Fig. 2

The microenvironment in glomerulonephritis. Types of glomerulopathy that may occur during PD-1 immunotherapy include minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), pauci-immune glomerulonephritis (PIGN), and membranoproliferative glomerulonephritis (MPGN). (1) In MCD, injured podocytes undergo foot process effacement whereby they lose filtration slits and cell-cell junctions, leading to loss of the size-selective and charge-selective filtration barrier. (2) FSGS also involves podocyte injury that progresses to the obliteration of the capillary lumens. (3) Antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis is a primary form of PIGN. Autoantibodies activate neutrophils to adhere to the endothelium, and these cells migrate into tissue and release damage-associated molecular pattern molecules (DAMPs). Activated neutrophils also release neutrophil extracellular traps (NETs) and granules that damage the endothelium and rupture the glomerular basement membrane. The subsequent release of plasma proteins and coagulation factors into Bowman space promote parietal epithelial cell hyperplasia and result in crescentic glomerulonephritis. (4) Immune complex MPGN (IC-MPGN) is characterized by capillary wall thickening, mesangial expansion, and may involve the formation of crescentic glomerulonephritis. Complement C1q binds autoantibodies which bind to mesangial cells and promote the deposition of the membrane attack complex (MAC). This pore-forming complex can damage cells in a lethal or sublethal manner. The subsequent wound repair response encourages cell proliferation. (5) Inflammatory cytokines induce mesangial cell and proximal tubule epithelial cell production of CCL2, which recruits macrophages and monocytes, and M-CSF, which promotes monocyte to macrophage differentiation. (6) Tubulointerstitial fibrotic lesions are characterized by excessive accumulation of extracellular matrix (ECM) molecules and the recruitment of natural killer (NK) cells, macrophages, dendritic cells (DCs), and mast cells. (7) Germinal center structures may form and contain follicular dendritic cell (FDC) networks, B and T cell aggregates and plasma cells can form. (8) Lymphangiogenesis can occur in glomerulonephritis. (9) Epithelial cells produce stromal cell-derived factor 1 (SDF1) to recruit B and T cells and IL-8 for neutrophil chemotaxis. (10) Myeloid cells produce IL-23 and IL-18, which induces the formation of Th17 and Th1 cells. These cells are are recruited to the interstitium and glomerulus, in part, by myeloid CXCXL10. NK cells and Th1 cells produce interferon (IFN)-γ. Most IL-17 producing cells in glomerulonephritis are CD3⁺CD4^-CD8^- double negative. CD4+ IL-17 producing cells are also present. (11) IFN-α is primarily secreted by activated plasmacytoid DCs and by human proximal tubular epithelial cells in the interstitium. Cytotoxic T lymphocytes (CTL) are generated that destroy target cells. (12) Proteinuria is an identified marker of nephritis. (13) Immune checkpoint inhibitor (ICI) therapies may block homeostatic interactions that normally suppress inflammation. (14) Glomerulonephritis blood markers can include elevated levels of autoantibodies and altered complement turnover