Role of regulatory B-cells in pathogenesis and progression of autoimmune myocarditis

• Applicants: Professor Dr. Ziya Kaya; Theresa Tretter, Ph.D.
• Subject Area: Cardiology, Angiology
• Term: from 2016 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 317530962

The pathogenesis of autoimmune myocarditis that can progress into chronically dilated cardiomyopathy with an increased risk for heart failure is not completely understood. It is suggested that dysfunctional cellular immunoregulation might lead to an imbalance of pro- and anti-inflammatory processes and thereby support this complex disease. While the crucial impact of the T cells in autoimmune myocarditis is widely accepted, the role of B cells is still incompletely understood. Primarily, research is restricted to the auto-antibodies (auto-Abs) that accompany disease progression. Especially the subpopulation of regulatory B cells (Breg) that might be able to potentially counteract the inflammatory process has not been investigated, yet. Preliminary work in our mouse model of cardiac troponin I (cTnI) -induced experimental autoimmune myocarditis (EAM) already points to a strong impact of Breg in control of this disease: while adoptive transfer of T cells from cTnI immunized mice resulted in development of EAM in the majority of non-immunized mice, as expected, adoptive cotransfer of those T cells together with autologous B-cells strongly reduced incidence and extent of EAM. This implies that different subpopulations of B cells might exist, with the potential to support or to counteract myocardits. In this project proposal we pursue 3 aims: 1) Characterize the conditions under which Breg in EAM are activated and functional: To this end B cells will be stimulated under different conditions before transfer with cTnI specific T cells into non-immunized mice. Further Breg will be transferred to EAM- mice before or after their immunization to evaluate, whether they can protect from EAM or even down regulate symptoms in an inflammatory environment.2) Assess the influence of Breg on the cellular environment. Here functional assays with various immune cells from cTnI immunized and Breg treated mice will be performed to investigate the modulatory effects of Breg on immune responses. Further we attempt to reveal the Breg phenotype by sorting B-cell subtypes that might represent Breg and test their regulatory abilities.3) Evaluate the role of Breg subtypes and impact of auto-Abs on EAM. To this end B cell deficient mice (JH-/-) will be immunized with cTnI and compared to B cell competent mice. In addition Breg cells (or Breg candidates found in part 2) are added. Further, cotransfer of Breg, with cTnI-T cells into Breg deficient mice will be performed. The experiments are supplemented by addition of B cell culture supernatant and EAM-serum with and without depletion of containing antibodies to assess the impact of auto-Abs in progression of EAM. By investigating of the role of Breg in EAM we aim to find clues to restore the immunological balance in myocarditis This might help to develop novel immunotherapeutics in future. We therefore plan to merge our long-standing expertise in the cTnI-EAM (Dr.Kaya) with that of Breg in chronic inflammation (Dr.Tretter).

• DFG Programme: Research Grants