Comparison of rheumatoid factors of rheumatoid arthritis patients, of individuals with mycobacterial infections and of normal controls: evidence for maturation in the absence of an autoimmune response.
We analyzed the rheumatoid factors (RF) produced by Epstein-Barr virus-transformed monoclonal B cells established from four patients with rheumatoid arthritis (RA), three individuals with a history of Mycobacterium tuberculosis (TB) and four normal controls (NI). Fifty-eight RF were analyzed for specific activity (international units-RF/microgram) for the Fc part of IgG and their interaction with tetanus toxoid (TT) and DNA (polyspecificity). Furthermore, we sequenced the V-D-J heavy chain region of 16 (9TB-/7RA-) RF. Significant differences were observed between the NI-RF and the TB- and RA-RF. While the RF repertoire of normal individuals comprised of low-avidity RF of which the majority (15/17) were polyspecific, more than half of the TB- and RA-RF were monoreactive. Furthermore, the monospecific TB- and RA-RF were of significantly higher avidity than the NI-RF (RA > TB > > NI). With respect to polyspecificity specificity, the RF in the three groups were comparable: the interaction with DNA, TT as well as with Fc was inhibited either by an increase of the ionic strength to 0.3-0.5 M NaCl or by addition of the polyanion dextran sulfate, indicating that the antibodies interacted with similar anionic epitopes shared by the three antigens. Analysis of the V-D-J heavy chain regions showed significant differences between the respective RF. The salt-sensitive binding was highly correlated with the presence of arginine in the complementarity-determining region 3 (CDR3). Furthermore, whereas the polyspecific RF consisted predominantly of germ-line encoded antibodies, the genes of the monospecific RA/TB-RF were somatically mutated (RA > TB). It is therefore likely that maturation of RF can be initiated by chronic infections and that monospecific, somatically mutated RF are not a unique characteristic of autoimmune diseases.
Department of Medicine, Hôpital cantonal universitaire de Genève, Switzerland.
N
N
Djavad
S
S
Bas
X
X
Shi
J
J
Schwager
M
M
Jeannet
T
T
Vischer
E
E
Roosnek
D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D000838:Anions; D000918:Antibody Specificity; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D001483:Base Sequence; D000939:Epitopes; D005260:Female; D005803:Genes, Immunoglobulin; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D012217:Rheumatoid Factor / Q000235:genetics / Q000276:immunology*; D014391:Tuberculosis, Miliary / Q000276:immunology*; D014394:Tuberculosis, Osteoarticular / Q000276:immunology*
D000838:Anions; D000939:Epitopes; D012217:Rheumatoid Factor