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Flashcards in Immune Complex Disease Deck (33):

Lupus erythematosus is a classic example. What type of hypersensitivity disease? Describe the likely mechanism.
(Immune complexes of circulating antigens and IgM or IgG antibodies).

What are the mechanisms of tissue injury and disease?

Hypersensitivity disease Type III

Complement and Fc receptor mediated recruitment and activation of leukocytes.

systemic lupus erythematosus is most likely due to abnormal TLR activation and faulty T cell regulation with secondary production of excess immune complexe


Immune thrombocytopenia or Graves would be an example of what type of hypersensitivity disease?

Describe the mechanism of tissue injury and disease.

Hypersensitivity disease type II

Diseases caused by antibodies against cell
surface or extracellular matrix proteins.

-antibody against thing. (1 antibody against protein or peptide) Graves (1 antibody against TSH receptor can stimulate thyroid to overprod. that hormone) that example of 1 antibody against thing. antibody against protein or peptide, can lead to complement deposition

-Opsonization and phagocytosis of cells
-Complement and Fc receptor mediated recruitment and activation of leukocytes (neutrophils, macrophages). Abnormalities in cellular functions like hormone receptor signaling, neurotransmitter receptor blockade


Diseases associated with “delayed hypersensitivity” or TMMI. CD4+ (Th1 & Th17) or CD8+ CTLs; cytokine &
direct killing more prominent than Ig’s, FcR’s and complement. What type of hypersensitivity disease?

(Poison Ivy)

Hypersensitivity disease Type IV

Type IV- mediated by helper T cells, cytotoxic T cells even, Th17 cells, macrophages, antigen presenting cells, T cells getting together and prod. cytokines, not dep. on antibodies at all. PPD reaction - Poison ivy! not associated w antibody problems

-cytokine mediated inflammation
- direct target cell killing
cytokine mediated inflammation

sarcoidosis has a major CD8 cytotoxicity component and a TMMI component, maybe even a Th17 component also.


IgE antibody, Th2 cells. Lip swelling, throat closing up, hives. What type of hypersensitivity response?
What are the mechanisms of tissue injury and disease?

Hypersensitivity disease Type I. allergy/asthma

mast cells, eosinophils and their mediators (vasoactive amines, lipid mediators, cytokines)


Which hypersensitivity classifications are antibody mediated?

Types 1-3 antibody mediated

Type IV- mediated by helper T cells, cytotoxic T cells even, Th17 cells, macrophages, antigen presenting cells, T cells getting together and prod. cytokines, not dep. on antibodies at all. PPD reaction - Poison ivy! not associated w antibody problems



What type? What cell is predominant? What treatment?

angioedema? Think: type I, mast cells - get benadryl & epinephrine


Itchy, blistering rash 2 weeks after starting new medication?

Think: type IV, T cells, macrophages - get prednisone & stop med.


Describe the Fab and Fc portions of antibody in immune complex formation. To what/when do they attach?

Formation of IC is based on a specific binding between an antigen and the antigen-binding site on the Fab terminus of the antibody molecule.

Only after antigen binding occurs, do biologic activities mediated by the Fc portion of the complexed Ig molecule ensue

The most important inflammatory reaction is mediated via binding of
antigen complexed with IgG to the Fcgamma R on monocytes and neutrophils. The receptor binding triggers a wide spectrum of antimicrobial activities, including phagocytosis, cytokine upregulation; antibody mediated cytotoxicity and generation of reactive oxidants.

IC also efficiently activate the complement system via the direct or
classical pathway

The end result is the generation of multiple inflammatory systems
including interleukins, chemokines and the kinin and leukotriene cascades,
which work in concert to mobilize neutrophils to the site of IC deposition,
which is often times in small capillaries such as those found in the kidney
or the joints.


How are IC controlled and reduced?

How are IC metabolized or disposed?

Effective neutrophil destruction of antigen at the site of inflammation will
reduce the amount of antigen exposure (e.g., treatment of infection) and
decrease the rate of immune complex formation. Fc Receptors on
neutrophils and monocytes promote uptake and catabolism of immune complexes.

Immune complexes not metabolized on site must be transported via
CR1 receptors on erythrocytes to the liver for disposal. The extremely
large number of circulating erythrocytes is a very effective delivery
mechanism in most cases.


Define the following terms:


Valency: how many identical epitopes within an antigen

Affinity: How strong is an antibody-binding site to a single epitope?

(affinity- many epitopes, multivalent, but when grabbing on, how good is grab? somatic mutation- antibody binding site gets better at holding onto its epitope)

Avidity: How strong is the overall attachment to the antigen?
Affected by valency of the antigen & affinity of antibody


Is a monovalent or polyvalent antigen better immunogens?

Give an example.

Polyvalent antigens are better immunogens & activators of immune effector functions

IgG- bivalent
IgM- polyvalent (very high affinity)


When do you have small or large complexes? Zone of antigen excess, zone of equivalence or zone of antibody excess?

What is the significance of complexed antibodies vs free antibodies?

zone of antibody excess or antigen excess- small complexes

zone of equivalence- large complexes

Complexed antibodies, not free antibodies, lead to effector functions…


Complexed antibodies, not free antibodies, lead to effector functions…

What do immune complexes activate?

Describe the downstream effects.

Direct (Classic) complement Pathway activation by immune complexes

- Close proximity of bound antibody Fc regions allow binding of the C1 complex
- Production of potent C3a and C5a chemokines
- Lysis of microbe by MAC complex

IgG - allow C1q complex to start to be activated. only activated when antibody is bound to epitope, and only when Fc portions are near each other
-can stimulate C1qrs to go cleave other complement proteins, get C3 convertase w part of C4 and C2…cleaves more C3. C3b sits on cell surface and C3a recruits more neutrophils and mast cells to site. then form C5 convertase, cleave C5 to C5b and C5a (most potent messenger=C5a… draws in a LOT of neutrophils and mast cells) most powerful anaphalatoxin (v important chemoattractant) in innate immune system

Activated complement components bound to immune complexes,
especially C3b, and immune complexes bound to their respective Fc receptors are strong regulators of B-cell activation, differentiation and
antibody formation.


Complexed antibodies, not free antibodies, lead to effector functions…

How is the alternative pathway stimulated?

…Produces C3b which can then stimulate alternative pathway & can bind to C3b receptor on phagocytes .... phagocytosis

c3b can land on microbe surface which can also be recognized by Cr1 which is a receptor on phagocytes and the phagocyte itself can, instead of Fc receptor can recognize C3b on microorganism and phagocytose microbe
c3b can stimulate alternative pathway too (without classical pathway) or in theory immune complex and prod. enough C3b could stimulate alt. pathway and that can go on by itself which could be a big problem is there is no real infection.


What can happen if antigenic stimulus does not go away?

excess small complexes may not be cleared fast enough, they can circulate and get trapped in blood vessels/tissue and cause damage.

Slide 18

(Because these small complexes can circulate, get trapped in blood vessels/tissue & cause damage…
Unlike the large complexes which are cleared easily by phagocytes)


How does the body or medicine work to prevent IC excess?

Get rid of the antigen
-Quick & Effective immune response
-Medical Intervention - e.g. antibiotics, drainage

Eat the immune complexes
-Neutrophils & Monocyte phagocytosis via FcR or C3b

- Take them to the dump…


Describe which cells have a CR1 receptor and their role in IC management.

All blood cells, except platelets, have the CR1 receptor

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

CR1 binds C3b and converts it to iC3b (inactivated) during

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. The spleen can also remove them but does so for different reasons- mainly for immune activation of B cells systems to the complexed antigen- a future lecture.


What are Kupffer cells? Where are they and what are they involved with?

fixed macrophages in liver... they remove IC-C3b complexes delivered to it by CR1 on erythrocytes.


What is ITAM? ITIM? How are they stimulated? What cells are these found on?

ITAM (immunoreceptor tyrosine-based activation motif) IgG1 and IgG3…these associated with ITAM motif

BCR + its co-receptor: stimulated by Antigen binding

Innate cells & their activating FcR: stimulated by ICs

shuts down immune activity...
ITIM (immunoreceptor tyrosine-based inhibitory motif)
Found on B cells & other cells
Can be stimulated by ICs via inhibitory FcR

-ITIM gets phosphorylated which causes translocation of certain internal proteins that are cell surface, from here on, this works transcriptional magic in nucleus and prod. inflammatory molecules that drive the response.

(see slide)



Describe the scenarios in which this can happen.

At any given time during an immune response, free antigen, immune
complexes and free antibody will be present at the site of an immune
stimulus. If immune complex formation exceeds their rate of disposal, pathologic inflammation, either local or systemic, can result

Possible causes of production exceeding disposal (catabolism) are:
a. Intensity and duration of the antigenic stimulus- exuberant
production of specific antibody if prolonged
b. Impaired disposal-usually secondary to increased production of
complexes and hepatic receptor saturation, CRI deficiency,
medications. Also, small complexes are often not phagocytosed &
tend to be deposited in vessels more than large complexes which
are usually cleared.
c. a + b above


What could happen to circulating immune complexes that are not bound to CR1 on RBC?

are 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.

If erythrocyte transfer to the liver cannot keep up with the formation of complexes at the site of formation, local accumulation of immune
complexes leads to neutrophil recruitment and activation. The presence of
activated neutrophils at the site release destructive enzymes and oxidants
after phagocytosis of the non-transported complexes and inflammation


Describe how ITIM works.

Fc portion of immune complex also stimulating the FcgammRIIb receptor which will inhibit downstream signaling that will usually cause B cell to be activated

Slide 24


Describe the binding affinity of:

Fc gamma RII-B
Fc gamma RI

Fc gamma RI has high affinity binding: low amount of ICs are enough to activate

Fc gamma RII-B has lower affinity binding (102 less): high amount of ICs are needed for sustained activation (signals that response should probably be ending soon)


A 31 y/o woman in a rural town delivered a healthy baby boy, her first child, at home. She had no prenatal care. Post-partum was complicated by prolonged bleeding, & so she was admitted to the local hospital for transfusion. Prior to transfusion, she was found to be blood type O- (Rhesus (Rh) factor negative)
Her newborn son was tested & found to be Rh+
She was counseled to see high risk maternal fetal medicine prior to subsequent pregnancies
However, she did not, & she had a late miscarriage with her second pregnancy

Rh- mother & Rh+ father
1st child is Rh+

Some fetal RBCs escape into maternal circulation

Rh- mother makes anti-Rh antibody

Next pregnancy escaped fetal RBCs stimulate mother’s memory B cells

Anti-Rh antibodies cross the placenta & lyse the fetus’ RBCs, causing severe anemia (hydrops fetalis)


A 31 y/o woman in a rural town delivered a healthy baby boy, her first child, at home. She had routine, standard prenatal care by her OB/GYN in the 1st trimester & was found to be Rh-.
Because of this, she was given 300 mg of human IgG anti-Rh at 28 weeks & again within 72 hrs of her delivery.
Her newborn son was tested & found to be Rh+
With each subsequent pregnancies she followed the same protocol.
She went on to have 3 more children, 2 of which were Rh+, without complications

What if you gave anti-IgM Rh?

Rhogam (pooled anti-Rh antibody)

Passive anti-Rh antibody

May bind fetal RBCs before free antigen can stimulate B cells via ITAM

Immune complex could also inhibit B cells via FcRIIb binding - ITIM

The clinician can preempt this response by giving the mother IgG anti Rh during
pregnancy (the route by which it is given prevents significant transfer across the
placenta) and within 72’ after birth. In a sense, the high level of specific IgG anti-
Rh “tells” the maternal immune system it already has had immunologic exposure to the antigen and doesn’t need to mount an immune response. More importantly, Rh specific CD4 and B memory cells are not generated.

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.


A certain rheumatologist’s son is animal & pet-crazed. He has fish, a pet lizard, a toad & is now requesting a hamster.
Against her better judgment, she allows him to get said hamster, and, as expected, he quickly loses interest after 2 days.
Thereafter, he takes the hamster out every 2-4 weeks to play with it. Almost each time, the hamster nips his hand and breaks the skin slightly.
About 6 months into owning the hamster, he becomes more interested & decides to play with it daily. On the 5th day, he is nipped for the 5th time, only this time his hand swells, becomes warm, red and painful, and he develops small, red, non-blanching patches after about 1 hr of being bitten.
What happened?

What is this reaction called? What type of reaction?

RBC have been compromised bc they don’t blanch.

The boy had been immunized & repeatedly boosted with intermittent nips, but antigen was cleared each time.
However, antigen load markedly increased with daily handling & antigen-antibody equivalence occurred causing deposition of local ICs with activation of Complement & FcRs
This is called an “Arthus Reaction” & it is a type III hypersensitivity reaction, NOT delayed hypersensitivity (which is type IV-e.g. is a PPD test)

it’s type 3 bc its antigen mediated and immune complex mediated.

The classic example of a local immune complex reaction, an Arthus
reaction, when there are high levels of pre-existing antibodies to the
antigen introduced at the site-usually under the skin. This scenario can
occur clinically when a patient who has been previously repeatedly
immunized is given the same vaccine again by injection. The immediate,
immense accumulation of immune complexes overwhelm the red cell
transport system and there is rapid neutrophil activation as the complexes
activate complement proteins and bind to neutrophil receptors. The
activated neutrophils and other cells (most likely mast cells and basophils)
release Il-8 and other vasoactive mediators that cause pain, swelling
(increased fluid extravasation) and redness (increased blood flow) at the
site of antigen injection.


Describe the arthus reaction.

Locally injected antigen in immune individual with IgG antibody

circulating antibodies coming out of small arterioles
antigen and nearby mast cell

local immune-complex formation

activation of complement releases inflammatory mediators C5a, C3a, and C4a. C5a also induces mast-cell degranulation

Local inflammation, increased fluid and protein release, phagocytosis, and blood vessel occlusion.


As luck would have it, the son from the previous case developed the rash while his physician mother & father were out of town.
He was taken to the hospital by his grandmother where he was given IV penicillin for a possible soft tissue infection.
He was given 3 days of IV penicillin & was discharged with 7 more days of oral penicillin when his swelling started to decrease (which it would have on its own anyway)…
On day 6, he was rushed back to the hospital for fever, tachycardia, tachypnea, a lower extremity rash & swollen joints
He was found to also have blood & protein in the urine, lymphadenopathy & low serum complement levels
What happened now?

Complement and IC deposits cross-linked to endothelial FcR & C3bR…

Induces production of pro-inflammatory cytokines...

Recruits effector cells...

Release damaging molecules which destroys tissue.

Small complexes of IgG – penicillin are not cleared fast enough

Serum complements are consumed faster than they are regenerated in this process & levels go DOWN

time frame is prob secondary response - had gotten penicillin in the past and was already sensitized to it then got IV and oral so his memory B reed up and prod lots of IgG (and some IgM) and that complexed w penicillin and that overwhelmed dump, phagocytosis, fCR2B system, all immune complexes started to deposit in small arteries and capillaries


How do immune complexes activate cellular inflammatory responses? (cytokines, etc)

Immune complexes activate cellular inflammatory responses by crosslinking
FcγR on multiple types of cells and stimulating the release of IL- 8 (and other chemokines we are not going to worry about), a potent chemokine that recruits neutrophils to the area of FcR crosslinking.

Immune complexes also activate the classic complement pathway with
subsequent generation of C3a, C567 and multiple other vasoactive
molecules. Complement activation amplifies neutrophil recruitment to the
area of immune complex deposition.


Describe acute serum sickness. What is this a classic example of?

A classic example of circulating immune complex disease-classic example: acute serum sickness.

Disease manifestations depend on site of deposition-usually in synovium, kidney/skin with loss of function and
tissue destruction.


In theory what would detection of decreased levels of C3 and C4 in the serum suggest?

IN THEORY, detection of decreased levels of C3 and C4 in the serum should suggest that direct (classical) activation of the complement
pathway has occurred.


If infection is the problem, what does treatment depend on?

Treatment depends on reduction of antigen load by antibiotics (if infection
is the problem), surgical drainage of an abscess, etc.


How does spleen and lymphoid tissue differ from he liver in regards to IC?

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. The spleen and lymphoid tissue are NOT disposal
sites like the liver is for IC.