Investigating the origin and role of the IgA+ B cell response to intracerebral hemorrhage - PROJECT SUMMARY Stroke is the second highest cause of death and the leading cause of disability globally. Intracerebral hemorrhage (ICH) is the second most prevalent form of stroke with a high mortality of ~40% and high rates of long-term cognitive decline in surviors.1-4 The B cell response to stroke is well established, and in ischemic stroke models in mice B cells have been linked to slow cognitive decline.5 However, the B cell response to ICH is currently unknown and represents a major gap in knowledge. Our preliminary work has demonstrated an influx of IgA+ B cells into the brain starting 8 weeks post-ICH, similar to the IgA+ B cell aggregates in the brain and spinal cord in multiple sclerosis patients and experimental autoimmune encephalitis (EAE) mouse models.8 While IgA+ B cells are traditionally associated with mucosal tissues like the small intestine, their presence in the CNS is spurring new inquiry into the function of these cells in the context of neuroinflammation. I hypothesize that there is a late influx of IgA+ B cells from the meninges into the brain post-ICH that serves a neuroprotective role in post-stroke recovery. The goal of this project is to utilize a murine collagenase injection model of ICH to elucidate the origin and function of brain-infiltrating IgA+ B cells in post- ICH inflammation and recovery in the following aims. Aim 1. To determine the timing of the IgA+ B cell influx into the post-ICH brain over 16 weeks, investigate whether these cells are locally proliferating or constantly recruited, determine whether tertiary lymphoid structures (TLSs) exist in the post-ICH brain, and identify the brain regions IgA+ B cells localize to. Aim 2. To elucidate the origin of brain-infiltrating IgA+ B cells post-ICH using both meningeal plasma cell depletion and clonal analysis of B cells from blood, gut, meninges, and brain B cells using B cell receptor sequences generated by single-cell RNA-sequencing. Aim 3. To determine the effector functions of brain-infiltrating IgA+ B cells on post-ICH recovery. These experiments will provide much needed insight on the role of B cells in the brain in the weeks and months after ICH, and specifically on IgA in the context of stroke and neuroinflammation more broadly. My results therefore have the potential to shape our understanding of the adaptive immune response to ICH and inform therapeutic approaches to mitigate the long-term effects of this disease on patients and families.
