Guillain-Barre syndrome (GBS), an autoimmune post-infectious neuropathy, is the most frequent cause of acute flaccid paralysis since the eradication of polio. It is now widely accepted that there are two major forms of the disease, acute inflammatory demyelinating polyradiculoneuropathy (AIDP) and acute motor axonal neuropathy (AMAN). Molecular mimicry has been proposed as a pathogenic mechanism for AMAN because it mostly follows Campylobacter jejuni infection, the LPS of AMAN associated C. jejuni contain ganglioside-like moieties, patients with AMAN have specific IgG anti-ganglioside antibodies including those against GD1a, and pathological studies demonstrate deposition of IgG and complement on motor axons and specific motor fiber injury. However, a direct relationship between anti-ganglioside antibodies and nerve fiber injury has not been established. Further, in vitro or animal models of antibody mediated motor axonal injury are not available. This largely reflects difficulties in generating high affinity IgG complement fixing anti-ganglioside antibodies similar to those seen in AMAN. We propose to use mice lacking complex gangliosides, which are immune naive to complex gangliosides, to generate the desired monoclonal (mAb) anti-ganglioside antibodies. These mAbs will be used to reproduce motor axonal injury in passive transfer animal models and in an in vitro spinal cord culture system. mAbs will also be used for localization and biochemical studies to probe the basis of the preferential motor axonal damage seen in AMAN. The ganglioside nature of antigens targeted by anti-ganglioside antibodies will be established by genetic and or pharmacologic manipulation of ganglioside expression in in vitro and animal models. An in vitro system will also be used to investigate the components of complement cascade involved in antibody-mediated axonal degeneration. Finally, affinity purified anti-ganglioside antibodies from patients with AMAN will be used in parallel to establish the causal relationship between the human antibodies and motor axonal degeneration. These studies will prove the hypothesis of molecular mimicry as an underlying mechanism for the pathogenesis of AMAN.