HLA Class II Polymorphisms Modulate Gut Microbiota and Experimental Autoimmune Encephalomyelitis Phenotype

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.