Anti-GBM Antibody-Induced Nephritis

In this type of injury, antibodies are directed against intrinsic fixed antigens that are normal components of the GBM proper. It has its experimental counterpart in so-called Masugi or

nephrotoxic nephritis, produced in rats by injections of anti-rat kidney antibodies prepared in rabbits by immunization with rat kidney tissue. The injected antibodies bind along the entire

length of the GBM, resulting in a diffuse linear pattern of staining for the antibodies by immunofluorescent techniques ( Figs. 20-10B and E ). This is contrasted with the granular lumpy

pattern of immunofluorescent staining seen in other in situ models, such as the Heymann model of membranous glomerulopathy, or after deposition of circulating immune complexes.

In the Masugi model, the injected anti-GBM antibody is rabbit immunoglobulin, which is foreign to the host and thus acts as an antigen eliciting anti-Ig antibody in the rat. The rat

antibodies then react with the rabbit immunoglobulin deposited in the basement membrane, leading to further glomerular injury. Thus, experimental anti-GBM antibody-mediated

glomerulonephritis consists of an initial heterologous phase caused by the injected anti-GBM antibody, and a subsequent, more injurious, autologous phase caused by host antibodies

against the injected Ig. Often the anti-GBM antibodies cross-react with other basement membranes, especially those in the lung alveoli, resulting in simultaneous lung and kidney lesions

(Goodpasture syndrome). The GBM antigen that is responsible for classic anti-GBM antibody-induced nephritis and Goodpasture syndrome is a component of the non-collagenous domain

(NC1) of the a3 -chain of collagen type IV, which, as was discussed earlier (see Fig. 20-3 ), is critical for maintenance of GBM superstructure.[3] [4] [5] [27] Anti-GBM antibody-induced

nephritis accounts for fewer than 5% of cases of human glomerulonephritis. It is solidly established as the cause of injury in Goodpasture syndrome, discussed later. Most instances of anti-

GBM antibody-induced nephritis are characterized by severe crescentic glomerular damage and the clinical syndrome of rapidly progressive glomerulonephritis.

Heymann Nephritis

The Heymann model of rat glomerulonephritis is induced by immunizing animals with an antigen contained within preparations of proximal tubular brush border ( Fig. 20-10C ). The rats

develop antibodies to this antigen, and a membranous glomerulopathy, resembling human membranous glomerulopathy, develops (discussed later; see also Fig. 20-19 ). On electron

microscopy, the glomerulopathy is characterized by the presence of numerous electron-dense deposits (made up largely of immune reactants) along the subepithelial aspect of the basement

membrane. The pattern of immune deposition by immunofluorescence microscopy is granular rather than linear ( Fig. 20-10C ). It is now clear that this type of disease results largely from

the reaction of antibody with an antigen complex located on the basal surface of visceral epithelial cells and cross-reacting with the brush

Figure 20-10Antibody-mediated glomerular injury can result either from the deposition of circulating immune complexes (A) or, more commonly, from in situ formation of complexes

exemplified by anti-GBM disease (B) or Heymann nephritis (C). D and E, Two patterns of deposition of immune complexes as seen by immunofluorescence microscopy: granular,

characteristic of circulating and in situ immune complex nephritis (D) and linear, characteristic of classic anti-GBM disease (E).

Figure 20-12Epithelial cell injury. The postulated sequence is a consequence of antibodies against epithelial cell antigens, toxins, cytokines, or other factors causing injury with foot

process effacement and sometimes detachment of epithelial cells and protein leakage through defective GBM and filtration slits.

Figure 20-13Mediators of immune glomerular injury including cells and soluble mediators (see text). (Modified from Couser WG: Mediation of immune glomerular injury. J Am Soc

Nephrol 1:13, 1990.)

Figure 20-14Renal ablation focal segmental glomerulosclerosis. The adaptive changes in glomeruli (hypertrophy and glomerular capillary hypertension), as well as systemic hypertension,

cause epithelial and endothelial injury and resultant proteinuria. The mesangial response, involving mesangial cell proliferation and extracellular matrix (ECM) production together with

intraglomerular coagulation, causes the glomerulosclerosis. This results in further loss of functioning nephrons and a vicious circle of progressive glomerulosclerosis.

Figure 20-15Mechanisms of chronic tubulointerstitial injury in glomerulonephritis (see text). Various components of the protein-rich filtrate and cytokines derived from leukocytes cause

tubular cell activation and secretion of cytokines, growth factors, and other mediators. These, together with products of macrophages, incite interstitial inflammation and fibrosis. ET-1,

endothelin-1, PAI-1, plasminogen activator inhibitor-1; TIMP-1, tissue inhibitor of metalloproteinases. (Adapted and modified from Remuzzi G, Ruggenenti P, Benigni A: Understanding

the nature of renal disease progression. Kidney Int 51:2, 1997; Schena FP, et al: Progression of renal damage in human glomerulonephritis. Kidney Int 52:1439, 1997; Fogo AB:

Progression and potential regression of glomerulosclerosis. Kidney Int 59:804, 2001.)

TABLE 20-6-- Summary of Major Primary Glomerulonephritides

Date: 2016-04-22; view: 928