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1

Antibodies can react

Antibodies can react in situ with antigens that are not normally present in the glomerular but are "planted" there
-such antigens may localize in the kidney by interacting with various intrinsic components of the glomerulus

2

Planted antigens include

cationic molecules that bind to anionic components of the glomerulus; DNA, nucleosomes, and other nuclear proteins, which have an affinity for GBM components; bacterial products; large aggregated proteins, which deposit in the mesangium because of size; and immune complexes themselves, since they continue to have reactive sites for further interaction with free antibody, free antigen, or complement

3

In anti-GBM antibody induced glomerulonephritis,

-antibodies bind to intrinsic antigen homogeneously distributed along the entire length of the GBM, resulting in a diffuse linear pattern of staining for the antibodies by immunofluorescence techniques
-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)
-causes severe necrotizing and crescentic glomerular damage and the clinical syndrome of rapidly progressive glomerulonephritis

4

GBM antigen that is responsible for classic anti-GBM antibody-induced glomerulonephritis and Goodpasture syndrome is

a component of the non collagenous domain (NC1) of the alpha3 chain of type IV collagen that is critical for maintenance of GBM superstructure

5

In glomerulonephritis resulting from deposition of circulating immune complexes,

-injury is caused by trapping of circulating antigen-antibody complexes within glomeruli
-the antibodies have no immunologic specificity for glomerular constituents, and the complexes localize within the glomeruli because of their physiochemical properties and the hemodynamic factors peculiar to the glomerulus

6

Antigens that trigger formation of circulating immune complexes may be

of endogenous origin, as in the glomerulonephritis associated with SLE or in IgA nephropathy, or they may be exogenous, as may occur in the glomerulonephritis that follows certain infections
-microbial antigens that are implicated include bacterial products (streptococcal proteins), the surface antigen of hepatitis B virus, hepatitis C virus antigens, and antigens of Treponema palladium, Plasmodium falciparum, and several viruses

7

Inflammation and injury following immune complex formation

-binding of complement and also engagement of Fc receptors on leukocytes and perhaps glomerular mesangial or other cells as mediators of injury process
-glomerular lesions may exhibit leukocytic infiltration and proliferation of mesangial and endothelial cells

8

In Immune complex mediated glomerulonephritis, electron microscopy

reveals electron-dense deposits, presumably containing immune complexes, that may lie in the mesangium, between the endothelial cells and the GBM (sub endothelial deposits), or between the outer surface of the GBM and the podocytes (subepithelial deposits)
-deposits may be located at more than one site in a given case

9

By immunfluorescence microscopy the immune complexes are seen

as granular deposits along the basement membrane, in the mesangium, or in both locations

10

Once deposited in the kidney, immune complexes may

eventually be degraded, mostly by infiltrating neutrophils and monocytes/macrophages, mesangial cells, and endogenous proteases, and the inflammatory reaction may then subside
-such a course occurs when the exposure to the inciting antigen is short-lived and limited, as in most cases of post streptococcal glomerulonephritis

11

If immune complexes are deposited for prolonged periods

-as may be seen in SLE or viral hepatitis
-repeated cycles of injury may occur, leading to a more chronic membranous or membranoproliferative type of glomerulonephritis

12

Highly cationic antigens tend to

cross the GBM, and the resultant complexes eventually reside in a sub epithelial location

13

Highly anionic macromolecules are

excluded form the GBM and are trapped subendothelially or are not nephritogenic at all

14

Molecular or neutral charge and immune complexes containing these molecules tend to

accumulate in the mesangium

15

Large circulating complexes are

not usually nephritogenic, because they are cleared by the mononuclear phagocyte system and do not enter the GBM in significant quantities

16

Immune complexes located in sub endothelial portions of capillaries and in mesangial regions are

accessible to the circulation and more likely to be involved in inflammatory processes that require interaction and activation of circulating leukocytes

17

Diseases in which immune complexes are confined to the sub epithelial locations and for which the capillary basement membranes may be a barrier to interaction with circulating leukocytes

-membranous nephropathy
-typically noninflammatory pathology

18

Alternative complement pathway activation occurs in

dense-deposit disease

19

Infiltrate the glomerulus in certain types of glomerulonephritis

neutrophils and monocytes
-largely as a result of activation of complement, resulting in generation of chemotactic agents (mainly C5a), but also by Fc-mediated adherence and activation

20

Neutrophils release

proteases, which cause GBM degradation; oxygen-derived free radicals, which cause cell damage; and arachidonic acid metabolites, which contribute to the reductions in GFR

21

Macrophages and T-lymphocytes

-infiltrate the glomerulus in antibody- and cell-mediated reactions
-when activated release a vast number of biologically active molecules.

22

Platelets

-may aggregate in the glomerulus during immune-mediated injury
-their release of eicosanoids, growth factors and other mediators may contribute to vascular injury and proliferation of glomerular cells

23

Resident glomerular cells, particularly mesangial cells, can be stimulated to produce

several inflammatory mediators, including ROS, cytokines, chemokines, growth factors, eicosanoids, NO, and endothelin

24

Complement activation leads to

the generation of chemotactic products that induce leukocyte influx (complement-neutrophil-dependent injury) and the formation of C5b-C9, the MAC.
-MAC causes cell lysis, and stimulates mesangial cells to produce oxidants, proteases, and other mediators
-even in the absence of neutrophils, MAC can cause proteinuria

25

Cytokines, particularly IL-1 and TNF

-may be produced by infiltrating leukocytes and resident glomerular cells
-induce leukocyte adhesion and a variety of other effects

26

Chemokines such as monocyte chemoattractant protein 1 promote

monocyte and lymphocyte influx

27

Seem to be critical in the ECM deposition and hyalinization leading to glomerulosclerosis in chronic injury

TGF-B, connective tissue growth factor, and fibroblast growth factor

28

Fibrin

-frequently present in the glomeruli and Bowman space in glomerulonephritis, indicative of coagulation cascade activation, and activated coagulation factors, particularly thrombin, may be a stimulus for crescent formation

29

Podocytopathy

-can be induced by antibodies to podocyte antigens; by toxins, as in an experimental model of proteinuria induced by puromycin amino nucleoside; conceivably by certain cytokines; by certain viral infections such as HIV or by still inadequately characterized circulating factors, as in some cases of focal segmental glomerulosclerosis

30

Podocyte injury causes changes in podocytes

-effacement of foot processes, vacuolization, and retraction and detachment of cells from the GBM, and functionally by proteinuria