Nucleotide sequences specific for nonnominal immunoglobulin allotypes in rheumatoid arthritis patients and in normal individuals and their expressionin synovial tissue of rheumatoid arthritis patients

The production of antibodies against nonnominal immunoglobulin allotypes in rheumatoid arthritis (RA) patients suggests that the immune system of thes e patients has been exposed to such foreign allotypes. The presence of nonn ominal allotypes is, however, a genetic enigma. We searched for nucleotide sequences specific for nonnominal G3m(g) and G3m(b) copies in individuals h omozygous for these alleles. Using a sensitive and specific nested polymera se chain reaction (PCR) method with genomic DNA from blood of 18 RA patient s and 5 normal controls, we found G3m(g) sequences in 18 of 18 tested G3m(b ) homozygous persons. The allele specificity of the PCR fragments was confi rmed by sequencing and RFLP analysis. The PCR products contained genomic no nspliced parts of the nonnominal sequences. An analysis of cDNA from inflam matory tissue of 5 RA patients detected nonnominal G3m(b) sequences in 1 of 3 tested G3m(g) homozygotes and G3m(g) sequences in 2 of 2 tested G3m(b) h omozygotes. The cDNA-derived PCR products contained sequences from normally spliced nonnominal Ig fragments. The results also showed that the nonnomin al Ig sequences were present in very low copy numbers, lower than the Mende lian 1-2 copies per cell. The origin of such a low copy number of Ig gene f ragments may be explained by a virus-mediated capture and transfer mechanis m of Ig gene fragments generated by the normal Ig switch-associated gene ex cision process.