Rheumatoid Factors and the Etiology of Rheumatoid Arthritis*

I n the absence of evidence for cell-mediated ("delayed hypersensitivity") phenomena in rheumatoid arthritis, the widely held concept that the disease is autoimmune is based largely on the high incidence of rheumatoid factor (RF) in affected individuals and on the concomitant assumption that these factors are autoantibodies with etiologic or pathogenetic ~ignificance.'-~As yet, however, data demonstrating that RF plays an etiologic role in the pathogenesis of rheumatoid arthritis are lacking.Indirect evidence for autoreactivity of RF with autologous 7-globulin exists, e.g., the occurrence of a 22 S complex and/or prozone in a minority of rheumatoid sera; however, serologic studies of the relationship of R F specificity to the genetic determinants of human 7- globulin suggest that the rheumatoid factors of single individuals display preferential specificity for Gm determinants absent in each patient's autologous 7-globulin, i.e., isospecificity rather than auto~pecificity.~The rare reports to the contrary5 may be attributable to mistaking an anti-Gm(r) agglutinator for an anti-Gm(a) agglutinator in a Gm(a+r -) subject, since 90 per cent of Gm(a+) subjects are Gm(r+).6tAlternatively, the observed data may reflect acquisition of serologic activity characteristic of Gm(a) or Inv(a) positivity by Gm(a-) or Inv(a-) 7 S yglobulin as a result of denaturation' during isolation procedures.Since Milgrom and Witebsky" have defined autoantibody as "an antibody capable of interacting with native unaltered antigens," such reactions with denatured autologous antigens fail to fulfill the criterion for autoantibody.Other reports have ascribed the prozone phenomenon occasionally seen in Gm systems to the simultaneous occurence in rheumatoid serum of an anti-Gm rheumatoid factor and ?-globulin of the corresponding 'These studies were aided by Contract No.-3656(12) (NR 105-308) between the Office of Naval Research, Department of the Navy, and the University of California Medical Center, San Francisco, by U. S. Public Health Service Grants H-5997, A-2594, A-1431 and A-5141, and by funds from the Northern California Chapter of the Arthritis and Rheumatism Foundation.tSuch examples may be analogous to the rare instances in which D+ (Rh+) individuals produce anti-D antibodies which react with all D + red cells other than the autologous cells.Hemolytic anemia does not result.Presumably such individuals have a rare variant of the D antigen in which a minor part of the normal "D" antigenic configuration is lacking.(For a complete list of such anti-D antibodies, see RACE, R. R. & R. SANGER.1962.Blood Groups in Man.4th Ed.Table 39.: 162.Blackwell.Oxford, England.