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Pathogenesis of GN.

Primary GN: eg minimal change GN, membranous GN

Secondary GN: DM, Amyloidosis,

3 mechanisms:
1.Nephritis Caused by Circulating Immune Complexes :

Endogenous antigen eg SLE(systemic lupus erythematosus)

Exogenous antigen:bacterial (streptococcal), viral (hepatitis B), parasitic (Plasmodium falciparum malaria), and spirochetal (Treponema pallidum)

Immune complexes are trapped in the glomeruli, where they produce injury, by activation of complement and the recruitment of leukocytes

electron-dense deposits or clumps that lie at one of three sites: in the mesangium, between the endothelial cells and the GBM (subendothelial deposits), or between the outer surface of the GBM and the podocytes (subepithelial deposits).

When fluoresceinated anti-immunoglobulin or anti-complement antibodies are used, the immune complexes are seen as granular deposits in the glomerulus

May be an acute event or chronic: such as in hepatitis B virus infection and self nuclear antigens in SLE

2. Nephritis Caused by In Situ Immune Complexes

Anti-Glomerular Basement Membrane (GBM) Antibody eg Goodpasture syndrome

linear pattern of staining when the bound antibodies are visualized with immunofluorescence

cross-react with basement membranes of lung alveoli also

Can be previously "planted" nonglomerular antigens

antibodies directed to distal zones of the GBM (epithelium and subepithelium) are largely noninflammatory

3. Podocyte Injury: reflected by morphologic changes in the podocytes, which include effacement of foot processes, vacuolization, and retraction and detachment of cells from the GBM, and functionally by proteinuria. Seen in minimal change GN

4. Nephron Loss: glomerulosclerosis that occurs as an adaptive change in the remaining glomeruli not destroyed by the initial disease

End result is activation of complement (mainly C5a) and the recruitment of neutrophils and monocytes. Neutrophils release proteases, which cause GBM degradation; oxygen-derived free radicals, which cause cell damage; and arachidonic acid metabolites, which contribute to reduction in GFR

C5-C9 lytic component (membrane attack complex) of complement, which causes epithelial cell detachment

monocytes and macrophages, platelets, epithelial, mesangial, and endothelial cells of glomerulus, and fibrin-related products are the main mediators of injury

Summary of immune injury in GN

In Situ Immune Complex Deposition

collagen type IV antigen (anti-GBM nephritis)

Heymann antigen (membranous glomerulopathy)

Mesangial antigens

Planted antigens

Exogenous (infectious agents, drugs)

Endogenous (DNA, nuclear proteins,
immunoglobulins, immune complexes, IgA)

Circulating Immune Complex Deposition

Endogenous antigens (e.g., DNA, tumor antigens)
Exogenous antigens (e.g., infectious products)

Cytotoxic Antibodies

Cell-Mediated Immune Injury

Activation of Alternative Complement Pathway.

Antibody-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).

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

Epithelial 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.

Mediators of immune glomerular injury including cells and soluble mediators

Mechanisms of chronic tubulointerstitial injury in glomerulonephritis