TY - JOUR
T1 - IgA natural antibodies are produced following T-cell independent B-cell activation following stroke
AU - Zbesko, Jacob C.
AU - Frye, Jennifer Beischel
AU - Becktel, Danielle A.
AU - Gerardo, Diana K.
AU - Stokes, Jessica
AU - Calderon, Kylie
AU - Nguyen, Thuy Vi V.
AU - Bhattacharya, Deepta
AU - Doyle, Kristian P.
N1 - Funding Information:
We would like to thank Dr. Dominik Schenten for his generous gift of the MyD88-/- mice as well as Dr. Emmanuel Katsanis for allowing us the use of the LSRFortessa cell analyzer. This work was funded by NIH R01NS096091 (KPD), NIH R01AI099108 (DB), NIH R01AI129945 (DB) United States Department of Veterans Affairs I01RX003224 (KPD), Foundation Leducq Transatlantic Network of Excellence (KPD), NIH F31NS105455 (JCZ), the Phoenix Chapter of ARCS Foundation, Inc. (JCZ), and NIH T32AG058503-01A1 (DAB)
Funding Information:
This work was funded by NIH R01NS096091 (KPD), NIH R01AI099108 (DB), NIH R01AI129945 (DB) United States Department of Veterans Affairs I01RX003224 (KPD), Foundation Leducq Transatlantic Network of Excellence (KPD), NIH F31NS105455 (JCZ), the Phoenix Chapter of ARCS Foundation , Inc. (JCZ), and NIH T32AG058503-01A1 (DAB)
Publisher Copyright:
© 2020 The Authors
PY - 2021/1
Y1 - 2021/1
N2 - 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.
AB - 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.
KW - B-lymphocytes
KW - CD4+ helper T-lymphocytes
KW - Chronic inflammation
KW - Cognitive decline
KW - IgA
KW - Stroke
KW - Thymus-independent type 2 antigen
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U2 - 10.1016/j.bbi.2020.09.014
DO - 10.1016/j.bbi.2020.09.014
M3 - Article
C2 - 32956832
AN - SCOPUS:85092214540
SN - 0889-1591
VL - 91
SP - 578
EP - 586
JO - Brain, Behavior, and Immunity
JF - Brain, Behavior, and Immunity
ER -