Low-Dose Exposure to Ganglioside-Mimicking Bacteria Tolerizes Human Macrophages to Guillain-Barré Syndrome-Associated Antigens.

Abstract

ABSTRACTEarly 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.