Role of HLA class II genes in demyelination

Summary

Principal Investigator: Chella David
Affiliation: Mayo Clinic
Country: USA
Abstract: DESCRIPTION (provided by applicant): Multiple sclerosis (MS), an inflammatory and demyelinating autoimmune disease has both a genetic and an environmental predisposition. Among all the genetic factors associated with MS susceptibility, HLA-class II haplotypes such as DR2/DQ6, DR3/DQ2, DR4/DQ8, show the strongest association. Although a direct role of HLA-DR alleles in MS have been confirmed, it has been difficult to understand the contribution of HLA-DQ alleles in disease pathogenesis, due to strong linkage disequilibrium. Population studies have indicated that DQ alleles may play a modulatory role in progression of MS. To better understand the mechanism by which HLA-DR and -DQ genes contribute to susceptibility and resistance to MS, we generated single and double transgenic mice expressing HLA class II genes and lacking endogenous mouse class II genes. Previously, we have shown that HLA-DR3 transgenic mice were susceptible to PLP91-110 induced EAE, while DQ6 (DQB1*0601) and DQ8 (DQB1*0302) transgenic mice were resistant. Surprisingly DQ6/DR3 double transgenic mice were resistant while DQ8/DR3 mice showed higher disease incidence and severity. Protective effect of DQ6 in DQ6/DR3 mice was mediated by anti-inflammatory IFN3, while disease exacerbating effect of DQ8 molecule was mediated by IL17. Based on these observations, we hypothesize that epistatic interaction between HLA-DR and -DQ genes play an important role in predisposition to MS. This proposal is aimed to enhance understanding of the mechanism by which epistatic interactions between HLA-DQ and -DR molecules determine the susceptibility vs. resistance to disease. We are proposing two aims to understand the mechanism by which HLA-DQ molecule modulate the disease outcome in HLA-DR/DQ double transgenic mice. In the first aim, we will examine how HLA-DQ8 molecule increases disease incidence and severity in DQ8/DR3 double transgenic mice by analyzing- i) role of HLA polymorphism and peptide-MHC affinity/avidity in generation of pro-inflammatory IL17 production from DQ8 restricted CD4 T cells;ii) mechanism by which IL17 cause increased encephalitogenicity in DR3DQ8 mice;and iii) role of GM-CSF produced by DQ8 restricted CD4 T cells in exacerbation of EAE in DR3DQ8 double transgenic mice. In the second aim, we will investigate how HLA-DQ6 restricted immune response leads to generation of high IFN3 producing regulatory CD4+ T cells, especially the role of MHC-peptide affinity/functional avidity. Next we will analyze mechanisms by which DQ6 restricted CD4+ T cells suppress EAE in HLA-DR3/DQ6 double transgenic mice. We will also generate a triple transgenic mice expressing disease susceptible HLA-DR3, disease protective -DQ6, and disease enhancing -DQ8 gene to simulate human heterozygous condition. The comprehensive studies outlined in this proposal should yield an insight into mechanism by which HLA class II molecules shape the T cell repertoire and regulate the pro-inflammatory and anti-inflammatory cytokine profile. This will facilitate the translational research development of novel therapeutic to treat inflammatory disease such as MS. PUBLIC HEALTH RELEVANCE: Although HLA haplotypes are linked to predisposition and onset of multiple sclerosis, it has been difficult in past to define a clear role of HLA molecule(s) in MS. We have used HLA transgenic mice successfully to understand their role in inflammatory and demyelinating disease of CNS such as MS using an experimental model experimental autoimmune encephalomyelitis (EAE). These humanized class II model of EAE can be used to evaluate potential therapeutic protocols and peptide vaccines applicable in the future to MS patients.
Funding Period: ----------------2006 - ---------------2015-
more information: NIH RePORT

Top Publications

  1. pmc A new humanized HLA transgenic mouse model of multiple sclerosis expressing class II on mouse CD4 T cells
    Ashutosh Mangalam
    Department of Immunology, Mayo Clinic College of Medicine, 200 1st Street SW, Rochester, MN 55905, USA
    Ann N Y Acad Sci 1103:112-7. 2007
  2. pmc HLA class II molecules influence susceptibility versus protection in inflammatory diseases by determining the cytokine profile
    Ashutosh K Mangalam
    Department of Immunology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
    J Immunol 190:513-8. 2013
  3. pmc HLA-DQ8 (DQB1*0302)-restricted Th17 cells exacerbate experimental autoimmune encephalomyelitis in HLA-DR3-transgenic mice
    Ashutosh Mangalam
    Department of Immunology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
    J Immunol 182:5131-9. 2009
  4. pmc Role of HLA class II genes in susceptibility and resistance to multiple sclerosis: studies using HLA transgenic mice
    David Luckey
    Immunology Department, Mayo Clinic, 200 Ist ST SW, Rochester, MN 55905, United States
    J Autoimmun 37:122-8. 2011
  5. pmc Two discreet subsets of CD8 T cells modulate PLP(91-110) induced experimental autoimmune encephalomyelitis in HLA-DR3 transgenic mice
    Ashutosh K Mangalam
    Department of Immunology, Mayo Clinic College of Medicine, 200, 1st Street SW, Rochester, MN 55905, USA
    J Autoimmun 38:344-53. 2012

Detail Information

Publications5

  1. pmc A new humanized HLA transgenic mouse model of multiple sclerosis expressing class II on mouse CD4 T cells
    Ashutosh Mangalam
    Department of Immunology, Mayo Clinic College of Medicine, 200 1st Street SW, Rochester, MN 55905, USA
    Ann N Y Acad Sci 1103:112-7. 2007
    ..Here, we describe development and characterization of a new humanized class II transgenic (tg) mouse expressing HLA-DR3 on mouse endogenous class II-negative background...
  2. pmc HLA class II molecules influence susceptibility versus protection in inflammatory diseases by determining the cytokine profile
    Ashutosh K Mangalam
    Department of Immunology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
    J Immunol 190:513-8. 2013
    ..Unfortunately, they also present self-peptides/mimics to activate autoreactive T cells secreting proinflammatory cytokines that cause autoimmune diseases...
  3. pmc HLA-DQ8 (DQB1*0302)-restricted Th17 cells exacerbate experimental autoimmune encephalomyelitis in HLA-DR3-transgenic mice
    Ashutosh Mangalam
    Department of Immunology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA
    J Immunol 182:5131-9. 2009
    ..Thus double Tg mouse provides a novel model to study epistatic interactions between HLA class II molecules in inflammatory and demyelinating disease...
  4. pmc Role of HLA class II genes in susceptibility and resistance to multiple sclerosis: studies using HLA transgenic mice
    David Luckey
    Immunology Department, Mayo Clinic, 200 Ist ST SW, Rochester, MN 55905, United States
    J Autoimmun 37:122-8. 2011
    ....
  5. pmc Two discreet subsets of CD8 T cells modulate PLP(91-110) induced experimental autoimmune encephalomyelitis in HLA-DR3 transgenic mice
    Ashutosh K Mangalam
    Department of Immunology, Mayo Clinic College of Medicine, 200, 1st Street SW, Rochester, MN 55905, USA
    J Autoimmun 38:344-53. 2012
    ..Our study suggests that CD8+ T cells play both regulatory as well as pathogenic role in disease pathogenesis of EAE. A better understanding of these subsets could aid in designing novel therapy for MS patients...