Basic and Translational Concepts of Immune-Mediated Glomerular Diseases 2

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Basic and Translational Concepts of Immune-Mediated Glomerular Diseases 2 (1)

Diseases Usually Presenting as GN

Postinfectious or Poststreptococcal GN

The acute, diffuse exudative and proliferative lesion of poststreptococcal GN (PSGN) was long regarded as the human equivalent of the acute, one-shot serum sickness model in rabbits leading to a prolonged search for the nephritogenic streptococcal antigen. streptococcal pyogenic exotoxin B (SpeB) is a small (28 kD), cationic (pK 9.3) cysteine protease with complement-activating and plasmin-binding properties and represents 90% of the secreted extracellular protein made in vivo by nephritogenic strains of group A streptococci. Antibodies to SpeB also exhibit molecular mimicry with endothelial cells. SpeB alone can activate complement directly through the MBL pathway independent of IgG. SpeB also exhibits plasmin-binding properties that facilitate complement activation and might cause proteolysis of glomerular basement membrane (GBM), facilitating the transit of dissociated subendothelial ICs to form subepithelial humps.

IgA Nephropathy

IgA nephropathy (IgAN) is the most common form of GN worldwide and is characterized by focal mesangial proliferation and matrix expansion accompanying diffuse mesangial deposits of IgA, and often IgG, C3, and C5b-9, usually associated with recurrent episodes of GN that often immediately follow mucosal viral infections. The failure to normally glycosylate IgA1, which exhibits deficient O-linked glycosylation at five sites in the hinge region of the molecule, can be inherited in IgA nephropathy. Underglycosylated IgA1 increases tendencies to self-aggregate, unmasking of MBL binding sites leading to complement activation, binding to other molecules like fibronectin, IgG, and collagen IV. TLR activation by IgA aggregates may account for the recurrent episodes of acute injury with hematuria, particularly those that immediately follow infections. C5b-9 generated from complement activation induced by interaction of IgA1 aggregates with MBL, upregulating genes for collagen type I, and increases production of cytokines and growth factors such as IL1, IL6, TNFα, PDGF, TGFβ, EGF, FGF, CTGF, and HGF.

Rapidly Progressive, Crescentic GN

Anti-GBM Nephritis

Anti-GBM nephritis is characterized initially by an acute, focal necrotizing GN with crescents and linear deposition of IgG, usually with C3, along the GBM. The GBM antigen itself consists of the noncollagenous domain of both the α3 and α5 chains of the NC1 hexamer of type IV collagen. Antibody deposition requires perturbation of the quaternary structure of the α3, α4, α5NCI hexamer, possibly initiated by oxidant injury, which results in a conformational change in the α3NCI and α5NCI domains. Nephritogenic GBM antigens can induce a T cell–mediated GN with crescents, proteinuria, and decreased renal function in the absence of anti-GBM antibodies. The disease can also be induced experimentally with a small nephritogenic T cell epitope, pCol28-40, from the α3NC1 domain, which exhibits molecular mimicry with PAMPs in some Gram-negative bacteria, especially Clostridia botulinum.

ANCA-Associated GN

Necrotizing crescentic GN without immune deposits linked to ANCA directed against myeloperoxidase (MPO) and proteinase 3 (PR3). Cytokine-primed neutrophils redistribute cytoplasmic primary granules containing MPO and PR3 to the cell surface where ANCA IgG binds directly or through Fc, Fab’2, or neutrophil-specific Mac-1 receptors activating a respiratory burst with release of cationic MPO and PR3 as well as other proteases and oxidants.

Neutrophil extracellular traps (NETs) are also formed containing entrapped MPO, PR3, and MPO DNA in a chromatin web and these can mediate injury directly through TLRs as well as modulate the immune response.

Lupus Nephritis

In lupus nephritis, IgG, IgM, IgA (full house), and C3 deposits are localized primarily in the mesangium in mild disease. The most prominent serologic feature of lupus is the presence of IgG anti-double-stranded DNA antibodies (anti-DNA) in serum and in glomerular deposits. Some monoclonal anti-DNA antibodies exhibit cross-reactivity with capillary wall antigens, especially laminin and α-actinin. Deposited anti-DNA reacts with extracellular DNA in the form of nucleosomes that consist of an anionic segment of DNA wound around a highly cationic histone core, giving the structure a net positive charge and thereby a high affinity for glomerular anionic sites. Nucleosomes exhibit the ability to activate dendritic cells through binding to TLRs 2 and 9, and likely directly activate resident glomerular cells through TLRs as well. The observation that deficiencies of classic pathway proteins C1>C4>C2 are associated with increased risk for lupus suggests protective roles for complement as well.

Type I Membranoproliferative GN

Type I membranoproliferative GN (MPGN I) has many clinical and pathologic similarities to a renal-limited lupus nephritis, including frequent autoantibodies such as rheumatoid factors and antinuclear, anticardiolipin, anti-C1q, anti-C3 convertase (C3Nef), and antiendothelial antibodies. The histologic features of capillary wall thickening, cellular proliferation, and infiltrating inflammatory cells associated with primarily mesangial and subendothelial deposits of IgG, IgM, and C3 are similar to lupus nephritis.

1. W. G. Couser, Basic and translational concepts of immune-mediated glomerular diseases. J. Am. Soc. Nephrol. 23, 381–399 (2012).

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