Guillain-Barré syndrome in Bangladesh: genetic polymorphism and pathogenesis

Abstract

Guillain-Barré syndrome (GBS) is a rapidly progressive, immune-mediated, paralytic disorder of the peripheral nervous system, which has led to significant morbidity and disability in the post-poliomyelitis era. Annually, there are 1 to 2 cases of GBS per 100,000 people worldwide. The pathological spectrum of GBS comprises acute inflammatory demyelinating polyneuropathy (AIDP), acute motor axonal neuropathy (AMAN), and acute motor sensory axonal neuropathy (AMSAN). Numerous microbial infections, including Campylobacter jejuni (C. jejuni), have been linked with the risk of developing of GBS. Molecular mimicry between lipooligosaccharides of C. jejuni and host nerve gangliosides is postulated to be an important mechanism by which an aberrant immune response triggers neuronal damage. However, the low occurrence of C. jejuni-induced enteritis GBS (1 in 1000- 5000 cases), the family history of GBS and rare phenomena of recurrent GBS clearly indicate that in addition to the molecular mimicry theory, genetic host factors are probably involved in the pathogenesis of GBS. We aimed to identify the contribution of several immune responserelated genetic host factors in the pathogenesis of GBS in a well-documented Bangladeshi cohort comprising 303 patients with GBS and 303 healthy individuals. The gene alterations studied included polymorphisms in human leukocyte antigen (HLA)-DQB1 and single nucleotide polymorphisms (SNPs) in nucleotide oligomerization domain (NOD), immunoglobulin G Fc-gamma receptors (FcγRs), and the promoters of interleukin-10 (IL-10) and matrix metalloproteinase-9 (MMP9). The HLA-DQB1 gene complex is highly polymorphic and possesses dense linkage disequilibrium (LD). Variation in the gene HLA-DQB1 and in haplotype patterns may play crucial roles by altering the ability of the immune system to recognizing self and foreign antigens implicated in the pathogenesis of GBS. The current study indicates that HLA-DQB1 polymorphisms are not associated with susceptibility to GBS. Haplotype 9 (DQB1*0303 - *0601) is less common among patients with GBS than in healthy control individuals (P = 0.006, OR = 0.49, 95% CI = 0.30-0.82; Pc = 0.06). Patients with the C. jejuni-triggered axonal variant of GBS possess a higher frequency of haplotype 5 (DQB1*0501-*0602; P = 0.024, OR = 4.06, 95% CI = 1.25-13.18; Pc = 0.24), and the DQB1*0201 alleles were predominant in the demyelinating subtype of GBS before correction of P-value (P = 0.027, OR = 2.68, 95% CI = 1.17-6.17; Pc = 0.35). Thus, our findings indicate that HLA-DQB1 polymorphisms are not risk factors for the development of GBS. Moreover, clinical features and serological subgroups of GBS are not influenced by these genetic markers. NOD receptors play an important role in the first line of innate immunity defense by sensing microorganisms. This study of NOD polymorphisms in 303 patients with GBS and 303 healthy control individuals implies there is no significant association between NOD polymorphisms (NOD1-Glu266Lys and NOD2-[Arg702Trp; Gly908Ar]) and GBS susceptibility or severity. Moreover, polymorphisms in NOD2 are rare in both patients with GBS and in healthy individuals from Bangladesh. FcγR is a key immune system regulator that bridges cellular and humoral immunity by modulating diverse effector functions, including phagocytosis, antibody-dependent cellular cytotoxicity (ADCC) and the release of inflammatory mediators. Our investigation on FcγR polymorphisms in patients with GBS and healthy individuals indicates an association of the FcγRIIIa-V158F genotype with the severe form of the disease (P = 0.005, OR = 2.24, 95% CI = 1.28-3.91; Pc = 0.015). Patients with a recent C. jejuni infection possess a higher frequency of the homozygous genotypes FcγRIIIa-V/V158 (P ≤ 0.001, OR = 0.36, 95% CI = 0.23-0.56; Pc ≤ 0.003) and FcγRIIIb-NA2/2 (P = 0.004, OR = 1.70, 95% CI = 1.18-2.44; Pc = 0.012) compared to patients with C. jejuni negative serology. However, no association was evident between GBS susceptibility and FcγR genotypes or haplotype patterns. There was a higher frequency of haplotype 1 (FcγRIIa-H131R - FcγRIIIa-V158F - FcγRIIIb-NA1/2) and the FcγRIIIb-NA2/2 genotype in patients positive for anti-GM1 antibodies than in patients who are negative for these antibodies (P = 0.031, OR = 9.61, 95% CI = 1.24-74.77, Pc = 0.279; P = 0.027, OR = 1.62, 95% CI = 1.06-2.5, Pc = 0.081; respectively). This study of IL-10 promoter polymorphisms in patients with GBS indicates that the homozygous -819 TT genotype is more prevalent in patients with the axonal variant of GBS than in patients with the demyelinating subtypes of GBS (P = 0.042, OR = 8.67, 95% CI = 1.03-72.97; Pc = 0.123) or healthy individuals (P = 0.005, OR = 4.2, 95% CI = 1.55-11.40; Pc = 0.015). The -1082G/A, -819C/T and -592 C/A polymorphisms in IL-10 were not significantly associated with disease susceptibility. Moreover, the haplotype combinations GCC/GTA, GCC/ATA and GCC/GCA are common in severe forms of GBS (P = 0.008, OR = 3.22, 95% CI = 1.4-7.43; Pc = 0.024). MMP-9 is an inflammatory mediator that is activated by pro-inflammatory cytokines and participates in macrophage recruitment. Our research on the association of the MMP9 (-1562 C/T) promoter polymorphism with the susceptibility and severity of GBS reveal the involvement of the variant allele and CT genotype in the severe form of GBS (P = 0.012, OR = 2.0, 95% CI = 1.14-3.38; Pc = 0.024 and P = 0.01, OR = 2.28, 95% CI = 1.22-4.22; Pc = 0.03, respectively). However, the MMP9 (-1562 C/T) promoter polymorphism was not associated with susceptibility to GBS. In summary, we conclude that genetic polymorphisms in HLA-DQB1, NOD, immunoglobulin G FcγR, and the IL-10 and MMP9 promoter regions are not risk factors for the development of GBS. However, the contribution of these polymorphisms to the clinical features and serological subgroups of GBS, including antecedent infections, presence of autoantibodies, severe or mild muscle weakness, and outcome of the disease, cannot be ignored and will enrich our knowledge about host-pathogen interactions in the pathogenesis of GBS. A large cohort of patients with GBS from multi-ethnic regions is required to confirm our findings on the contribution of genetic host factors to the pathogenesis of GBS.