In vivo and in vitro studies of immunodeficiency in Ataxia-telangiectasia

Carney, Ellen F. (2011). In vivo and in vitro studies of immunodeficiency in Ataxia-telangiectasia. University of Birmingham. Ph.D.

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Abstract

Ataxia-telangiectasia (A-T) is a rare neurodegenerative disorder caused by mutations in the ATM gene which has a central role in the cellular response to DNA double strand breaks, cell cycle checkpoint control and initiation of the intrinsic pathway of apoptosis. Ataxiatelangiectasia is classified as an immunodeficient disorder with patients commonly showing lymphopenia and abnormalities in immunoglobulin production. They also have a high incidence of leukaemia and lymphoma at young ages. I used multicolour flow cytometry and immunological assays to characterise lymphocyte subsets in a group of 18 A-T patients and analysed the sensitivity of A-T lymphoblastoid cell lines to CD95-mediated apoptosis. I also investigated the potential role for ATM in immune surveillance via DNA damage-induced upregulation of NKG2D ligands. My results confirm a deficiency in naive T and B cells as well as high expression of the death receptor CD95 on all lymphocyte subsets excluding NK cells which together may explain the lymphopaenia in A-T. Analysis of the sensitivity of A-T LCLs to CD95-mediated apoptosis showed increased sensitivity of these cells to apoptosis but there was no evidence for a role of ATM in regulating either CD95 or cFLIP expression. Consistent with this was the increased sensitivity to CD95-mediated apoptosis of T cell prolymphocytic leukaemia (T-PLL) cells. The cause of the tumour is primary loss of ATM activity (either germline loss similar to A-T LCLs or somatic loss) allowing chromosome translocations with malignant potential, as a result of a defect in immune system gene rearrangements. An immediate consequence for A-T patients is an immunodeficiency that is not progressive, but may be described as ‘congenitally aged’. Immunodeficiency per se is not the cause of cancer in A-T but both immunodeficiency and cancer are consequences of the same basic ATM defect affecting the lymphoid system. There was no evidence of a role for ATM in NKG2D ligand upregulation following DNA damage.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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