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

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.