Molecular Signatures of Antinuclear Antibodies-contributions of Heavy Chain CDR Residues

A database of the Ig heavy chains of 143 anti-ssDNA, 103 anti-dsDNA and 23 anti-nucleosome antinuclear antibodies (ANAs) was constructed, with no clonal overlap, gleaning from published literature. In comparison to the Kabat database of antibodies (N>3600), ANAs (total=269) demonstrated several significant changes, particularly in the incidence of charged or polar residues, in their CDR regions. In particular, anti-dsDNA ANAs differed significantly from anti-ssDNA ANAs in having (a) more 'D' residues at H31 and more 'Y' residues at H33, in CDR1, (b) significantly different distributions of charged or polar residues at H53, H55 and H56 of CDR2, and (c) more 'R' residues at H95-H100 of CDR3. Whereas, the differences in CDR1 and CDR3 are likely to characterize anti-dsDNA ANAs encoded by all VH families, the sequence differences in CDR2 are likely to be VH family specific. Finally, among anti-dsDNA ANAs, there was an enrichment of VH1/J558 germline genes (notably, VH 45.21.1), which bear germline-encoded amino acid residues in their CDR regions that may potentially facilitate nuclear antigen binding. This ANA heavy chain database thus constitutes a useful resource for analyzing the molecular requirements for nuclear antigen reactivity.