Myelin Basic Protein-Specific TCR/HLA-DRB5*01:01 Transgenic Mice Support the Etiologic Role of DRB5*01:01 in Multiple Sclerosis

Abstract

Genetic susceptibility to multiple sclerosis (MS) has been linked to the HLA-DR15 haplotype consisting of DRB1*15:01(DR2b)- and DRB5*01:01(DR2a) alleles. Given almost complete linkage disequilibrium of the two alleles, recent studies have suggested differential roles in susceptibility (DR2b) or protection from MS (DR2a). Our objective was to assess the potential contribution of DR2a to disease etiology in MS using a humanized model of autoimmunity. To assess the potential contribution of DR2a to disease etiology, we created DR2a humanized transgenic (Tg) mice and subsequently crossed them to Tg mice expressing TL3A6, an MS patient-derived myelin basic protein (MBP)83-99 -specific T cell receptor (TCR). In TL3A6/DR2a Tg mice, CD4 Tg T cells escape thymic and peripheral deletion and initiate spontaneous experimental autoimmune encephalomyelitis (EAE) at low rates depending on the level of DR2a expression. The ability to induce active EAE was also increased in animals expressing higher levels of DR2a. Inflammatory infiltrates and neuronal damage were present throughout the spinal cord consistent with a classical ascending EAE phenotype with minor involvement of the cerebellum, brainstem and peripheral nerve roots in spontaneous as well as actively induced disease. These studies emphasize the pathologic contribution of the DR2a allele to the development of autoimmunity when expressed as the sole MHC class II molecule, and strongly argue for DR2a as a contributor to CNS autoimmunity in MS.

Oral administration of the nitroxide radical TEMPOL exhibits immunomodulatory and therapeutic properties in multiple sclerosis models

“…Female C57BL/6J (Jackson Labs) or SJL/J (Harlan Laboratories) mice were acclimatized at least one week prior to study and then used as models of active chronic and passive relapsing-remitting model of MS, respectively. 8–10 week old C57BL6/J mice were immunized with 200 μg MOG35-55 (MEVGWYRSPFSRVVHLYRNGK; Stanford Pan Facility, Stanford CA) as described previously (Quandt et al, 2012). For passive disease, animals were immunized with 75 µg PLP139-151 (HCLGKWLGHPDKF, Stanford Pan Facility) and draining lymph node (LN) cells enriched with PLP before transfer to healthy recipients as described (Anderson et al, 2004).…”

A molecular view of multiple sclerosis and experimental autoimmune encephalitis: What can we learn from the epitope data?

“…In most cases, EAE is experimentally induced (as the acronym implies) using antigens (peptides and proteins) along with bacterially-derived adjuvants; spontaneous disease is achieved using transgenic mice models (Madsen et al, 1999; Quandt et al, 2012). Moreover, while both humoral (B cells, plasma cells and antibody) and cellular (CD4 + and CD8 + ) mechanisms have been shown to contribute to MS immunopathology (Lassman et al, 2007; Simmons et al, 2013 May 21), EAE represents the prototype T cell-mediated autoimmune model, whereby CD4 + T cells are the predominant effector cell in the disease, which is largely driven by a pro-inflammatory Th 1 /Th 17 cytokine milieu (Kroenke et al, 2008).…”

HLA DRB5*01 Association Survey with Multiple Sclerosis in Khuzestan Province of Iran

“…This region is in very strong linkage disequilibrium (LD). DR alpha chain and the two beta chains creates the two functional surface heterodimers, DR2b (DRA*0101, DRB1*1501) and DR2a (DRA*0101, DRB5*0101) [30]. Whether both or only one of the two alleles and resulting DR molecules contribute to MS etiopathogenesis are one of the most important questions in MS researches.…”

“…The present of antigens from outside of the cell to T-lymphocytes is the function of HLAs class II and it contains the classical alpha and beta chain genes including DP, DM, DOA, DOB, DQ , and DR. As Class II molecules can bind and present certain self-peptides, several studies indicated that HLAs class II have been associated to several autoimmune or immune mediated disorders, including MS [29]. An estimated 10-60% of the MS genetic risk appears to be conferred by the DR15 haplotype (DQB1*0602, DQA1*0102, DRB1*1501, DRB5*0101) [30]. Although several studies have been carried out on the association of HLA DRB5*01 with MS in various populations [31][32][33][34], there is no data about this issue in Khuzestan province in Iran.…”