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

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)578-586
Number of pages9
JournalBrain, Behavior, and Immunity
Volume91
DOIs
StatePublished - Jan 2021

Keywords

  • B-lymphocytes
  • CD4+ helper T-lymphocytes
  • Chronic inflammation
  • Cognitive decline
  • IgA
  • Stroke
  • Thymus-independent type 2 antigen

ASJC Scopus subject areas

  • Immunology
  • Endocrine and Autonomic Systems
  • Behavioral Neuroscience

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