Characterization of a human monoclonal autoantibody directed to cardiolipin/β2 glycoprotein I produced by chronic lymphocytic leukaemia B cells

Abstract

We determined the specificity and sequence of immunoglobulin molecules synthesized by monoclonal B cells from a patient with chronic lymphocytic leukaemia (CLL) who presented with a number of clinical and biological autoimmune symptoms. Heterohybrids obtained by fusion of CLL cells with the mouse X63-Ag 8.653 myeloma produced IgMλ MoAbs directed to the cardiolipin/β2 glycoprotein I (β2GPI) complex and ssDNA. They were devoid of polyreactivity. Nucleotide sequence analysis of the variable domain of the μ chain indicated the utilization of the V(H)4 71.2 gene or one allotypic variant, D(XP)4 and J(H)3 segments. The λ light chain used the single gene from the V(λ)8 subfamily, J(λ)3 and C(λ)3 genes. The V(H) gene displayed 11 nucleotide changes in comparison with its putative germline counterpart. However, these nucleotide changes correspond to variations observed in other published V(H)4 sequences, suggesting gene polymorphism rather than somatic mutation. D(XP)4 and J(H)3 were also in germline configuration. The V(L) gene exhibited a single replacement mutation in CDR1. These data suggest that the monoclonal CLL B cells in this patient retained V(H) and V(L) genes in germline configuration although they secreted a pathogenic anti-cardiolipin antibody associated with clinical symptoms, vasculitis and thrombosis, which may be provoked by antibodies to the phospholipid/β2GPI complex.