Overview Glomerular injury is the central basis of renal insufficiency, and immunologic mechanisms play critical roles for initiation and progression of glomerular diseases. Two axes of adaptive immune system involve the pathogenesis of glomerular injury: antibodymediated and cell-mediated immunity. In children, popular immune-mediated glomerular diseases include poststreptococcal acute glomerulonephritis, IgA glomerulonephritis, membranoproliferative glomerulonephritis (type 1), membranous

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... erulonephritis, ANCA-related glomerulonephritis, and lupus nephritis, all of which reveal various autoimmune features (Table 1) . Although ANCA-related glomerulonephritis is caused by Th1-predominant T-cell-mediated immunity in a pauci-immune fashion, remainders are thought to be processed by antibody-mediated immunity. The major steps of antibody-mediated glomerular injury are immune deposition on glomerular components and the subsequent activation of secondary inflammatory mediators. The glomerular deposition of antibodies is promoted by the humoral immune process of Th2 activation, which leads to antibody production via B-lymphocyte activation. This deposition may be composed of preformed immune complexes in the circulation, which are trapped in the glomerulus, or antibodies (autoantibodies) that bind to intraglomerular antigens or interact with intrinsic glomerular cellsurface antigens, as a result of changes to the cell surface (in situ immune complex). Antibody deposition on glomerular capillary walls or the mesangium activates the complement cascade, and intrinsic cell-derived chemotactic factors result in inflammatory cell influx, which is a crucial event in the glomerular injury by production/activation of proinflammatory cytokines, chemokines, growth factors, reactive oxygen species (ROS), eicosanoids, and nitric oxides (NO). These secondary mediators not only stimulate intrinsic cells to proliferate and/or produce matrix materials, but they also induce the synthesis of similar molecules by intrinsic glomerular cells. The secondary mediators involve severe endothelial injury which potentially results in dysregulation of local coagulation system, accompanied by exudation and the formation of cross-linking fibrins. These end products of the extrinsic coagulation cascade also damage glomeruli, particularly tuft necrosis, the common forerunner of crescentic formation. An alternative immune mechanism is cell-mediated immunity, with Th1 activation promoting cytotoxic glomerular injury by influx of delayed-type hypersensitivity (DTH) effectors, i.e., macrophages, T cells, and fibrin. Proliferative glomerulonephritis in the absence of immune complexes or antibodies suggests a role for cell-mediated immune injury. This is supported by the experiment showing that transfer of sensitized T cells successfully induced glomerular injury in the host. Cytokines secreted by DTH effectors are considered to injure the glomerular cells. It is clear that the antibody-and cell-mediated immune systems are not independent and often interact in glomerular injury. The complex mechanism of immune-mediated glomerular injury is integrated by a recent review by Couser (Fig. 1) [1]. *The GBM, which is a central component of the filtration barrier based on charge and size, is composed of extracellular matrix materials, including type IV collagen, nidogen (entactin), heparan sulfate proteoglycans (HSPG), laminin, and perlican. GBM is synthesized by podocytes and endothelial cells; however, the details of the formation of the membrane from the individually synthesized proteins remain unknown. Nevertheless, this unique permeability system traps macromolecules and antibodies and is responsible for their glomerular deposition. The GBM also contains potentially harmful antigens. Pathogenic autoantibodies directed against the C-terminal globular noncollagenous domain 1 (NC1) of the a3-chain of type IV collagen, which has a distinct GBM molecular composition, promote severe glomerulonephritis in patients with Goodpasture syndrome by epitope-specific autoantibody binding and effector T-cell reaction ( Fig. 3; [3]). Similar epitopes are targeted by alloantibodies in a subset of patients with Alport nephritis who have received allografts. GBM is also the target of bioactive substances released from inflammatory cells and intrinsic cells during inflammation. GBM changes may directly influence the physiologic stability of filtration, thereby reducing the glomerular filtration rate and causing proteinuria. Electron microscopy has revealed GBM alterations in association with immune deposits, and inflammatory cell influx can directly alter the morphology of the GBM (Fig. 4) . Proteolytic enzymes derived from neutrophils may directly alter the GBM, resulting in membranolysis, lamination, gaps, and edema (typical features of GBM injury), which may lead to urinary abnormalities. Immune deposition on the GBM, as seen in membranous glomerulonephritis and lupus nephritis, can also alter the GBM by changing its barrier of charge and size properties. Pediatric Nephrology Fig. 2 Typical features of immune-mediated glomerular injury seen in human biopsy samples by LM and IF. (a) Mesangial proliferation in IgA glomerulonephritis (PAS stain), (b) crescentic formation with tuft necrosis and fibrin deposition in ANCA-related glomerulonephritis (PAM stain), (c) subendothelial immune deposition in lupus nephritis (PAM stain), (d) granular and peripheral pattern of IgG in membranous glomerulonephritis, (e) fringe pattern of C3 deposition in MPGN, (f) subendothelial IgG deposits in lupus nephritis Pediatric Nephrology Platelets Platelets are involved in glomerular injury, through leukocyte recruitment, increased vascular permeability, and the vasoactive effects of their intrinsic chemical substances. Platelets contain two types of cytoplasmic granules, a and s. The a granules express P-selectin on their membranes and contain fibrinogen, fibronectin, factors V and VIII, platelet-activating factor (PAF), platelet factor 4, PDGF, and TGF-al. The s granules contain adenosine diphosphate (ADP), calcium ions, histamine, and serotonin. In local injury in glomerular capillaries, platelets adhere to the extracellular matrices at sites of endothelial injury and become activated. Activated platelets secrete granular products and synthesize TXA2, PDGF, and PAF, which together stimulate clot formation, cell Pediatric Nephrology