CD8+ cells and glomerular crescent formation: outside-in as well as inside-out

Abstract

Crescentic glomerulonephritis, a complication of severe immune glomerular injury, is the pathological correlate of rapidly progressive glomerulonephritis, mediated by both humoral and cellular effectors. In the current issue of the JCI, Chen et al. have implicated Bowman's capsule in functionally isolating potentially immune effectors, specifically antigen-specific CD8+ T lymphocytes, from podocytes. They suggest that, in crescentic glomerulonephritis, immune-mediated glomerular endothelial injury results in inside-out injury to the glomerulus, with subsequent leukocyte migration through a weakened or ruptured Bowman's capsule, resulting in outside-in injury. Effector T cells then recognize nephritogenic antigens presented by podocytes or other cells within the urinary space, enhancing injury and crescent formation.

Figure 1. Schematic diagram summarizing inside-out and outside-in elements of glomerular crescent formation.

Left panel: The basic structure of a healthy glomerulus consisting of the Bowman’s capsule lined with parietal epithelial cells and the glomerular filtration barrier composed of endothelial cells, the glomerular basement membrane (GBM), and podocytes. Podocytes line the GBM with foot processes that wrap around the glomerular capillaries. Middle panel: Examples of some of the inside-out mechanisms that can cause endocapillary damage and early crescent formation following glomerulonephritis. Inset, left to right, neutrophils bind to autoantibodies in the GBM, as in anti-GBM glomerulonephritis. Antibodies bind to antigens lodged in the glomerulus with subsequent macrophage recruitment. ANCA activates neutrophils and mediates their recruitment to the glomerulus. CD8⁺ T cells can recognize antigenic peptides, potentially presented by endothelial cells. Right panel: Chen and colleagues describe the outside-in mechanism in which the antigen-specific CD8⁺ T cells, along with macrophages, located outside the glomerulus migrate into the urinary space following a breach in Bowman’s capsule. Within the urinary space, CD8⁺ cells recognize antigens presented on podocytes, exacerbating injury and crescent formation.