Molecular signatures of anti-nuclear antibodies--contribution of heavy chain framework residues

It is clear that besides the CDR residues, framework residues (particularly those on FR1 and FR3) can contribute towards antigen reactivity. This study was designed to compare the immunoglobulin heavy chain FR regions of anti-nuclear antibodies (comprised of 142 anti-ssDNA, 103 anti-dsDNA and 23 anti-nucleosome Abs) with those of non-nuclear antibodies (N=165), all drawn from the GenBank. The anti-nuclear antibodies depicted residue-usage differences that reached statistical significance in their FR1 (at H1 and H29), FR2 (at H40), and FR3 (at H69, H73, H76, H80 and H87) regions. Interestingly, these residue-usage differences were intimately linked to differences in the usage frequencies of different V(H) germline genes between the different groups of antibodies; thus, whereas J558.4, J558.47, J558.m, and 7183.9 germline genes were over-utilized among the ANAs, J558.17, V130, V(H) 36-60 and VGk1a were over-represented among the non-ANAs. In conclusion, although the framework regions of ANAs exhibited distinctly different residue-usage patterns, they may simply be markers of associated germline-encoded CDR differences that appear to have been co-selected. Further studies are warranted to ascertain if any of the observed framework residue differences do actually contribute to nuclear antigen reactivity.