Ingrid 't Hart

96 Chapter 5 5 Introduc�on Autoimmune diseases are triggered by autoan�bodies. These an�bodies can be naturally present or are induced a�er infec�on by viruses, bacteria or parasites. 1,2 An�ganglioside an�bodies are involved in acute and chronic neuropathies, such as Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis (ALS). 3 Guillain-Barré Syndrome (GBS) is an acute peripheral neuropathic disease, in which an�ganglioside an�bodies are mainly formed a�er infec�ons. 4 GBS is the most common paraly�c disease in the world, affects 0.6-4/100,000 person each year and symptoms vary from weakness and �ngling sensa�ons up to complete muscular failure. 5,6,7 Approximately one quarter to a third of GBS cases is preceded by Campylobacter jejuni infec�on. 5,6 These bacteria bear glycans in their core lipooligosaccharides (LOS) that are structurally similar to gangliosides present in human nervous �ssue. In some cases, C. jejuni elicits an�bodies that cross-react with endogenous gangliosides resul�ng in an autoimmune disease. 2,4,7 C. jejuni is a gram-nega�ve bacterium and is the main cause for gastroenteri�s. The full genome has been sequenced in 2000. High variability was detected in the C. jejuni genome in sequences responsible for glycosyltransferases and surface structures such as its LOS. 8 Gram-nega�ve bacteria have a double membrane and the outer membrane contains lipopolysaccharides (LPS). The outer membrane of C. jejuni contains a short form of LPS, LOS, which lacks a repea�ng oligosaccharide polymer. 9 LOS consists of lipid A and an oligosaccharide core, which can be further divided into an inner core and outer core. Various LOS structures of C. jejuni have been described which may be beneficial for adapta�on or avoiding host defenses. The inner core contains unusual monosaccharides such as 3-deoxy-α- D -manno-2-octulopyranosonic acid (Kdo) and L -glycero- D -manno-heptose (Hep) and is highly conserved among C. jejuni serotypes (Figure 1A). 10,11,12 The outer core varies between bacterial strains and o�en contains sialylated structures mimicking gangliosides (Figure 1). 11,12 LOS ganglioside mimics of C. jejuni are biosynthesized by the enzymes Cst-II (α2,3- and α2,8-sialyltransferase), CgtA (β1,4-N-acetylgalactosamine-transferase) and CgtB (β1,3-galactosyltransferase). 13 Figure 1. ( A ) The lipooligosaccharide (LOS) core structure from C. jejuni mimicking GM1. ( B ) Human GM1 ganglioside. Ceramide β1,3 β1,4 β1,4 α2,3 B Lipid A Inner core Outer core β1,3 β1,4 β1,3 β1,4 α2,3 α2,4 α1,3 α1,5 A GalNAc Gal Glc Hep Kdo Neu5Ac