Despite the fact that HLA class-II alleles, especially HLA-DR2/DQ6, DR3/DQ2, and DR4/DQ8 haplotypes show the strongest association with MS, it has been difficult to understand their specific role in MS pathogenesis due to a number of factors such as the high polymorphism, linkage disequilibrium and heterogeneity of human populations. Therefore, to overcome this hurdle, we utilized HLA class II transgenic mice (generated by Dr. Chella David, Mayo Clinic Rochester), to identify immunodominant as well as encephalitogenic epitopes of myelin antigens (proteolipid protein (PLP) and myelin oligodendrocyte glycoprotein (MOG)—) in the context of MS associated HLA class II genes such HLA-DR2, -DR3, -DR4, -DQ6 and –DQ8 (Mangalam et al, Eur J Immunol 2004; J NeuroImmunol 2005; Eur J Immunol 2006; Adv. Immunol 2008, J Autoimmun 2011). We have also shown that MOG is the major encephalitogenic epitope in HLA-DR2 transgenic mice, whereas PLP is a major encephalitogenic epitope in HLA-DR3 transgenic mice. I have shown that HLA transgenic mice expressing the human class II DR3 gene were susceptible to PLP induced EAE, while transgenic mice expressing HLA-DQ6 or -DQ8 were resistant (Mangalam et al, Eur J Immunol 2004).

We also showed that the protective effect of DQ6 in DQ6/DR3 mice was mediated by high levels of IFNγ (Mangalam et al J Immunol 2008), while the disease exacerbating effect of DQ8 in DR3/DQ8 mice was mediated by IL17 (Mangalam et al J Immunol 2009). Based on these studie, we hypothesized that HLA class II molecules regulate autoimmune disease through modulation of the pro- and anti-inflammatory cytokine network (Mangalam et al, J Immunol 2013).

To further understand the role of IFNγ and IL17 in disease pathogenesis, we have generated HLA class II transgenic mice lacking either IFNγ (HLA-DR3.IFNγ-/-) or IL17 (HLA-DR3.IL-17-/-) or both (HLA-DR3.IFNγ-/-.IL-17-/-) to investigate their respective role in initiation as well as progression of CNS inflammatory and demyelinating disease.