Rheumatoid arthritis--a gene transfer disease

Sera from patients with rheumatoid arthritis (RA) were from the very start instrumental in detecting and delineating the human immunoglobulin (Ig) allotypes in the Gm system. Knowledge that human Ig production is under Mendelian control and not determined by templates of antigen would not have come to the fore if it were not for RA patients. Worldwide experience shows that RA patients are prone to mount an immune response to human Ig allotypes. Major Gm allotypes are defined at the amino acid and nucleotide levels. Gene technology has been developed for defining these allotypes. Studies of the Gm allotypes and anti-Gms have led to two apparently paradoxical findings: (1) In conflict with Mendelian law, non-nominal or hidden allotypes have been observed and recently documented at the DNA level. (2) In RA, an immune response to other individuals' Mendelian allotypes is prevalent, although RA is generally considered an autoimmune disease. These findings led us to conclude that RA is not initially an autoimmune disease but a gene transfer disease. A brief review of viral high-jacking and transfer of human genes is given along with reasons for considering the herpesvirus family in particular. Genes determining incompatible Ig allotypes are transferred. We have shown that these genes are expressed in RA synovia. Ig-anti-Ig complexes arise and may have arthritogenic potential, as observed in serum sickness.