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Published on: August 21, 2017
HLA-DQ8 (DQB1*0302)-restricted Th17 cells exacerbate experimental autoimmune encephalomyelitis in HLA-DR3-transgenic
Ashutosh Mangalam1, David Luckey, Eati Basal
1Department of Immunology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Abstract:
Among all of the genetic factors associated with multiple sclerosis (MS) susceptibility, MHC class II molecules have the strongest association. Although a direct role of DR alleles in MS have been confirmed, it has been difficult to understand the role of DQ alleles in disease pathogenesis due to strong linkage disequilibrium with certain DR alleles. Population studies have indicated that DQ alleles may play a modulatory role in progression of MS. Using HLA class II transgenic (Tg) mice, we investigated gene complementation between DR and DQ genes in the disease process. Previously, using single Tg mice (expressing HLA-DR or DQ gene), we showed that PLP(91-110) peptide induced experimental autoimmune encephalomyelitis (EAE) only in DR3.Abeta degrees mice, suggesting that DR3 (DRB1*0301) is a disease susceptibility gene in the context of PLP. We also showed that DQ6 protects development of EAE in DQ6/DR3 double Tg mice by production of anti-inflammatory IFN-gamma. In this study, we investigated the ability of DQ8 to modulate disease in DR3/DQ8 double Tg mice. Introduction of DQ8 onto DR3 Tg mice led to higher disease incidence and increased disease severity on immunization with PLP(91-110), indicating that DQ8 had an exacerbating effect on the development of EAE. Increased susceptibility in DR3/DQ8 Tg mice was due to increased production of proinflammatory cytokine IL-17 by DQ8-restricted T cells. HLA-DR3/DQ8 mice with EAE also demonstrated increased inflammation and demyelination in CNS as compared with single DR3 Tg mice. Thus double Tg mouse provides a novel model to study epistatic interactions between HLA class II molecules in inflammatory and demyelinating disease.
Insights
The DQ8 gene variant exacerbates multiple sclerosis (MS) development by increasing pro-inflammatory responses. This study reveals epistatic interactions between HLA class II genes in MS pathogenesis.
Area of Science:
- Immunogenetics
- Neuroimmunology
- Autoimmune Diseases
Background:
- Major Histocompatibility Complex (MHC) class II molecules are strongly associated with multiple sclerosis (MS) susceptibility.
- The specific roles of Human Leukocyte Antigen (HLA) DQ alleles in MS pathogenesis are unclear due to linkage disequilibrium with HLA DR alleles.
- Previous studies suggest DQ alleles may modulate MS progression.
Purpose of the Study:
- To investigate the gene complementation between HLA DR and DQ genes in MS pathogenesis using HLA class II transgenic (Tg) mice.
- To determine the specific effect of the DQ8 allele on disease development in the context of the DR3 susceptibility gene.
Main Methods:
- Utilized single and double HLA class II transgenic (Tg) mouse models expressing specific DR and DQ alleles.
- Induced experimental autoimmune encephalomyelitis (EAE) using the myelin oligodendrocyte glycoprotein (MOG) peptide PLP(91-110).
- Assessed disease incidence, severity, cytokine production (IL-17, IFN-gamma), and central nervous system (CNS) inflammation and demyelination.
Main Results:
- DR3 Tg mice immunized with PLP(91-110) developed EAE, confirming DR3 as a susceptibility gene.
- DQ6 conferred protection against EAE in DQ6/DR3 double Tg mice by promoting anti-inflammatory IFN-gamma production.
- Introduction of DQ8 onto DR3 Tg mice (DR3/DQ8 double Tg) significantly increased EAE incidence and severity.
- DQ8-restricted T cells in DR3/DQ8 Tg mice produced higher levels of the pro-inflammatory cytokine IL-17.
- DR3/DQ8 Tg mice exhibited heightened CNS inflammation and demyelination compared to single DR3 Tg mice.
Conclusions:
- The DQ8 allele exacerbates EAE development and severity in the presence of the DR3 susceptibility gene.
- Exacerbation by DQ8 is mediated by increased production of IL-17 from DQ8-restricted T cells.
- This study establishes a novel double Tg mouse model for dissecting epistatic interactions between HLA class II molecules in inflammatory and demyelinating diseases like MS.
