CD4 T Cell Affinities for Myelin in Clinically Relevant Models of Multiple Sclerosis Público
Kersh, Anna Elizabeth (2015)
Abstract
Multiple sclerosis is an autoimmune disease mediated primarily by myelin-specific CD4 T cells that is characterized by inflammation, demyelination and scarring in the central nervous system (CNS). As autoimmune disease has been suggested to persist and progress through the recognition of new or modified epitopes, we use the micropipette adhesion frequency assay to evaluate the frequency and two-dimensional (2D) affinity of myelin-reactive CD4 T cells in two clinically relevant mouse models of demyelinating disease: a relapsing-remitting turned secondary progressive model and a humanized mouse model. We first explore the nonobese diabetic (NOD) mouse model in which myelin oligodendrocyte glycoprotein (MOG) immunization elicits a relapsing-remitting disease that evolves into secondary progressive phenotype, the disease course experienced by the vast majority of MS patients. Many believe that progression of relapsing-remitting disease occurs due to epitope spread, the development of reactivity to distinct CNS antigens due to the release of antigens during demyelination. In NOD mice, the vast majority of CNS-infiltrating CD4 T cells remains reactive to MOG throughout symptom onset, remission, relapse and chronic progression which limits the contribution of CD4 T cells reactive to distinct epitopes to disease progression. Cells with the highest affinity for MOG were observed during acute disease demonstrating increased TCR affinity is not required for disease progression. As the HLA-DR4 gene is associated with an increased risk for MS, we then used a humanized mouse model of demyelinating disease in which mice express HLA DRB1*0401 (HLA-DR4) instead of murine MHC Class II genes. We explore CD4 T cell affinities for MOG and an epitope of MOG that contains citrulline in place of arginine in position 101, the result of an inflammation-induced post-translational deimination modification. We found a substantial population of cells cross-reactive to both MOG and citrullinated MOG had infiltrated the CNS before symptom onset and persisted through chronic symptoms. Further, a substantial population of CD4 T cells reactive only to citrullinated MOG was detected at symptomatic time points both in the CNS and in the periphery indicating CD4 T cell reactivity to citrulline may hold great value as a biomarker of disease in DR4+ patients.
Table of Contents
INTRODUCTION. 1
CHAPTER 1. 45
Abstract. 46
Introduction. 47
Material and Methods. 50
Results. 54
Discussion. 62
Figure 1. 69
Table I. 70
Figure 2. 71
Figure 3. 72
Figure 4. 73
Figure 5. 74
Supplemental Figure 1. 75
Figure Legends. 76
CHAPTER 2. 83
Abstract. 84
Introduction. 86
Material and Methods. 89
Results. 94
Discussion. 105
Figure 1. 110
Figure 2. 111
Table I. 112
Figure 3. 113
Figure 4. 114
Figure 5. 115
Figure 6. 116
Figure 7. 117
Figure Legends. 118
CONCLUSIONS & DISCUSSION. 125
REFERENCES. 135
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