TNFR2 Deficiency Acts in Concert with Gut Microbiota To Precipitate Spontaneous Sex-Biased Central Nervous System Demyelinating Autoimmune Disease

Abstract

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.

CNS Demyelination with TNF-α Blockers

“…TNF-α blockers could alter cytokine responses by downregulating interleukin-10 and upregulating interleukin-12 and interferon-γ, creating a profile similar to that of MS patients [54, 55•, 56]. …”

The Gut Microbiome as Therapeutic Target in Central Nervous System Diseases: Implications for Stroke

“…Females are more prone to EAE, whereas males, having different microbiome composition, are EAE resistant. Additionally, antibiotic treatment ameliorates disease, suggesting a crucial role of microbiota in the development of EAE [48]. Furthermore, EAE has been linked to the dysfunction in the intestinal barrier [49].…”

Environmental control of autoimmune inflammation in the central nervous system

“…Of note, the interaction between the gut microbiome and the host seems to be based on reciprocity: T cell receptor transgenic mice lacking the TNF-α receptor 2 (TNFR2 −/− 2D2) show changes in the gut microbiome and its interaction with pathogenic T cells, resulting in increased susceptibility to spontaneous CNS autoimmunity 58 . Taken together, both disease promoting and ameliorating mechanisms can be induced by the gut microbiota, which interact closely and mutually with the host immune system.…”