Investigating the Chronic Inflammatory Response to Stroke: The Role of Glial Scar Astrocytes and B-Lymphocytes

Abstract

Stroke affects nearly 800,000 Americans every year and, of survivors, around one third will develop dementia. Not only personally devastating to sufferers, this disease places an enormous financial and emotional burden on their loved ones. Currently, the thrombolytic agent Tissue Plasminogen Activator (tPA) is the only Food and Drug Administration (FDA) approved medication for stroke. Thrombolytic therapy with tPA can prevent irreversible injury by restoring blood flow if administered within 6 hours of stroke onset. However, there are no approved therapeutics designed to prevent or treat post-stroke dementia, partly due to our lack of understanding of the mechanism(s) that lead to its development. The goal of this dissertation is to further our understanding of the basic biology of stroke recovery in order to facilitate the development of treatments that prevent or alleviate post-stroke dementia. To accomplish this goal, we investigated the cellular and molecular mechanisms of brain repair by glial scar formation following stroke, as well as the role of T-lymphocytes and Immunoglobulin (Ig) A antibodies in the B-lymphocyte response to stroke. Results from our investigation of glial scar formation indicate that although glial scar astrocytes form a physical and endocytic barrier that encapsulates chronic stroke infarcts, the barrier they form is permeable to the chronic inflammatory response that takes place within the infarct. This leakage allows neurotoxic factors present within the infarct to permeate into the surrounding brain tissue in the weeks following stroke, which correlates with secondary neurodegeneration. Results from our investigation of the role of T-lymphocytes and IgA antibodies in the B-lymphocyte response to stroke indicate that following stroke, B-lymphocytes mature into IgA+ plasma cells through a T-lymphocyte independent mechanism and produce natural antibodies. Together these data indicate that although a role of glial scar astrocytes is to segregate the chronic inflammatory response to stroke from the surviving brain, this function is insufficient to prevent secondary neurodegeneration. They also indicate that a novel role of the B-lymphocyte response to stroke is to produce IgA natural antibodies within the infarct. Natural antibodies are known to be polyreactive to cellular debris and are often associated with the clearance of apoptotic cells and oxidized lipids. We hypothesize that these antibodies, and other neurotoxic factors present within the stroke infarct, enter the surrounding brain tissue through the permeable glial scar causing damage to the surviving brain tissue, suggesting a potential mechanism for the development of post-stroke dementia.