B-Lymphocyte-Mediated Delayed Cognitive Impairment following Stroke

Abstract

Each year, 10 million people worldwide survive the neurologic injury associated with a stroke. Importantly, stroke survivors have more than twice the risk of subsequently developing dementia compared with people who have never had a stroke. The link between stroke and the later development of dementia is not understood. There are reports of oligoclonal bands in the CSF of stroke patients, suggesting that in some people a B-lymphocyte response to stroke may occur in the CNS. Therefore, we tested the hypothesis that a B-lymphocyte response to stroke could contribute to the onset of dementia. We discovered that, in mouse models, activated B-lymphocytes infiltrate infarcted tissue in the weeks after stroke. B-lymphocytes undergo isotype switching, and IgM, IgG, and IgA antibodies are found in the neuropil adjacent to the lesion. Concurrently, mice develop delayed deficits in LTP and cognition. Genetic deficiency, and the pharmacologic ablation of B-lymphocytes using an anti-CD20 antibody, prevents the appearance of delayed cognitive deficits. Furthermore, immunostaining of human postmortem tissue revealed that a B-lymphocyte response to stroke also occurs in the brain of some people with stroke and dementia. These data suggest that some stroke patients may develop a B-lymphocyte response to stroke that contributes to dementia, and is potentially treatable with FDA-approved drugs that target B cells.

Clinical Trials of Immunomodulation in Ischemic Stroke

“…Currently, the target of immunomodulation translated into clinical trials is focused on the early phase of toxic neuroinflammation. However, the neuroinflammatory reaction after acute brain injury continues for months [4,34,35], and the complex effect on repair and degeneration after stroke remains to be unravelled. This further highlights the dualistic nature of the immune response to stroke, acting not only to exacerbate damage with detrimental effects, but also to propagate repair and recovery.…”

Antigen Presentation After Stroke

“…Autoantibodies may also have a role in the development of poststroke cognitive impairment. In mouse models, infiltration by B lymphocytes occurred weeks after cerebral ischemia, in parallel with the appearance of signs of cognitive decline [84], and IgG autoantibodies against MBP after stroke were more frequent in patients with cognitive decline than in patients without it [85].…”

Stroke, Inflammation and the Immune Response: Dawn of a New Era

“…For instance, both depression and fatigue are common after stroke, and these Bsilent sequelae of strokem ay be related to poststroke inflammation [9,10]. There are also convincing data suggesting that cognitive decline after stroke may be related to immune responses put into play by the stroke [11,12]. New immunomodulatory therapies will thus target symptoms that affect quality of life but have not received adequate recognition in stroke trials to date.…”