Rheumatoid factor autoantibodies in health and disease.

Since their discovery, a vast amount of work has been done on the incidence, specificity, and genetics of human rheumatoid factors (RF) in a great many laboratories. In the main, these studies were inspired by the association of RF with RA and the hope that understanding mechanisms of their production may help define disease pathogenesis. However, studies of RF production and incidence have shown that RF are not restricted to patients with RA and that genes encoding RF are inherited in the normal human population. Furthermore, the documentation that RF specificity can be part of the natural antibody repertoire during early fetal life and that normal adults can produce RF following immunization are important indications for their physiological role in normals and in understanding mechanisms of B cell regulation in health and disease. The initial attempts to define RF structure and genetics benefited from serological analysis with anti-idiotypic reagents and amino acid sequence analysis of RF paraproteins, or “M” components, from patients with mixed cryoglobulinemia, Waldenstrom’s macroglobulinemia, and chronic lymphocytic leukemia. More recently, nucleotide sequence analysis of RF genes isolated from immortalized human B cell hybridomas from normals and RA patients in our laboratories, and others, provided significant insight into how RF are produced and likely to be r e g ~ l a t e d . ~ ~ Here, we show that RF produced in normal individuals are different from those found in the synovium of RApatients. RF in normals are frequently encoded by a limited set of IgV genes, do not appear to switch isotype, and have few replacement mutations in the CDRs. These observations support the concept that RF are under strict control to prevent the emergence of high-affinity RF in normals.