TY - JOUR
T1 - Role of HLA class II genes in susceptibility and resistance to multiple sclerosis
T2 - Studies using HLA transgenic mice
AU - Luckey, David
AU - Bastakoty, Dikshya
AU - Mangalam, Ashutosh K.
N1 - Funding Information:
This work was supported by NS52173 from NINDS . AKM was supported by DOD grant 10-1-0254 and NS52173 . We thank Julie Hanson and her staff for mouse husbandry and Michele Smart for tissue typing of transgenic mice.
PY - 2011/9
Y1 - 2011/9
N2 - Multiple sclerosis (MS), an inflammatory and demyelinating autoimmune disease of CNS 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, and 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 the progression of MS. To better understand the mechanism by which HLA-DR and -DQ genes contribute to susceptibility and resistance to MS, we utilized single and double transgenic mice expressing HLA class II gene(s) lacking endogenous mouse class II genes. HLA class II transgenic mice have helped us in identifying immunodominant epitopes of PLP in context of various HLA-DR and -DQ molecules. We have shown that HLA-DR3 transgenic mice were susceptible to PLP 91-110 induced experimental autoimmune encephalomyelitis (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 than DR3 mice. The protective effect of DQ6 in DQ6/DR3 mice was mediated by IFNγ, while the disease exacerbating effect of DQ8 molecule was mediated by IL-17. Further, we have observed that myelin-specific antibodies play an important role in PLP 91-110 induced EAE in HLA-DR3DQ8 transgenic mice. Based on these observations, we hypothesize that epistatic interaction between HLA-DR and -DQ genes play an important role in predisposition to MS and our HLA transgenic mouse model provides a novel tool to study the effect of linkage disequilibrium in MS.
AB - Multiple sclerosis (MS), an inflammatory and demyelinating autoimmune disease of CNS 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, and 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 the progression of MS. To better understand the mechanism by which HLA-DR and -DQ genes contribute to susceptibility and resistance to MS, we utilized single and double transgenic mice expressing HLA class II gene(s) lacking endogenous mouse class II genes. HLA class II transgenic mice have helped us in identifying immunodominant epitopes of PLP in context of various HLA-DR and -DQ molecules. We have shown that HLA-DR3 transgenic mice were susceptible to PLP 91-110 induced experimental autoimmune encephalomyelitis (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 than DR3 mice. The protective effect of DQ6 in DQ6/DR3 mice was mediated by IFNγ, while the disease exacerbating effect of DQ8 molecule was mediated by IL-17. Further, we have observed that myelin-specific antibodies play an important role in PLP 91-110 induced EAE in HLA-DR3DQ8 transgenic mice. Based on these observations, we hypothesize that epistatic interaction between HLA-DR and -DQ genes play an important role in predisposition to MS and our HLA transgenic mouse model provides a novel tool to study the effect of linkage disequilibrium in MS.
KW - Anti-myelin antibody
KW - Complement
KW - Cytokine
KW - EAE/MS
KW - HLA transgenic mice
UR - http://www.scopus.com/inward/record.url?scp=80052674692&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=80052674692&partnerID=8YFLogxK
U2 - 10.1016/j.jaut.2011.05.001
DO - 10.1016/j.jaut.2011.05.001
M3 - Article
C2 - 21632210
AN - SCOPUS:80052674692
SN - 0896-8411
VL - 37
SP - 122
EP - 128
JO - Journal of Autoimmunity
JF - Journal of Autoimmunity
IS - 2
ER -