Immunoglobulin variable region sequences of humanmonoclonal anti-DNA, antibodies

Abstract

Objective: Anti-DNA antibodies are believed to be important in the pathogenesisof systemic lupus erythematosus (SLE). Antibodies that bind specifically and with high affinity to dsDNA are most closely involved in tissue damage. Analysis of the sequences of the variable regions of human monoclonal anti-DNA antibodies is useful in defining the structural features that give rise to these binding properties. This article systematically reviews the evidence derived from such sequences. Method: Previous reviews of this subject have been hampered by incompleteknowledge of the human immunoglobulin variable region repertoire. In this article, the original sequence data from reports of over 50 human monoclonal antibodies (mAb) are reinterpreted by alignment to the most similar alleles of the most similar germline genes. This allows accurate estimation of the site and nature of somatic mutations. Results: Human IgG monoclonal anti-DNA antibodies generally carry more mutations than IgM. In many cases these have been selected by an antigen-driven process. In many of the more specific, higher affinity dsDNA binders, there is an accumulation of basic residues in the complementarity determining regions. However, many exceptions to this rule exist, particularly among IgM mAb. Conclusions: Unlike murine anti-DNA antibodies, these human mAb show littleevidence for preferential use of particular V H, V κ and V λ genes or families to encode antibodies of this specificity.