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Associations were sought between major histocompatibility complex (MHC) genes on chromosome 6 and the complement component C3 and immunoglobulin genes located on other chromosomes which might contribute to susceptibility to mild inflammatory arthritis (IA) or definite rheumatoid arthritis (RA). Frequencies of the complement C3F allele were raised in patients with IA but were normal in patients with RA and controls. When associations between C3F and MHC genes were sought frequencies of some MHC genes were greater in patients with C3F than in those without--for example, HLA-B8 and DR3 in patients with RA and DR2 in patients with IA. Conversely, DR4 frequency was lower in patients with IA with C3F than in those without. Thus the C3F allele may act independently or exert an epistatic effect on MHC genes to increase susceptibility or protect against disease. The frequency of the immunoglobulin heavy chain allotype Glm(2) on chromosome 14 was increased in patients with RA but only in those with the phenotype Gm1,2,3,17;21,5; no significant associations were found between MHC genes and Gm phenotypes. Further, no associations of MHC, C3F, and immunoglobulin genes were shared by patients with RA and those with IA, indicating a different genetic basis for the two clinical entities.

Patients with mild inflammatory arthritis (IA) were compared with patients with definite rheumatoid arthritis (RA) for abnormal frequencies of major histocompatibility complex (MHC) antigens and haplotypes to determine whether a genetic predisposition either to RA or to mild self-limiting arthritis/arthralgia was present in the patients with IA. In general the MHC antigens with abnormal frequencies found in patients with IA differed from those in patients with RA and were mainly at the A and B loci. In patients with IA the frequencies of HLA-A24, A25, B27, and B35 antigens were significantly higher than those of controls and HLA-DR5 and C4A4 were slightly raised. In contrast, in patients with RA abnormal frequencies of the MHC antigens DR4 and DR2 and the extended haplotypes associated with them [B62 BfS C4A3 C4B3 DR4 GLO2] and [B7 BfS C4A3 C4B1 DR2] confirmed the observations reported on other white populations. Thus MHC antigen associations with IA and RA differ sufficiently to suggest a different genetic basis for the two conditions.

A new method has been developed to determine the specificities of polyclonal rheumatoid factors (naturally occurring antibodies which react with human Fc gamma) (RF) found in sera from patients with rheumatoid arthritis. In this method, monoclonal anti-Rh(D) antibodies of known IgG isotype and allotype are bound to erythrocytes and then act as the target IgG antigen for RF in a direct haemagglutination test. Using two monoclonal anti-D antibodies of the IgG3 isotype and G3m(21) allotype, which were cloned from different donors, we found that a large number of rheumatoid sera reacted with both these G3m(21) proteins. In contrast reactivity of rheumatoid sera with polyclonal anti-D of the G3m(21) allotype in the direct haemagglutination test was rare. A strong correlation was found between reactivities to both G3m(21) monoclonal anti-D antibodies but not with a monoclonal anti-D antibody carrying the alternative allele, namely G3m(5). Haemagglutination inhibition experiments using human paraproteins of known IgG isotype and allotype provided some additional evidence that this method can detect RF with specificity for the G3m(21) allotypic determinant or a related allotypic determinant in polyclonal rheumatoid sera. When each patient's autoantibody response was related to their Gm phenotype, we found that the frequency of reactivity for G3m(21) monoclonal anti-D antibodies was significantly greater in patients negative for G3m(21) than in patients positive for the G3m(21) allotype. IgM preparations from patients' sera were dissociated at acid pH but no 'hidden' antibodies were found. We suggest trans-placental sensitization as one of several possible interpretations of this finding.

Evidence of recent infection with human parvovirus B19 (HPV) was found in two patients with early rheumatoid arthritis (RA) and in four patients with acute inflammatory arthritis (IA). Both of the patients with RA but only one of the four patients with IA carried RA associated haplotypes. No evidence of persistent infection with HPV was found, but evidence of past infection with HPV was significantly more common in patients with RA than in controls. The results confirm the arthritogenic potential of HPV and are consistent with the hypothesis that rheumatoid arthritis may develop in a genetically predisposed patient after an arthritogenic insult such as an HPV infection.

Human monoclonal anti-Rh(D) antibodies of known IgG isotype and Gm allotype were bound to erythrocytes and then used as the target IgG antigens for rheumatoid factors (RFs) in a direct haemagglutination test. When serum samples from patients with rheumatoid arthritis (RA) were tested for RF specificity towards these IgG monoclonal anti-D antibodies the incidence and titre of reactivity towards an IgG3 monoclonal anti-D antibody was considerably greater than for a polyclonal anti-D antibody of the same Gm allotype, G3m(5). This difference was not explained by the amount of each anti-D antibody which bound to erythrocytes. Furthermore, when patients with RA were divided into groups according to their Gm phenotype, sera from a greater proportion of patients negative for the phenotype G3m(5) reacted to the G3m(5) monoclonal anti-D antibodies than sera from those patients positive for this allotype. Analysis of RF reactivities towards two IgG3 and three IgG1 monoclonal anti-D antibodies, each with different Gm allotypic epitopes, indicated, however, that individual serum samples contained RFs with a spectrum of specificities; some sera appeared to react to a single set of Gm alleles, whereas others also reacted to isotypic or iso-allotypic epitopes, or both. Our data suggest that RFs with specificity for Gm allotypes do not arise in patients who carry that particular allotype owing to tolerance induced in fetal-neonatal life. Conversely, RFs with apparent specificity for a Gm allotype formed in patients negative for that allotype may be reacting to a closely related but different epitope. Final proof requires precise specificities for each RF formed, and IgG3 monoclonal anti-D antibodies would be useful reagents for this purpose.