The structural and functional diversity of anti-glycolipid antibody repertoires and their nerve binding domains in human autoimmune neuropathy. (360G-Wellcome-092805_Z_10_Z)

The concept that formation of heteromeric complexes between two different glycolipids might influence antibody binding has long been suspected, but has never been systematically investigated in a clinically relevant context. In autoimmune neuropathy driven by anti-glycolipid antibodies, this is becoming of major importance as we uncover countless examples of new autoantibody specificities whose antigen binding capability is entirely dependent upon the formation of complexes between different gly colipids. This expands the extensive existing data on single glycolipids as the key antigens in these disorders. Three patterns of neuropathy-associated anti-complex autoantibody binding have emerged to date: complex enhanced, complex inhibited and complex independent, all of which are likely to profoundly influence pathogenic capability, and thus clinical classification and prognostics. New analytical methods and transgenic mouse models we have developed now provide a tractable route into disco vering complex-dependent autoantibody specificities and their neuropathological significance. Our key goals are to map the relationships between clinical phenotypes and anti-complex antibody patterns and to explore pathological effects of clinically-relevant complexes in mouse models. In doing so we will build a comprehensive understanding of complex recognition by autoantibodies, and how these antibodies underlie the undiscovered pathogenic pathways in human autoimmune neuropathy.