? Copyright 2007, Society for Neuroscience. Future directions The notion that anti-glycan Propineb antibodies are the primary pathogenetic effectors in GBS continues to be contested. motor axonal neuropathy?- Acute motor-sensory axonal neuropathy?- AIDP with secondary axonal Propineb degenerationRegional or focal paralytic forms?- Fisher syndrome?- OropharyngealNon-paralytic forms?- Sensory ataxic variant?- Acute pandysautonomia Open in a separate window GBS is considered to be an autoimmune disease triggered frequently by common infections of upper respiratory and gastrointestinal tracts [1-3] in a susceptible host . What constitutes a susceptible host remains enigmatic. Autoantibodies directed against cell surface glycans carried by gangliosides (sialic acid-containing glycosphingolipids enriched in peripheral nerve fibers) have become the main focus of research in GBS. Over the last 15-20 years, several lines of evidence have linked these autoantibodies to the pathogenesis of GBS, particularly to axonal and Fisher variants of the disease. The clinical studies focusing on serological immune markers and GBS phenotype and recovery have identified associations of specific anti-glycan antibodies with different variants of GBS  and poor recovery [5,6]. The association studies have implied that specific anti-glycan antibodies not only can induce neuropathy (i.e., injury to intact nerve fibers) but also can adversely affect recovery by inducing more severe neuropathic disease or interfering with the nerve repair process required for recovery (or both). Identification of specific anti-glycan antibodies in GBS patients led to the development of cell culture , tissue culture [8-10], and animal [11-14] models that showed the pathogenetic effects of anti-glycan antibodies on intact nerves or nerve cells. Cumulatively, these studies indicate that specific anti-glycan antibodies target relevant antigens in neural cells, especially at motor nerve terminals or nodes of Ranvier (or both) to disrupt the nerve fiber function [15-17]. Human and experimental studies indicate that complement activation is involved in structural injury to the nerve fibers [18-20]. Several issues regarding the anti-glycan antibody-mediated nerve injury remain unresolved . For example, unconditional passive transfer with sera containing anti-glycan antibodies obtained from patients or active immunization animal models of axonal GBS [11,13] has not been reported to induce injury to the intact nerve fibers in experimental animals. This brief review describes some salient recent developments Propineb that enhance our understanding of the complex pathobiologic mechanisms involved in anti-glycan antibody-mediated deleterious effects on intact and injured nerve fibers. Major recent advances Several recent observations are beginning to unravel the complexity involved in anti-glycan antibody-associated selective nerve fiber injury seen in different variants of GBS. For example, antibodies against GM1 and GD1a or related minor gangliosides are associated with acute motor axonal neuropathy (AMAN) and anti-GQ1b/GT1a with FS [1-3]. The association of specific anti-glycan antibodies with specific GBS variants had raised an important critique; that is, how do specific anti-glycan antibodies induce selective injury to different nerve fibers (e.g., motor versus sensory) or selective topographical involvement of nerves/pathways despite minor or no differences in the biochemical content of gangliosides in different nerves or nerve fibers? The group led by Kusunoki , in a series of studies, have presented a novel concept that some GBS sera/anti-glycan antibodies bind to ganglioside complexes (pairs of gangliosides) but not to individual components of ganglioside in solid-phase assays. The authors propose that Propineb antibodies against ganglioside complexes recognize new conformational epitope(s) TLN1 formed by mixing. Whether or not gangliosides and other glycans Propineb that constitute cell surface glycocalyx form complexes or unique conformational epitopes in biological/cellular membranes remains to be determined. If this concept is validated, then this has far-reaching implications and could provide an explanation of how different neuronal/nerve fiber populations could be selectively targeted by specific anti-glycan antibodies despite similar biochemical content of individual major gangliosides. That an individual ganglioside can assume a different conformation/orientation in motor and sensory fibers was supported by data published by our group recently . This study focused on anti-GD1a antibodies in the context of AMAN and selective motor fiber injury. We found that some anti-GD1a antibodies selectively bound to motor but not sensory axons and that different anti-GD1a antibodies had different binding patterns to various chemical derivatives of GD1a (fine specificity). On the basis of data derived from biochemical, immunocytochemistry, computer modeling, and enzymatic studies, we proposed a model in which critical GD1a epitopes recognized by selective motor anti-GD1a antibodies are differentially expressed in motor and sensory nerves. Yet another mechanism was suggested by a study showing that motor nerve terminal injury with anti-GM1 antibodies was enhanced with prior enzymatic treatment with sialidase . Based on these findings, it was proposed that a proportion of GM1 ganglioside is cryptic.
? Copyright 2007, Society for Neuroscience
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