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

Jacob C Zbesko; Jennifer Beischel Frye; Danielle A Becktel; Diana K Gerardo; Jessica Stokes; Kylie Calderon; Thuy-Vi V Nguyen; Deepta Bhattacharya; Kristian P Doyle

doi:10.1016/j.bbi.2020.09.014

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

Brain Behav Immun. 2021 Jan:91:578-586. doi: 10.1016/j.bbi.2020.09.014. Epub 2020 Sep 19.

Authors

Jacob C Zbesko¹, Jennifer Beischel Frye¹, Danielle A Becktel¹, Diana K Gerardo¹, Jessica Stokes², Kylie Calderon¹, Thuy-Vi V Nguyen³, Deepta Bhattacharya¹, Kristian P Doyle⁴

Affiliations

¹ Department of Immunobiology, University of Arizona, Tucson, AZ 85719, USA.
² Department of Pediatrics, University of Arizona, Tucson, AZ 85719, USA.
³ Department of Immunobiology, University of Arizona, Tucson, AZ 85719, USA; Department of Neurology, University of Arizona, Tucson, AZ 85719, USA.
⁴ Department of Immunobiology, University of Arizona, Tucson, AZ 85719, USA; Department of Neurology, University of Arizona, Tucson, AZ 85719, USA; Arizona Center on Aging, University of Arizona, Tucson, AZ 85719, USA. Electronic address: doylekr@email.arizona.edu.

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.

Keywords: B-lymphocytes; CD4+ helper T-lymphocytes; Chronic inflammation; Cognitive decline; IgA; Stroke; Thymus-independent type 2 antigen.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
B-Lymphocytes
CD4-Positive T-Lymphocytes
Humans
Immunoglobulin A
Lymphocyte Activation*
Mice
Stroke*

Substances

Immunoglobulin A

Abstract

Publication types

MeSH terms

Substances

Grants and funding