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Medizinische Fakultät - Digitale Hochschulschriften der LMU - Teil 17/19 Podcast
Characterization of disease-related CD8+ T cells and their antigens from patients with Multiple Sclerosis

Characterization of disease-related CD8+ T cells and their antigens from patients with Multiple Sclerosis

Medizinische Fakultät - Digitale Hochschulschriften der LMU - Teil 17/19 vor 12 Jahren

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Multiple Sclerosis is most probably an autoimmune inflammatory
disease of the central nervous system. Demyelination of neurons and
axonal loss occur in temporal and spatial resolution in multiple
areas of the brain and spinal cord. This impairment manifests in
neurological symptoms. The course of disease varies between
individuals and the causing mechanisms still remain elusive.
Environmental factors as well as genetic predispositions are widely
discussed. Recent studies stressed the prominent role of CD8+ T
lymphocytes in the autoimmune pathomechanism. They notably exceed
the amount of CD4+ T cells in acute lesions yet target cells and
activating antigens remain elusive. A genetic linkage between the
human leukocyte antigen gene locus and disease susceptibility was
observed. Carrying the HLA A*0301 allele or the HLA A*0201 allele
correlates with a risk factor or protective effect for Multiple
Sclerosis susceptibility, respectively. Thus during this thesis two
main questions were followed: 1. Which CD8+ T lymphocytes
participate in the autoimmune attack on central nervous system
tissue and what are their receptors for antigen recognition? 2. How
does the expression of HLA-A2 molecules lead to a decreased disease
susceptibility? In the first part, the T cell receptor molecules of
potentially disease-related single CD8+ T cells from frozen patient
tissue samples were characterized. T lymphocytes were considered
disease-related when they either belonged to a clonally expanded T
cell population or expressed an activation marker on their cell
surface. In a clone-specific approach, the T cell receptor beta
chains of pre-analyzed, clonally expanded T cell populations were
investigated. Further an unbiased approach independent of
pre-analyses was established. In the second part, antigen
recognition of the probably disease-related T cell receptor 2D1 was
investigated. This receptor was isolated from a Multiple Sclerosis
patient and was known to be activated by a myelin-derived peptide
presented on HLA-A3 molecules. In an animal model double-transgenic
mice expressing HLA-A3 and the 2D1 T cell receptor developed a
Multiple Sclerosis-like disease after immunization with the known
peptide. Surprisingly not a single triple-transgenic mouse
expressing HLA-A3, the T cell receptor 2D1 and HLA-A2 showed
symptoms after immunization. In these mice 2D1 T lymphocytes were
shown to be depleted in the thymus. To characterize HLA-A2-bound
peptides which mediate this protective effect a novel technology
for unbiased identification of antigenic peptides recognized by
human leukocyte antigen class I-restricted T lymphocytes was
employed. 28 peptides presented on HLA-A2 molecules were found to
be recognized by the T cell receptor 2D1. Those peptides displayed
very closely related sequences. Eight possible parent proteins
existing in mouse, therefrom even four equally expressed in humans
were identified. Finally those putative parent proteins were
further characterized and first investigations of antigen
processing in different antigen presenting cell lines were
performed.