Surface Layer Protein A Expressed in Clostridioides difficile DJNS06-36 Possesses an Encephalitogenic Mimotope of
John E Mindur1,2, Sudhir K Yadav1, Naoko Ito1
1Department of Neurology, Rutgers-Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.
Abstract:
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Recent studies suggest that migration of Th1 and Th17 cells specific for enteric bacteria from the gut to the CNS may lead to the initiation and/or exacerbation of autoimmune diseases including MS. Human leukocyte antigen (HLA)-DR15 is an MHC class II (MHCII) haplotype highly associated with the development of MS that contains the two HLA-DRB* genes, DRB1*1501 (DR2b) and DRB5*0101 (DR2a). To identify enteric bacteria which harbor antigenic epitopes that activate myelin-specific T cells and drive CNS inflammation, we screened for enteric bacteria which express cross-reactive epitopes ('mimotopes') of an immunodominant myelin basic protein 89-98 (MBP89-98) epitope. Based on known MHCII HLA-DR2a amino acid binding motifs and cultivation with splenic T cells isolated from MBP-T cell receptor (TCR)/DR2a transgenic (Tg) mice, we discovered that a certain variant of surface layer protein A (SLPA), which is expressed by a subtype of Clostridioides difficile, contains an amino acid sequence that activates MBP89-98-reactive T cells. Furthermore, activation of MBP-specific T cells by SLPA upon active immunization induced experimental autoimmune encephalomyelitis (EAE) in MBP-TCR/DR2a Tg mice. This study suggests that a unique strain of C. difficile possesses an encephalitogenic mimotope of MBP that activates autoreactive, myelin-specific T cells.
Insights
A specific strain of Clostridioides difficile contains a protein that mimics myelin, activating T cells and potentially triggering multiple sclerosis (MS) in genetically susceptible individuals.
Area of Science:
- Neuroimmunology
- Microbiology
- Genetics
Background:
- Multiple sclerosis (MS) is an inflammatory central nervous system (CNS) disease.
- Gut-derived Th1/Th17 cells may initiate or worsen MS.
- The HLA-DR15 haplotype is strongly associated with MS development.
Purpose of the Study:
- Identify enteric bacteria with epitopes that activate myelin-specific T cells.
- Investigate the role of bacterial mimicry in CNS autoimmunity.
Main Methods:
- Screened enteric bacteria for mimicry of myelin basic protein (MBP) epitopes.
- Used MBP-T cell receptor (TCR)/DR2a transgenic mice and splenic T cells.
- Analyzed bacterial surface layer protein A (SLPA) from Clostridioides difficile.
Main Results:
- A variant of C. difficile SLPA contains an epitope mimicking MBP.
- This SLPA epitope activates MBP-reactive T cells in HLA-DR2a mice.
- Active immunization with SLPA induced experimental autoimmune encephalomyelitis (EAE) in mice.
Conclusions:
- A unique C. difficile strain harbors an encephalitogenic mimic of MBP.
- This mimic activates autoreactive T cells, suggesting a gut-bacterial trigger for MS.
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