Anti–Double‐Stranded DNA Antibodies Recognize DNA Presented on HLA Class II Molecules of Systemic Lupus Erythematosus Risk Alleles

Objective Specific HLA class II alleles are associated with susceptibility to systemic lupus erythematosus (SLE). The role of HLA class II molecules in SLE pathogenesis remains unclear, although anti‐DNA antibodies are specific to SLE and correlate with disease activity. We previously demonstrated that misfolded proteins bound to HLA class II molecules are specific targets for the autoantibodies produced in autoimmune diseases. This study was undertaken to validate our hypothesis that DNA binds to HLA class II molecules in a manner similar to that of misfolded proteins and that DNA bound to HLA class II molecules is involved in SLE pathogenesis. Methods We analyzed the binding of DNA to HLA class II molecules, as well as the response of cells expressing anti‐DNA B cell receptors (BCRs) to cells expressing the DNA/HLA class II complex. Results Efficient binding of DNA to HLA class II molecules was observed in risk alleles of SLE, such as HLA–DRB1*15:01. The efficiency of DNA binding to each HLA–DR allele was positively associated with the risk of SLE conferred by the HLA–DR allele. In addition, reporter cells carrying anti‐DNA BCRs were activated by cells expressing DNA/HLA class II complexes. Conclusion These results provide evidence that DNA bound to HLA class II molecules is involved in SLE pathogenesis.