled that she had heard a paper given by Waller at the 2nd Microbiological Congress, before the war, in which he had described the agglutination of sensitized sheep cells by the sera of patients with rheumatoid arthritis. The other authors of the Columbia paper were not aware of this, and it is to be regretted that Waller's contribution was not acknowledged in that paper. Heller then took up the study of this phenomenon. He was able to circumvent the differential titer by adsorbing the unsensitized sheep cell agglutinin (Forsman antigen), permitting a single titration. He then observed that the reaction was inhibited by prior adsorption with Cohn Fraction I1 (human gamma-globulin) . Utilizing the tanned cell technique, Heller adsorbed Cohn Fraction I1 on tanned sheep erythrocytes and devised the F I1 tanned sheep cell agglutination (FII TSCA) . This proved to be a standardizable procedure, yielding consistent results with the same serum over a period of time. This had not been possible with the original sensitized sheep cell techniques in wliich titers varied from week to week. In the United States, the FII TSCA technique became the most reliable procedure. In Britain, Ball's sensitized sheep cell technique, which has an inner standard, was equally reproducible. Up to this time, the carrier system of particles revolved about the red cell. In the mid 194O's, Wallis had published a series of papers showing that rheumatoid serum would agglutinate collodion particles. This observation was checked in numerous laboratories and it developed that only the serum of patients with far-advanced disease would do this. It so happened that Wallis HISTORY OF RHEUMATOID FACTOR 573 was working with patients from a county hospital who were far-advanced in their disease. In retrospect it may be seen that these were patients with the capacity to produce a spontaneous precipitate. This phenomenon had been observed earlier by Chasis and McEwen. These sera will agglutinate any particulate matter, presumably because the rheumatoid factor forms a cryoprecipitate combining with a component of the patient’s own 7s gamma-globulin. Singer and Plotz then utilized the uniform characteristics of the latex particle as well as Heller’s observation regarding Cohn Fraction 11. Latex particles provided the ideal carrier and a component of Cohn Fraction I1 provided the reactant with which the rheumatoid factor reacted. This is, at present, one of the most commonly used and practicable methods for determining the rheumatoid factor in clinical practice. The Bentonite flocc!dation method devised by Bozicevich and Bunim and their co-workers is also widely used. It now became apparent that the rheumatoid factor was reacting with gamma-globulin. Epstein took the next logical step and showed that a precipitate could be derived from the combination of these two components. Certain peculiar characteristics of the curve developed. These were chiefly resolved by Christian, who showed that the factor reacted with aggregated-essentially, partially denatured-gamma-globulin and failed to combine with unaggregated 7s gamma-globulin. Foz and Batalla and Vaughan had previously shown that the factor reacted with immune complexes, bacterial-antibacterial globulin complexes and immune precipitates. In essence, it is assumed that the factor reacts with gamma globulin when in the aggregated form: naturally, when combined with antigen or artificially, when affected by heat. These observations provided the protein chemists, such as Kunkel and Franklin, with the opportunity to isolate the factor in relative purity. They also permitted the detailed immunopathologic studies of Mellors, localizing the origin of the factor in plasma cells and undifferentiated lymphocytes. There is now evidence to show that the factor may be multipl-at least one for rabbit gamma-globulin as in an immune complex, and one for aggregated human gamma-globulin. Serendipity has obviously played a large part in the development of our understanding of the rheumatoid factor. Regardless of its role, whether it is directly related to the lesion of rheumatoid arthritis or is only another Wassermann type reagin, investigation of the factor has widened the approach to the study of rheumatoid arthritis. It has interested many in the disease and for that reason alone-the attraction of some of the best investigative minds to the field-it has been a worthwhile project. Charles Ragun, M.D., Director, First Medical Dicision, Relleuue Hospital, N e w York, W .Y.