Department of Microbiology, University of Georgiagrid.213876.9, Athens, Georgia, USA.
Complex Carbohydrate Research Center, University of Georgiagrid.213876.9, Athens, Georgia, USA.
mBio. 2021 Feb 22;13(1):e0385221. doi: 10.1128/mbio.03852-21. Epub 2022 Feb 1.
Early in life, commensal bacteria play a major role in immune development, helping to guide the host response toward harmful stimuli while tolerating harmless antigens to prevent autoimmunity. Guillain-Barré syndrome (GBS) is an autoimmune disease caused by errant immune attack of antibody-bound ganglioside receptors on host nerve cells, resulting in paralysis. Lipooligosaccharides enveloping the prevalent enteric pathogen, Campylobacter jejuni, frequently mimic human gangliosides and can trigger GBS by stimulating the autoimmune response. In low- to middle-income countries, young children are consistently exposed to C. jejuni, and it is not known if this impacts GBS susceptibility later in life. Using a macrophage model, we examined the effect of training these cells with low doses of ganglioside-mimicking bacteria prior to challenge with GBS-associated antigens. This training caused decreased production of proinflammatory cytokines, suggesting tolerance induction. We then screened Campylobacter isolates from 154 infant fecal samples for GM1 ganglioside mimicry, finding that 23.4% of strains from both symptomatic and asymptomatic infants displayed GM1-like structures. Training macrophages with one of these asymptomatic carrier isolates also induced tolerance against GBS-associated antigens, supporting that children can be exposed to the tolerizing antigen early in life. RNA interference of Toll-like receptor 2 (TLR2) and TLR4 suggests that these receptors are not involved in tolerance associated with decreases in tumor necrosis factor (TNF), interleukin-6 (IL-6), or IL-1β levels. The results of this study suggest that exposure to ganglioside-mimicking bacteria early in life occurs naturally and impacts host susceptibility to GBS development. In this study, we demonstrated that it is possible to tolerize immune cells to potentially dampen the autoreactive proinflammatory immune response against Guillain-Barré syndrome (GBS)-associated antigens. The innate immune response functions to arm the host against bacterial attack, but it can be tricked into recognizing the host's own cells when infectious bacteria display sugar structures that mimic human glycans. It is this errant response that leads to the autoimmunity and paralysis associated with GBS. By presenting immune cells with small amounts of the bacterial glycan mimic, we were able to suppress the proinflammatory immune response upon subsequent high exposure to glycan-mimicking bacteria. This suggests that individuals who have already been exposed to the glycan mimics in small amounts are less sensitive to autoimmune reactions against these glycans, and this could be a factor in determining susceptibility to GBS.
早期，共生菌在免疫发育中起着重要作用，有助于引导宿主对有害刺激作出反应，同时耐受无害抗原以防止自身免疫。格林-巴利综合征（Guillain-Barré syndrome，GBS）是一种自身免疫性疾病，由抗体结合的神经节苷脂受体在宿主神经细胞上的异常免疫攻击引起，导致瘫痪。包裹常见肠道病原体空肠弯曲菌的脂寡糖经常模拟人类神经节苷脂，并通过刺激自身免疫反应引发 GBS。在中低收入国家，幼儿持续接触空肠弯曲菌，目前尚不清楚这是否会影响其日后患 GBS 的易感性。我们使用巨噬细胞模型，研究了在 GBS 相关抗原攻击前用低剂量模拟神经节苷脂的细菌对这些细胞进行训练的效果。这种训练导致促炎细胞因子产生减少，提示诱导了耐受。然后，我们从 154 份婴儿粪便样本中筛选空肠弯曲菌分离株，发现有症状和无症状婴儿的 23.4%的菌株显示出 GM1 样结构。用其中一种无症状携带者分离株训练巨噬细胞也可诱导对 GBS 相关抗原的耐受，支持儿童可以在生命早期接触到这种耐受抗原。Toll 样受体 2（TLR2）和 TLR4 的 RNA 干扰表明，这些受体不参与与肿瘤坏死因子（TNF）、白细胞介素-6（IL-6）或白细胞介素-1β水平降低相关的耐受。这项研究的结果表明，早期接触神经节苷脂模拟细菌是自然发生的，这会影响宿主对 GBS 发展的易感性。在这项研究中，我们证明了可以使免疫细胞耐受，从而潜在地抑制针对格林-巴利综合征（GBS）相关抗原的自身反应性促炎免疫反应。先天免疫反应的功能是使宿主免受细菌攻击，但当感染细菌显示出模拟人类聚糖的糖结构时，它可能会被误导而识别宿主自身的细胞。正是这种错误的反应导致了与 GBS 相关的自身免疫和瘫痪。通过向免疫细胞提供少量细菌糖模拟物，我们能够在随后高暴露于糖模拟物细菌时抑制促炎免疫反应。这表明已经少量接触过糖模拟物的个体对这些糖的自身免疫反应不那么敏感，这可能是决定 GBS 易感性的一个因素。
