Abstract
BackgroundPrevious studies indicate that natural bispecific antibodies can be readily produced in vivo when the body is simultaneously stimulated with 2 distinct antigens. Patients with rheumatoid arthritis (RA) usually exhibit persistent immune responses to various autoantigens, raising the possibility that natural bispecific antibodies against 2 distinct autoantigens might exist.Methodology/Principal FindingsWe identified the presence of natural bispecific antibodies against cyclic citrullinated peptide (CCP) and immunoglobulin G (IgG) in RA patients' sera by means of a double-antigen sandwich enzyme-linked immunosorbent assay (ELISA). The spontaneous emergence of bispecific antibodies was confirmed by mixing different proportions of 1 anti-CCP-positive serum and 1 rheumatoid factor (RF)-positive serum in vitro. Among the tested samples, positive correlations were found between the presence of bispecific antibodies and both IgG4 anti-CCP antibodies and IgG4 RF (r = 0.507, p<0.001 and r = 0.249, p = 0.044, respectively), suggesting that the IgG4 subclass is associated with this phenomenon. Furthermore, bispecific antibodies were selectively generated when several anti-CCP- and RF-positive sera were mixed pairwise, indicating that factors other than the monospecific antibody titers may also contribute to the production of the natural bispecific antibodies.Conclusions/SignificanceWe successfully identified the presence of natural bispecific antibodies. Our results suggest that these antibodies originate from anti-CCP and RF in the sera of RA patients. The natural occurrence of bispecific antibodies in human diseases may provide new insights for a better understanding of the diseases. Further investigations are needed to elucidate their precise generation mechanisms and explore their clinical significance in disease development and progression in a larger study population.
Highlights
We have previously reported the production of natural bispecific antibodies in rabbits that were simultaneously immunized with 2 unrelated antigens [1]
The bispecific antibodies were strongly correlated with immunoglobulin G (IgG) rheumatoid factor (RF) (r = 0.792, p,0.001) and were reasonably correlated with IgG4 anti-cyclic citrullinated peptide (CCP) (r = 0.507, p,0.001); relatively weak correlations were found with IgG antiCCP and IgG4 RF (r = 0.401, p = 0.001 and r = 0.249, p = 0.044, respectively) (Fig. 3)
Another 3 anti-CCP-positive but bispecific antibody–negative samples were mixed with 5 RF predominant samples pairwise; the bispecific antibody and anti-CCP assays were performed for each pair
Summary
We have previously reported the production of natural bispecific antibodies in rabbits that were simultaneously immunized with 2 unrelated antigens [1]. 2 distinct antigens’ simultaneous stimulation is critical for the natural occurrence of bispecific antibodies in vivo. Another research group working on natural bispecific antibodies originating from half-molecule exchanges of IgG4 obtained similar results. The mechanism for the production of natural bispecific antibodies is indicated by exchanges of IgG4 halfmolecule(s) (a heavy chain and an attached light chain) between 2 antibody molecules [3,4,5]. The simultaneous stimulation with 2 distinct antigens is the precondition for the production of natural bispecific antibodies in vivo. Previous studies indicate that natural bispecific antibodies can be readily produced in vivo when the body is simultaneously stimulated with 2 distinct antigens. Patients with rheumatoid arthritis (RA) usually exhibit persistent immune responses to various autoantigens, raising the possibility that natural bispecific antibodies against 2 distinct autoantigens might exist
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