Hd (04-21-06) Immune Complex Disease

Front 1

What are 2 causes of intense antigen exposure that may result in an immune complex disease?

Back 1

1) Persistent pathogens exposure
2) Loss of self-tolerance

Front 2

What factors contribute to the intensity of antigen stimulus?

Back 2

Type of antigen, length of exposure, site of exposure.

Front 3

What factors determine the rate of immune complex formation?

Back 3

Rate of Ab production, avidity of Ab, valency of antigen, Fc-Fc interactions.

Front 4

What determines the vigor of an immune response?

Back 4

Gender variability, age, MHC DR genes.

Front 5

What segment of the Ig mediates the immune response?

Back 5

Fc portion of the complexed Ab-Ag molecule.

Front 6

What is the most important inflammatory reaction?

Back 6

Ag-IgG complex binding to the Fc-gamma-R's on monocytes and neutrophils because it activates such a spectrum of antimicrobial activities.

Front 7

Which aspect of the complement system may be activated by immune complexes?

Back 7

Classical pathway.

Front 8

What is the role of C3b in IC clearance?

Back 8

C3b's bind to (opsonize) immune complexes, recruiting neutrophils and macrophages to the site of deposition, since they both have C3b-R's on their surface.

Front 9

What is the normal end result of a bound immune complex?

Back 9

Mobilization of neutrophils to the site of IC deposition by IL's, chemokines, etc.

Front 10

What mechanisms exist to reduce immune complex-mediated inflammation?

Back 10

Reduce antigen exposure following a successful immune response.

Front 11

What happens when there is too much immune complex for the local immune response (Fc-gamma-R, C3b-R) to handle?

Back 11

IC's have C3b's attached, which bind to CR1's (receptors) located on RBC membrane surfaces. This will transport excess immune complexes to the liver where macrophages (Kupffer cells) can destroy the excess. Some are also taken to the spleen where B-cell response will occur.

Front 12

What is the one type of blood cell that does not have CR1's?

Back 12

Platelets.

Front 13

What feature of RBC's cause this method of IC removal to be effective?

Back 13

Vast amount of RBC's in the circulation, relative to WBC's.

Front 14

What is the cause of pathophysiology involving immune complexes?

Back 14

Immune complex formation is greater than the rate of disposal.

Front 15

Where are free circulating immune complexes typically found, when the liver has been saturated?

Back 15

Skin, glomerulus of kidney, and synovial joints due to the fact that Fc-gamma-R and C3b-R exist in these sites.

Front 16

What is the result of immune complexes building up in peripheral tissue?

Back 16

Fc-gamma-R cross linking causes the release of IL-8, which is released to recruit neutrophils, classical complement pathway is activated by cleaving C3, which will amplify neutrophil recruitment (C3b-R).

Front 17

When will a systemic response be seen in immune complex disease?

Back 17

When excess immune complexes (acute serum sickness) begin to circulate and cause inflammation in extra-hepatic tissue (skin, kidney, synovia).

Front 18

When will a localized immune-complex inflammation occur?

Back 18

If insufficient RBC transport of immune complexes to the liver, local neutrophils will get recruited to the local region.

Front 19

What is an Arthus reaction? Describe its sequence in detail.

Back 19

Pre-existing Ab to the antigen (usually a vaccine) results in an intense accumulation of immune complexes at the next antigen exposure. This overwhelms the red cell transport system activating neutrophils and complement proteins (C3 cleavage), IL-8 is released and more neutrophils are recruited, and pain, swelling, and redness occurs at the site of infection (typically the skin).

Front 20

How might levels of C3 and C4 theoretically be diagnostic in a patient?

Back 20

Decreases in C3 and C4 suggest classical activation of the complement pathway.

Front 21

How might one treat immune complex diseases?

Back 21

Reducing the antigen load with antibiotics, surgical drainage, etc. If ineffective, suppress Ab formation or remove the complexes directly.

Front 22

How will immune complexes delivered to the spleen via RBC CR1 activate the immune system?

Back 22

These immune complexes are an extremely potent stimuli for efficient Ab production. C3b bound to immune complexes, and cross linked Fc-gamma-R's are strong regulators for B-cell activation, differentiation, and Ab formation.

Front 23

What signal will Fc-M-R crosslinking to Ag-IgM send to B-cells?

Back 23

Signal for an isotype switch and more production of IgG (ITAM).

Front 24

What signal will Fc-gamma-R crosslinking to Ag-IgG send to B-cells?

Back 24

Stop producing Ab's, the goal has been met (ITIM).

Front 25

What signal will Fc-gamma-R crosslinking to Ag-IgG send to non-B-cell APC's?

Back 25

Activate more presentation of antigens (ITAM).

Front 26

What is the Rh problem?

Back 26

Mother is Rh-. Father is Rh+. A child that is Rh+ will have RBC's with the Rh antigen present, exposing the Rh- mother to the antigen, since leakage often occurs. Her immune response will remember this antigen, so the next pregnancy with a Rh+ child will mount a huge secondary response against the baby since maternal IgG's cross the placenta.

Front 27

What is the solution to the Rh problem?

Back 27

Injecting anti-Rh IgG intravenously to the mother immediately after birth, tricking the mother's immune system into thinking that a response has already occurred - Fc-gamma-R crosslinking to B-cells will shut down B-cell response (ITIM).

Front 28

What would happen if an anti-Rh IgM is given to a pregnant mother in the Rh problem?

Back 28

The maternal immune response will detect this as a new antigen and mount an immune response against the fetal blood. Fc-M-R crosslinking to IgM results in activation of Ab production (ITAM).