Anti–γ-globulins or rheumatoid factors (RF) were first described in the early 1940s. They are present in >70% of patients with rheumatoid arthritis (RA) and high titers are associated with severe disease, but they also appear in a large number of other diseases including viral, bacterial, and parasitic infections (1). In spite of their wide spread occurrence, it is still a puzzle how or why RF are generated.
RF come in two varieties. Low affinity RF (Kd of ∼10−5 M) are IgM natural antibodies with specificity for IgG-Fc determinants and cross-reactivity with other autoantigens, i.e., polyreactivity. They are produced by CD5+ B cells in normal subjects (2). Frequently they are IgM κ antibodies and use selected germline V genes for both H and L chains. This is why they share cross-reactive idiotypes, as discovered by Kunkel et al. in the 1970s (3...
