Immunogenetic studies of Guillain - Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy

Abstract

Guillain-Barre syndrome (GBS) is an acute inflammatory neuropathy that is frequently triggered by an infectious illness. It is thought to be autoimmune in origin, but differs from other autoimmune diseases in being of male predominance and not showing a HLA-association.Chronic inflammatory demyelinating polyradiculoneuropathy is a chronic inflammatory neuropathy, which shares some pathological features with GBS.We investigated the clinical features of GBS in an Australian cohort of subjects by performing a retrospective chart review. We obtained subjects from several public hospitals and private neurologists in Queensland and New South Wales.We found 335 patients, for 228 of whom electrophysiological data was available. Of these acute inflammatory demyelinating polyradiculoneuropathy (AIDP) with 168 cases was the most common form, whilst axonal and focal forms were rarer. We identified upper respiratory tract infections, occurring predominantly in winter months, as the most frequently named triggering factor for GBS.The illness severity in our cohort was similar to that in earlier Australian studies.Also, we identified a cohort of 78 subjects fulfilling diagnostic criteria for CIDP from similar sources.We investigated a possible underlying genetic susceptibility to develop GBS or CIDP by contacting members of this cohort and collecting their DNA. We embarked on both a candidate gene approach to investigate the killer immunoglobulin-like receptors (KIRs) and their HLA ligands, as well as performing a genome-wide association study (GWAS) of the subjects with GBS as a hypothesis-free method.For the KIR/HLA system, whilst no significant differences were detected in the frequency of KIR genes, HLA-C2 and HLA-B Bw4-T were more frequent in subjects with GBS than controls (p<0.001). The inhibitory pairs of KIR-2DL2/HLA-C2 and KIR-3DL1/HLA-B Bw4-T were more frequent in GBS than controls (p<0.005). Whilst there were some differences between CIDP subjects and controls, interestingly, there were no difference between subjects with GBS and CIDP.This could point to similarities of pathogenesis between these two inflammatory neuropathies.A GWAS was performed on a largely identical cohort of 190 subjects with GBS. Whilst this cohort is relatively small for a modern GWAS and no genome-wide significant results were expected, we were able to identify a number of regions of interest based on clusters of SNPs in linkage disequilibrium of increased significance. These included rs10519519 on Chromosome 2, which is associated with MYT1L, a transcription factor in neuronal development; rs7663689 on Chromosome 4, which is in the promotor region of IL15; rs11151180 on Chromosome 18 which is in a gene-free region; rs17095496 on Chromosome 14, which amongst other genes is associated with DACT1, which encodes a regulator of cell division involved in the NF-κB pathway; and rs2302524 on chromosome 19, associated among other genes with NFKBIB, which encodes an inhibitor of the NF-κB pathway. Relative negatives included the HLA region, a...