Does B lymphocyte-mediated autoimmunity contribute to post-stroke dementia?

Abstract

Post-stroke cognitive decline and dementia pose a significant public health problem, with 30% of stroke survivors suffering from dementia. The reason for this high prevalence is not well understood. Pathogenic B cell responses to the damaged CNS are one possible contributing factor. B-lymphocytes and antibodies are present in and around the stroke core of some human subjects who die with stroke and dementia, and mice that develop delayed cognitive dysfunction after stroke have clusters of B-lymphocytes in the stroke lesion, and antibody infiltration in the stroked hemisphere. The ablation of B-lymphocytes prevents post-stroke cognitive impairment in mice. Multiple drugs that target B cells are FDA approved, and so if pathogenic B cell responses are occurring in a subset of stroke patients, this is potentially treatable. However, it has also been demonstrated that regulatory B cells can be beneficial in mouse models of stroke. Consequently, it is important to understand the relative contribution of B-lymphocytes to recovery versus pathogenicity, and if this balance is heterogeneous in different individuals. Therefore, the purpose of this review is to summarize the current state of knowledge with regard to the role of B-lymphocytes in the etiology of post-stroke dementia.

Keywords: Alzheimer’s Disease; Autoantibody; Autoimmune; Dementia; Lymphocyte; Stroke; Vascular dementia.

Figure 1. Autoimmunity after stroke

Left to right: In response to stroke antigenic material exits the CNS and is taken up by dendritic cells in cervical lymph nodes. Macrophages from the periphery also migrate to the damaged tissue to participate in the clearance of dead cells and cellular debris. We propose that a subset of these phagocytic cells exit the brain via the meningeal lymphatic system and also reach the cervical lymph nodes. Here they come into contact with, and present antigen to, autoreactive B- and T-lymphocytes that have escaped negative selection. Once activated, autoreactive B-lymphocytes proliferate, secrete antibody into the circulation, and home to the infarct. Within the infarct they encounter additional antigen resulting in the further production of autoantibodies within the CNS compartment. Finally, neurodegeneration may occur and contribute to post-stroke cognitive decline and dementia.

Figure 2. B Lymphocytes accumulate in the stroke core in the weeks after stroke

Fluorescent immunostaining for B220 (red) and CD11c (green) demonstrate that B cells are present in the lesion 7 weeks following stroke in C57BL/6 mice, and are organized into clusters surrounded by cells expressing CD11c. CD11c is a marker found on most dendritic cells and some plasma cells. B cell clusters commonly form at sites of chronic inflammation, and their presence is associated with poor outcome in multiple sclerosis, traumatic brain injury, rheumatoid arthritis and spinal cord injury (Ankeny and Popovich, 2010; Carragher et al., 2008). Scale bar, 20µm.