HLA Class II Polymorphisms Modulate Gut Microbiota and Experimental Autoimmune Encephalomyelitis Phenotype
Shailesh K Shahi1, Soham Ali1,2, Camille M Jaime1
1Department of Pathology, University of Iowa, Iowa City, IA.
Abstract:
Multiple sclerosis (MS) is an autoimmune disease of the CNS in which the interaction between genetic and environmental factors plays an important role in disease pathogenesis. Although environmental factors account for 70% of disease risk, the exact environmental factors associated with MS are unknown. Recently, gut microbiota has emerged as a potential missing environmental factor linked with the pathobiology of MS. Yet, how genetic factors, such as HLA class II gene(s), interact with gut microbiota and influence MS is unclear. In the current study, we investigated whether HLA class II genes that regulate experimental autoimmune encephalomyelitis (EAE) and MS susceptibility also influence gut microbiota. Previously, we have shown that HLA-DR3 transgenic mice lacking endogenous mouse class II genes (AE-KO) were susceptible to myelin proteolipid protein (91-110)-induced EAE, an animal model of MS, whereas AE-KO.HLA-DQ8 transgenic mice were resistant. Surprisingly, HLA-DR3.DQ8 double transgenic mice showed higher disease prevalence and severity compared with HLA-DR3 mice. Gut microbiota analysis showed that HLA-DR3, HLA-DQ8, and HLA-DR3.DQ8 double transgenic mice microbiota are compositionally different from AE-KO mice. Within HLA class II transgenic mice, the microbiota of HLA-DQ8 mice were more similar to HLA-DR3.DQ8 than HLA-DR3. As the presence of DQ8 on an HLA-DR3 background increases disease severity, our data suggests that HLA-DQ8-specific microbiota may contribute to disease severity in HLA-DR3.DQ8 mice. Altogether, our study provides evidence that the HLA-DR and -DQ genes linked to specific gut microbiota contribute to EAE susceptibility or resistance in a transgenic animal model of MS.
Insights
Genetic factors like HLA class II genes influence gut microbiota composition, impacting multiple sclerosis (MS) risk and severity in a mouse model. This highlights the interplay between genes and gut bacteria in MS pathogenesis.
Area of Science:
- Neuroimmunology
- Microbiome Research
- Genetics of Autoimmune Diseases
Background:
- Multiple sclerosis (MS) is a central nervous system (CNS) autoimmune disease influenced by genetic and environmental factors.
- Gut microbiota is a potential missing environmental factor in MS pathogenesis.
- The interaction between genetic factors (e.g., HLA class II genes) and gut microbiota in MS is not well understood.
Purpose of the Study:
- To investigate if HLA class II genes, known to influence MS susceptibility, also affect gut microbiota composition.
- To explore the role of specific HLA class II genes (HLA-DR3 and HLA-DQ8) in modulating gut microbiota and experimental autoimmune encephalomyelitis (EAE) severity.
Main Methods:
- Utilized HLA-DR3 and HLA-DQ8 transgenic mouse models, including double transgenic and knockout mice (AE-KO).
- Induced EAE, an animal model of MS, using myelin proteolipid protein (PLP) peptide.
- Analyzed gut microbiota composition in different transgenic mouse lines using sequencing techniques.
Main Results:
- HLA-DR3 transgenic mice were susceptible to EAE, while HLA-DQ8 transgenic mice were resistant.
- HLA-DR3.DQ8 double transgenic mice exhibited increased EAE prevalence and severity compared to HLA-DR3 mice.
- Gut microbiota composition differed significantly between AE-KO mice and HLA class II transgenic mice, with DQ8 mice microbiota being more similar to double transgenic mice.
Conclusions:
- HLA class II genes (HLA-DR3 and HLA-DQ8) significantly influence gut microbiota composition.
- The presence of HLA-DQ8 on an HLA-DR3 background exacerbates EAE severity, suggesting a role for DQ8-specific microbiota.
- Specific HLA genes interacting with distinct gut microbiota profiles contribute to EAE susceptibility and resistance in this MS animal model.
