title: Modulation of Immune response by Ultra-violet light in HLA class-II transgenic mice.
abstract: Multiple Sclerosis (MS) is a chronic and debilitating disease of the central nervous system linked to both genetic and environmental factors. Among the genetic factors, MHC, especially HLA class-II, is strongly associated with predisposition to MS. Although in vitro studies have helped us understand some aspects of HLA class-II association with the disease, performing in vivo analysis is necessary in order to further understand this correlation. Studying the role of class-II genes in vivo is a difficult task due to the heterogeneity of human population, the complexity of MHC, and the strong linkage disequilibrium among different class-II genes. To overcome this challenge, we generated HLA class-II transgenic mice to study the role of these molecules in MS. Among the environmental factors linked with MS, ultra violet radiation (UVR)/vitamin-D is suggested to have protective effect against the development of the disease. Indeed, genetic studies have shown that presence of susceptible HLA-Class II and decrease in UVR exposure or vitamin D levels together increase risk of MS. Therefore, this study was designed to investigate the direct effect of UVR on immune response using novel humanized HLA-class II transgenic mice. HLA-class II transgenic mice expressing MS susceptible HLA-DR2 allele were treated with different doses of UVR (0.50-3.75 kJ/day) for seven consecutive days. T-cell proliferation, immune cell sub-populations and cytokines levels were analyzed. Our results show that treatment with UVR increased levels of regulatory CD4+FoxP3+ T cells and Gr1+ CD11b+ suppressive macrophages. Thus our study indicates that UVR modulates the immune response towards a tolerogenic phenotype in HLA-transgenic mice immunized with MOG35-55. Therefore, HLA class-II transgenic mice offer a novel tool to decipher the mechanism by which interaction between environmental and genetic factors play a role in predisposition and/or protection against development of MS.
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Daniel Bastardo
authors.initials: DB
authors.lastname: Blanco
authors.affiliation: Department of Dermatology, Mayo Clinic, Rochester, MN, USA.
authors.forename: David
authors.initials: D
authors.lastname: Luckey
authors.affiliation: Department of Nephrology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Michele
authors.initials: M
authors.lastname: Smart
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Pittelkow
authors.forename: Rajiv
authors.initials: R
authors.lastname: Kumar
authors.forename: Chella S
authors.initials: CS
authors.lastname: David
authors.forename: Ashutosh K
authors.initials: AK
authors.lastname: Mangalam
keywords: EAE/MS; HLA-transgenic mice; MHC; cytokines; epitopes; neuroimmunology; regulatory cells; ultraviolet light; vitamin D