The role of BTLA in the pathogenesis of glomerulonephritis

• Applicant: Dr. Sebastian Brähler
• Subject Area: Nephrology
• Term: from 2019 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 420236825

Glomerulonephritides (GN) are a heterogeneous group of inflammatory kidney diseases that can lead to end-stage renal disease by destruction of the kidney filtering units (glomeruli). Their molecular mechanisms are incompletely understood, which limits our therapeutic options to broad immunosuppression. T-cells and dendritic cells (DCs) have been identified as key players in a mouse model of experimental GN, the so-called nephrotoxic nephritis (NTN), making them interesting targets for the treatment of the disease. BTLA (B and T lymphocyte attenuator) is an immunoglobulin superfamily protein, which has anti-inflammatory properties in several autoimmune disease models by limiting the magnitude of T-cell activation. We have recently shown that the minor subset of classical DCs (cDC1) has a robust anti-inflammatory function in glomerulonephritis and that BTLA is among the most significantly upregulated proteins in these cells during the course of the disease.In this project we will investigate the function of BTLA in GN by challenging Btla-knockout mice with nephrotoxic nephritis and analyzing the outcome of the disease and the chances in infiltrating immune cell subsets and the systemic immune response. In a second step we will focus on the specific function of BTLA on cDC1 by challenging mixed-bone marrow chimeras, that selectively lack BTLA in this DC subset. We will then evaluate the therapeutic potential by treating mice during GN with agonistic antibodies for BTLA.Lastly, we will analyze the dynamic recruitment behavior and interactions of the two major classical DCs subsets (cDC1 and cDC2) at the site of inflammation by multiphoton intravital imaging of Xcr1-Venus and Zbtb46-GFP bone marrow chimeras during the course of GN.By combing these different approaches, we are confident that this project will yield new insights on essential pathomechanisms in glomerulonephritis, which will not only advance our understanding of the disease but also have the potential to reveal new treatment strategies for our patients.

• DFG Programme: Research Grants