SUMMARY Multiple Sclerosis (MS) is an autoimmune disease against the central nervous system (CNS) and breakage of immune tolerance to the CNS antigens has been suggested to initiate the CNS autoimmunity. Recent animal studies have suggested that immune dysregulation caused by gut commensal bacteria affects the CNS autoimmune diseases. Interestingly, dysbiosis of gut microbiota was observed in MS patients as well as in the mice with experimental autoimmune encephalomyelitis (EAE). These data suggest that dysbiosis of gut commensal bacteria affects the disease initiation and progression of CNS autoimmune diseases. To investigate the mechanism how immune tolerance to myelin proteins is broken, we created transgenic (Tg) mice that express HLA-DR2a, and a 3A6 T cell receptor (TCR) specific for myelin basic protein (MBP)87- 99/HLA-DR2a, which were isolated from an MS patient. Interestingly, 3A6/DR2a Tg mice developed EAE spontaneously, and notably, the development of spontaneous EAE was abolished by antibiotic treatment. Interestingly, elevation of fecal IgM levels, a biomarker of dysbiosis, was associated with the development of spontaneous EAE. Furthermore, dysbiosys of gut commensal bacteria up-regulates complement C3 in the spleen and down-regulates anergy-associate E3 ubiquitin ligase gene, CBLB, and development of Foxp3 Tregs. Similarly, development of Foxp3 Tregs is inefficient and CBLB gene expression is reduced in MS patients. However, it is largely unknown how gut dysbiosis affects the development of MS. In this study, we will assess the association between gut dysbiosis and development of MS and investigate up-regulation of complement C3, development of pathogenic and regulatory T cells, and induction of EAE in human microbiota-associated 3A6/DR2a mice created with gut microbiota isolated from MS patients.
|Effective start/end date||7/1/17 → 6/30/20|
- National Institute of Allergy and Infectious Diseases: $229,650.00
- National Institute of Allergy and Infectious Diseases: $198,750.00
- Clinical Neurology
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