IgA natural antibodies are produced following T-cell independent B-cell activation following stroke

Abstract

Up to 30% of stroke patients experience cognitive decline within one year of their stroke. There are currently no FDA-approved drugs that can prevent post-stroke cognitive decline, in part due to a poor understanding of the mechanisms involved. We have previously demonstrated that a B-lymphocyte response to stroke, marked by IgA + cells, can cause delayed cognitive dysfunction in mice and that a similar adaptive immune response occurs in the brains of some human stroke patients that suffer from vascular dementia. The stimuli which trigger B-lymphocyte activation following stroke, and their target antigens, are still unknown. Therefore, to learn more about the mechanisms by which B-lymphocytes become activated following stroke we first characterized the temporal kinetics of the B-lymphocyte, T-lymphocyte, and plasma cell (PC) response to stroke in the brain by immunohistochemistry (IHC). We discovered that B-lymphocyte, T-lymphocyte, and plasma cell infiltration within the infarct progressively increases between 2 and 7 weeks after stroke. We then compared the B-lymphocyte response to stroke in WT, MHCII −/− , CD4 −/− , and MyD88 −/− mice to determine if B-lymphocytes mature into IgA + PCs through a T-lymphocyte and MyD88 dependent mechanism. Our data from a combination of IHC and flow cytometry indicate that following stroke, a population of IgA + PCs develops independently of CD4 + helper T-lymphocytes and MyD88 signaling. Subsequent sequencing of immunoglobulin genes of individual IgA + PCs present within the infarct identified a novel population of natural antibodies with few somatic mutations in complementarity-determining regions. These findings indicate that a population of IgA + PCs develops in the infarct following stroke by B-lymphocytes interacting with one or more thymus independent type 2 (TI-2) antigens, and that they produce IgA natural antibodies.

Repeated administration of 2-hydroxypropyl-β-cyclodextrin (HPβCD) attenuates the chronic inflammatory response to experimental stroke

“…3C) . These perturbations in innate and adaptive immunity demonstrate that chronic inflammation persists in infarcts for at least 7 weeks after stroke, as we have shown previously (Chung et al, 2018; Doyle et al, 2015; Zbesko et al, 2020).…”

“…Similar to atherosclerotic plaques, chronic stroke infarcts contain foamy macrophages, lipid droplets, and intracellular and extracellular cholesterol crystals (Chung et al, 2018). We have also shown that the development of these pathologies coincides with the recruitment and infiltration of adaptive immune cells (Doyle et al, 2015;Zbesko et al, 2020). Importantly, in atherogenesis, the formation of foamy macrophages, caused by dysregulated lipid metabolic processes, leads to the recruitment of adaptive immune cells and the production of cytokines and degradative enzymes.…”

“…To accomplish these aims, we used the distal middle cerebral artery occlusion + hypoxia mouse model of ischemic stroke in conjunction with immunohistochemistry, RNA-Seq, lipidomics, and behavioral analyses. Our resulting data indicate that, coincident with the substantial accumulation of infiltrating immune cells (Doyle et al, 2015; Zbesko et al, 2020), chronic stroke infarcts amass lipids, including sphingomyelins, cholesterol esters, and sulfatides. We also demonstrate that repeated administration of HPβCD in young adult and aged mice attenuates immune cell and lipid accumulation within chronic stroke infarcts and improves recovery at transcriptional and functional levels.…”

“…Correspondingly, activated B lymphocytes and autoantibodies have been shown to cause neuropathology in models of experimental autoimmune encephalomyelitis (EAE), SCI, and transient middle cerebral artery occlusion (Ankeny, Lucin, Sanders, McGaughy, & Popovich, 2006; Ortega et al, 2015; Raine, Cannella, Hauser, & Genain, 1999). Recently, we also found that the production of natural IgA antibodies is a part of the B-lymphocyte response to stroke (Zbesko et al, 2020). However, future studies are required to determine if the function of these natural IgA antibodies is to aid in the clearance of myelin debris and the neutralization of apoptotic foamy macrophages.…”

“…We previously reported, in a mouse model of post-stroke dementia, that delayed cognitive impairment is caused by a chronic inflammatory response to stroke that is mediated in part by B lymphocytes (Doyle et al, 2015; Doyle, Fathali, Siddiqui, & Buckwalter, 2012). In addition to the progressive infiltration of B lymphocytes, T lymphocytes, and IgA+ plasma cells into the infarct in the weeks following stroke, the chronic inflammatory response is also characterized by the production of neurotoxic molecules such as antibodies, cytokines, and degradative enzymes (Zbesko et al, 2020; Zbesko et al, 2018). These neurotoxic molecules permeate the glial scar and promote chronic inflammation and secondary neurodegeneration in the surrounding parenchyma (Zbesko et al, 2018).…”