Role of regulatory B-cells in pathogenesis and progression of autoimmune myocarditis
Final Report Abstract
Experimental autoimmune myocarditis (EAM) can be induced in healthy mice by immunization with cardiac troponin-I (cTnI) or a pathogenic peptide sequence of cTnI and complete Freund's adjuvant (CFA). In these mice, immunization leads to mononuclear infiltration into the myocardium, followed by inflammation of the same and a measurable increase in anti-TnI antibodies (TnI-Ab) and cardiac troponin T (TnT) in the animals' blood. A transfer of T cells from diseased mice also triggers myocarditis in recipient animals. Until now, little was known about the role of B cells in this process. Preliminary tests from our laboratory indicated a regulatory role for B cells in this process. This should be examined more closely in the present project. For this purpose, T cells from the spleens of TnI peptide-immunized mice together with autologous B cells were transferred to irradiated healthy donors after a brief intermediate culture in vitro. In order to investigate the extent to which the B cells must be activated or be antigen-specific, B cells from non-immunized animals were also used, either unstimulated or partly pre-stimulated with CD40L. As controls T cells from non-immunized, only CFA receiving donors were transferred. The mice were observed for 21 days, sacrificed and the spleens and hearts removed and examined. The results showed that the addition of B cells, regardless of their origin or initial activation, inhibited myocardial inflammation in recipient animals: both mononuclear infiltration into the myocardium and the production of inflammatory cytokines and chemokines were significantly reduced. The TnI-Ab concentration in the serum, however, did not correlate with the extent of the inflammation. In vitro culture supernatants of TnI-T cell recipient spleens showed a significantly reduced production of the TH2 cytokines IL-10, IL-13 and IL-4 as compared to spleens of animals receiving control cells. However, co-transfer of B cells did not alter the shifted TH1/TH2 imbalance, indicating that the immunoregulatory effects of B cells in the EAM model are not mediated through this axis. Of note, immunization of B-cell deficient mice with TnI peptide did not induce myocarditis, implying that B-cells can have both pathogenic and immunosuppressive effects.
Publications
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Die Rolle regulatorischer B-Zellen in der Autoimmunmyokarditis. DGK Jahrestagung 2019
C. Meckes, M. Bockstahler, A. Fischer, A.-M. Müller, R. Öttl, A.-M. Suhr, H.A. Katus, T. Tretter & Z. Kaya
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Poster, DGK Jahrestagung 2023 Effects of B-cell depletion on the development and progression of autoimmune myocarditis
R. Ignatz, V. Zirkenbach, C. Meckes, R. Öttl, Z. Cehreli, N. Frey, T. Tretter & Z. Kaya
