TNF-α antagonists provide benefit to patients with inflammatory autoimmune disorders such as
Crohn's disease,
rheumatoid arthritis, and
ankylosing spondylitis. However, TNF antagonism unexplainably exacerbates CNS autoimmunity, including
multiple sclerosis and
neuromyelitis optica. The underlying mechanisms remain enigmatic. We demonstrate that
TNFR2 deficiency results in female-biased spontaneous autoimmune CNS
demyelination in
myelin oligodendrocyte glycoprotein-specific 2D2 TCR transgenic mice. Disease in
TNFR2(-/-) 2D2 mice was associated with CNS infiltration of T and B cells as well as increased production of
myelin oligodendrocyte glycoprotein-specific
IL-17, IFN-γ, and
IgG2b. Attenuated disease in TNF(-/-) 2D2 mice relative to
TNFR2(-/-) 2D2 mice identified distinctive roles for
TNFR1 and
TNFR2. Oral
antibiotic treatment eliminated spontaneous autoimmunity in
TNFR2(-/-) 2D2 mice to suggest role for gut microbiota. Illumina sequencing of fecal
16S rRNA identified a distinct microbiota profile in male
TNFR2(-/-) 2D2 that was associated with disease protection. Akkermansia muciniphila, Sutterella sp., Oscillospira sp., Bacteroides acidifaciens, and Anaeroplasma sp. were selectively more abundant in male
TNFR2(-/-) 2D2 mice. In contrast, Bacteroides sp., Bacteroides uniformis, and Parabacteroides sp. were more abundant in affected female
TNFR2(-/-) 2D2 mice, suggesting a role in disease causation. Overall,
TNFR2 blockade appears to disrupt commensal bacteria-host immune symbiosis to reveal autoimmune
demyelination in genetically susceptible mice. Under this paradigm, microbes likely contribute to an individual's response to anti-TNF
therapy. This model provides a foundation for host immune-microbiota-directed measures for the prevention and treatment of CNS-demyelinating autoimmune disorders.