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Title: B lymphocyte prevalence in the brain in health and disease
Author: Anthony, Iain C.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2003
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In recent years evidence has accumulated which suggests that the brain may not be the immunologically privileged site it was once considered to be. It is now widely accepted that T lymphocytes perform surveillance functions in normal brain parenchyma. However as yet there are no reports of B lymphocytes entering brain parenchyma in the healthy state. This study aimed first to determine the prevalence of B lymphocytes in normal human brain, and subsequently whether advancing human immunodeficiency virus (HIV) infection leads to changes in the brain B lymphocyte population which might contribute to the increased risk of lymphoma seen in aquired immunodeficency syndrome (AIDS). Our results show that B lymphocytes do enter all areas of normal brains in very low numbers and that the B lymphocytes within the brain parenchyma display an activated (CD23 positive) phenotype. In contrast intravascular B lymphocytes had a much lower expression of activation markers. B lymphocytes were found in increased numbers in both the brain parenchyma and perivascular spaces of pre-AIDS brains. However brains from the majority of AIDS subjects, including those with primary central nervous system lymphoma (PCNSL) (out with the area of neoplastic involvement) contained fewer B lymphocytes than normal or pre-symptomatic HIV infected brains. A subset of AIDS brains, previously shown to have pleomorphic lymphoid infiltrates in the perivascular spaces had significantly increased numbers of B lymphocytes in both the brain parenchyma and perivascular spaces, which led us to hypothesise that these may represent a pre-malignant PCNSL state. These pleomorphic lymphoid infiltrates were shown to be polyclonal, as defined by immunoglobulin gene re-arrangements, in contrast to PCNSL in which two of three tumours were found to be monoclonal. Virtually all AIDS related PCNSL are known to be EBV positive, in contrast to non-HIV PCNSL and non-CNS AIDS related lymphomas. We examined the EBV status of brain parenchymal B lymphocytes to investigate whether EBV positive B lymphocytes are more frequent in HIV infected brains than normal thus explaining the propensity for CNS lymphomas in AIDS. In-situ hybridisation (ISH) studies showed EBV positive cells only in the tumours of AIDS related PCNSL cases. PCR based studies detected high EBV copy numbers in PCNSL tumour tissue and low copy numbers from AIDS cases with pleomorphic lymphoid infiltrates. As none of the B lymphocytes in this latter group were EBV ISH positive, and this appears to be a prerequisite for PCNSL development, we find no evidence that pleomorphic infiltrates represent a pre-malignant PCNSL state. However both PCNSL and AIDS associated pleomorphic infiltrates were associated with expression of the B lymphocyte chemoattractant, stromal cell derived factor-1 (SDF-1) in the brain. Humoral responses have been shown to play an important part in the immune response to many neurtropic viruses, therefore we assessed the role of B lymphocytes in HIV encephalitis (HIVE). Our results show that a slight increase in the brain B lymphocyte population occurs in HIVE compared to non-HIVE AIDS brains. However this response is far smaller than that seen either in pre-AIDS non-HIV encephalitis or in non-immunocompromised viral encephalitis. Finally we have shown that the presence of B lymphocytes in the brain is not associated with damage or disruption to the blood-brain barrier.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available