Flashcards in L20: Immune Complex Disease Deck (40):
Hypersensitivity disease Type I
Allergies and asthma
Hypersensitivity disease Type II
Diseases caused by antibodies, immune
thrombocytopenia would be an example
Hypersensitivity disease Type III
Diseases caused by antigen/antibody
complexes, lupus erythematosus is a classic example
Hypersensitivity disease Type IV
Diseases associated with “delayed
hypersensitivity” or TMMI.
What factors influence the RATE of IC formation?
rate of antibody formation, antibody avidity, valence of antigen and complement and Fc-Fc interactions that influence the final size and solubility of the immune complex.
What factors influence the VIGOR of the immune response?
The vigor of the immune response is based on characteristics of antigen acting in concert with host factors such as gender, age and major histocompatibility complex (MHC) and other "immune" related genetic loci of the host.
IC formation is based partially on...
intensity of antigen stimulus-which, in turn, is based on type of antigen, length of host exposure to it and the route and site of the exposure.
If immune complex formation exceeds ______, pathologic inflammation, either local or systemic, can result.
their rate of disposal
3 Possible causes of production exceeding disposal (catabolism) are:
1. Intensity and duration of the antigenic stimulus- exuberant production of specific antibody if prolonged
2. Impaired disposal- usually secondary to increased production of complexes and hepatic receptor saturation, CRI deficiency, medications.
What can happen to circulating immune complexes, not bound to CR1 on RBCs?
They're not efficiently trapped by spleen or liver and bind to FcγR and C3b receptors at other sites, most commonly in kidney/skin and synovium, where they generate an inflammatory response that will cause collateral damage and disease.
Immune complexes not metabolized on site must be transported via ____ receptors on erythrocytes to the liver for disposal. The extremely large number of circulating erythrocytes is a very effective delivery mechanism in most cases.
What receptorson neutrophils and monocytes promote uptake and catabolism of immune complexes?
All blood cells, except platelets, have _____
the CR1 receptor
What converts C3b to iC3b?
Which has more CR1: RBC or WBC?
WBC! RBC have about 400 copies per cell while WBC may have 50K per cell but...there are 1000x more RBC than WBC in the peripheral blood
What organ is the most effective at removing IC-C3b complexes?
The liver, by virtue of its high blood flow and enormous surface area of fixed macrophages (Kupffer Cells), is the most effective removal site of IC-C3b complexes delivered to it by the CR1 on erthryocytes.
What is the spleen's role in removing IC-C3b complexes?
The spleen can also remove them but does so for different reasons than liver - mainly for immune activation of B cells systems to the complexed antigen- a future lecture.
IC's activate cellular inflammatory responses by cross-linking ______ on multiple types of cells, thus stimulating the release of ______ that recruits neutrophils to the area of FcR cross-linking.
FcγR, IL- 8
IC's also activate the classic _________ with subsequent generation of C3a, C567 and multiple other vasoactive molecules. This further amplifies neutrophil recruitment to the area of IC deposition.
If erythrocyte transfer to the ____ cannot keep up with the formation of IC's at the site of formation, local accumulation of IC's leads to
2. Neutrophil recruitment and activation.
The presence of activated neutrophils at the site release
__________ after phagocytosis of the non-transported complexes and inflammation ensues.
destructive enzymes and oxidants
What is a classic example of a LOCAL immune complex reaction, and how does it work?
Arthur reaction: occurs when there are high levels of pre-existing antibodies to the antigen introduced at the site-usually under the skin.
Arthus reactions clinically when a patient who has been previously ___________ is given the same vaccine again by injection.
Arthus reaction ctd: the immediate, immense accumulation of IC overwhelm the red cell transport system and there is rapid activation of
neutrophils as the complexes activate complement proteins and bind to neutrophil receptors.
The activated neutrophils and other cells (most likely mast cells and basophils) release _______ and other vasoactive mediators that cause pain, swelling (increased fluid extravasation) and redness (increased blood flow) at the site of antigen injection.
IC's bind what receptors, on neutrophils, to induce IL-8 secretion?
A classic example of CIRCULATING immune complex disease-classic:
Acute serum sickness. Disease manifestations depend on site of deposition-usually in synovium, kidney/skin with loss of function and tissue destruction.
Since there is such a wide variation in the avidity of complexes, size of complexes formed and rapidity of antibody formation dictated by the genetic disparity of the outbred human population...
Immune complex diseases are diagnosed CLINICALLY--even though there are multiple assays available for the detection of circulating complexes
IN THEORY, detection of decreased levels of ________ in the serum should suggest that direct (classical) activation of the complement pathway has occurred.
C3 and C4.
....Unfortunately in real life this doesn’t hold up.
Treatment depends on reduction of antigen load by
antibiotics (if infection is the problem), surgical drainage of an abscess, etc.
Immune complexes delivered to the spleen via erythrocyte receptors or to
regional lymph nodes via lymphatic drainage, or formed in situ in lymphoid tissue (future lecture) are extremely potent stimuli for
efficient antibody production
Unlike the liver, the spleen and lymphoid tissue are NOT
disposal sites like the liver is for IC. Rather, IC's are potent still for efficient anti-body production
Activated complement components bound to immune complexes, especially _____, and IC's bound to their respective _____ are strong regulators of B-cell activation, differentiation and antibody formation.
What motif, located on the macrophage, induces phacocytosis of IgG-IC immune complexes?
Immunoreceptor tyrosine-bases activation motif (ITAM).
When a IgG -IC targets an antigen to an Fcγ R on a macrophage, monocyte, neutrophil or dendritic cell, the cell is prompted to phagocytose the complex.
What happens if the IgG- IC targets an antigen to an Fcγ R on its B-cell?
It activates an immunoreptor based tyrosine inhibitory motif (ITIM) that shuts down further B-cell proliferation.
Which has a higher affinity for IgG-IC: ITAM on macrophages, or ITIM on B-cells? Why?
ITAM has higher affinity; only small amounts of IgG-IC are required to signal phagocytosis by macrophage.
ITIM has lower affinity; this is a sensing mechanism that tells B-cells "okay you've done enough. Stop making B-cells because the poor guy is smothered with IgG!"
Rh positive dad mates with Rh negative mom. Is 1st child at risk? 2nd child?
Children may be Rh+, so mom will make anti-Rh+ IgG against the fetal RBC. However, 1st child will be unaffected. 2nd child will be at risk because mom is effectively immunized against Rh. Need rhogam.
Will Rhogam treated moms develop CD4 and B memory against Rh?
Rh specific CD4 and B memory cells are not generated.
What happens if anti-IgM Rh is given?
If anti-IgM Rh is given, no such inhibitory signal is provided and the mother will become sensitized to the Rh antigen on the fetal blood cells that she was exposed to at time of birth.