A way out of the maze: Campylobacter jejuni gene polymorphisms define Guillain-Barré syndrome.

In the last decade, experimental and clinical studies have laid a solid foundation under the molecular mimicry hypothesis to explain the pathogenesis of the Guillain–Barré syndrome (GBS). Bacterial or viral infections and genetic host factors are important. In brief, in the weeks following infection with known and unknown micro-organisms, previously healthy persons develop a devastating acute inflammatory disease of the peripheral nervous system. The immune system of the patient is apparently deceived by bacterial ganglioside-like epitopes that mimic peripheral nerve components, thereby triggering a cascade of inflammatory responses against peripheral nerves. Cross-reactive anti-ganglioside antibodies may be directed against myelin, Schwann cell components, and axonal membranes.1,2 Mechanisms by which damage is induced include activation of inflammatory cells by interaction of antibodies with Fc receptors (Fc Rs) on macrophages and / T cells. Efficient Fc R-IgG interactions increase efficacy of leukocyte effector functions such as phagocytosis, cellular cytotoxicity, and cytokine production. Fc RIII genotypes are host factors that could modify severity of GBS.3 Also, an association has been found between polymorphisms in genes that are involved in immune homeostasis and the presence of antiganglioside antibodies in GBS.4 Most of these host factors and many aspects of antecedent infections are not fully known or understood. As the inflammatory process is self-limiting, GBS can be considered a hit-and-run disease of the peripheral nervous system. By definition, in 95% of patients, the nadir is reached within 4 weeks5 and in up to 70% within 2 weeks after onset.6 Treatment with plasma exchange or IV human immunoglobulins within 4 weeks of onset of neuropathic symptoms hastens recovery.7 Interestingly, early IV administration of methylprednisolone has no additional benefit.8 In this issue of Neurology, Koga et al.9 provide important insight into the association between a bacterial gene that regulates the biosynthesis of cell surface lipo-oligosaccharides (LOSs) of Campylobacter jejuni and GBS subtypes. They hypothesized a relationship between polymorphisms in the Campylobacter cst-II gene and autoantibody reactivity and GBS subtypes. The cst-II gene is a likely candidate as it encodes sialyltransferase, an important determinant of the variation in expression of ganglioside epitopes, as the sialylation type determines ganglioside classification. cst-II polymorphisms leading to different enzyme activity could thus change the ganglioside epitopes on LOSs with consequences for autoantibody reactivity. They analyzed bacterial strains from 105 GBS patients and 65 enteritis control subjects for cst-II gene frequency and polymorphisms and further analyzed ganglioside epitopes on LOSs of C. jejuni. Next, these findings were correlated with the anti-ganglioside antibody profile and clinical features of the patients with GBS. The two main conclusions were a more frequent occurrence of the cst-II gene in the neuropathic bacterial strains and a relationship between cst-II gene polymorphisms and different ganglioside epitopes. The latter finding was clinically reflected by serum antibodies against these gangliosides and expected subtypes: GBS syndrome vs Fisher syndrome. The study represents a new step in the unraveling of the molecular mimicry of GBS after C. jejuni infection. The results provide important evidence that genetic polymorphisms of antecedent infectious agents determine the production of specific autoantibodies and clinical manifestations in a postinfectious disorder. Previously, the same group demonstrated that different bacteria may cause the Fisher subtype of GBS with anti-GQ1b antibodies being present in most patients.10 In that study, they could link anti-