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Immunology > Lecture 15 - Type III Hypersensitivity - Immune Complex > Flashcards

Lecture 15 - Type III Hypersensitivity - Immune Complex Flashcards

1
Q

What type of hypersensitivity is Immune Complex disease classified as?

A

Type III

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2
Q

What is the immune complex?

What does the formation of IC depend on? (3)

A

Antigen + Antibody = immune complex

  1. Source of intensity of antigen exposure
  2. RATE of IC formation (balance between Ag exposure, Ag/Ab binding, disposal by neutrophil catabolism, transport to distant disposal site –> LIVER)
  3. Vigor of B cell response to antigen-gender variability, TLR, MHC genes
    ex: women have vigorous responses to B cell antigens (important for child bearing)
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3
Q

The following are defects in what?

  1. Systemic Lupus
  2. Sarcoidosis
A
  1. Systemic Lupus - abnormal TLR activation & fault T cell regulation w/ secondary production of excess IC
  2. Sarcoidosis - major CD8 cytotoxicity component and a TMMI component
    - maybe even Th17
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4
Q

Physiology of IC:

  1. Biologic functions of IC are mediated by what binding to what?
  2. IC can activate what two inflammatory amplifying systems?

What do these systems generate in response to activation? (4)

A
  1. Fc portion of an antibody that has bound its specific antigen at the Fab terminus

2.
a)FcR crosslinking and activation

b)complement via the classic or direct pathway

  1. interleukins, 2.chemokines
  2. prostaglandin
  3. kinin cascades
  • mobilize neutrophils to the site of IC formation
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5
Q

C3b receptors are found where?

A

On neutrophils and Macrophages

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6
Q

IC promote beneficial immune responses and inflammation by enhancing ______ of encapsulated organisms.

WHat 2 mechanisms SPECIFICALLY?

A
  1. phagocytosis
    - Some bacteria have large capsules with substantial charge  to resist phagocytosis  IC overcomes this by binding antigen and opsonizising  allow it to be phagocytes better
  2. binding them to C3b receptors on neutrophils and macrophages
  3. cross linking FcR on the same cells and promoting uptake and cell activation
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7
Q

True of False:

No free antibody can bind to FcReceptors

A

TRUE

  • need to be cross linked on the antigen
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8
Q

What are the control mechanisms for IC mediated Inflammation? (3 examples)

A
  1. Reduce the antigen exposure- successful inflammatory response
  2. antibiotics
  3. drainage of an abscess are good examples
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9
Q

In a normal inflammatory response, most IC are catabolized by neutrophils and monocytes after binding to their ________.

What happens if the rate of neutrophil/mac disposal is exceeded by formation of the IC?

A
  1. Fc receptors/C3b

2. the free IC bind to CR1 RBC receptors via C3b and are transported to the liver and spleen.

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10
Q

What happens once the free IC binds to CR1 RBC receptors via C3b?

A
  1. Transported to the liver and spleen

2. The fixed macrophage system in the hepatic SINUSOIDS strips off the complex and degrades it

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11
Q

What is the main function of the CR1 RBC receptors?

A

Bind to C3b and take the IC complex to the garbage dump = LIVER

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12
Q

CR1 (receptor for C3b) ON ALL PERIPHERAL BLOOD CELLS EXCEPT______.

CR1 BINDS C3b and converts it to what?

Where does it transport it and why?

What role does the Spleen have?

A
  1. PLATELETS
  2. iC3b
  3. TRANSPORTS IC TO LIVER FOR DISPOSAL OR SPLEEN FOR B-CELL STIMULATION
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13
Q

What are the 4 steps of IC formation and degradation?

A
  1. Small antigen-antibody complexes form in the CIRCULATION and activate complement
  2. Immune complex is coated with C3b
  3. Bound C3b binds to the receptor CR1 on erythrocyte surfaces
  4. In the spleen and liver, phagocytic cells remove the immune complex
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14
Q

What 3 things can lead to circulation of FREE IC?

What happens if the net result isformation > than destruction?

What does Free IC do?

A
  1. Intensity and duration of antigen exposure
  2. size of the IC
  3. impaired disposal can lead to circulation of IC

FREE IC = time bombs

  • wreak havoc on endothelial layer
  • will bind to C3b and FcR receptors if not destroyed by the liver
  • -> once they bind they activate an intense INFLAMMATORY response

FREE IC:
1. activate complement
2. Activate Fc
= inflammation

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15
Q

What is systemic Immune Complex Disease?

What is it mediated by?

A

called systemic immune complex disease

  • is mediated by complexes binding to vascular C3b and Fc receptors
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16
Q

Immune complexes are dictated by site of _______.

What does this activate?

Which cytokine is released?

What is the result to the vascular layer/endothelium?

A
  1. FcR cross-linking
  2. activates neutrophils and macrophages
  3. causes release of IL8 and other pro-inflammatory cytokines that recruit more inflammatory cells to the area
  4. Destroys underlying vascular architecture and tissue damage
    - breakdown arterial wall!
17
Q

Local Immune Complex is not a _____ reaction.

A

Arthus

  • B cell sees the antigen
  • plasma cells produce antibody
  • binds antigen
  • binds with either C3b or FcR receptors
  • cell takes it up and neutrophil catabolizes and destroys it
  • anything left over is taken to the LIVER AND DESTROYED!!!
18
Q

What is an arthus reaction? What happens?

A
  1. If the patient has a ton of antibody to X (pre-existing antibodies)
  2. Physician gives a vaccine with the ANTIGEN X by injection
  3. massive Antigen-Antibody reaction (IC)
    - IC formation overwhelms the RBC transport system
  4. MASSIVE NEUTROPHIL ACTIVATION
    = a lot of FREE IC COMPLEXES (some taken to the liver)
    –> IL-8 and other vasoactive mediators that cause pain,swelling, and renew at site of antigen injection
  5. complexes can cause a SERIOUS INFLAMMATORY REACTION
19
Q

What is the key to the arthus reaction?

A

** key = exposure to antigen before and created a ton of antibody***

  • given a second injection of antigen X
  • form a lot of IC –> overwhelm RBC
  • cannot be transported and degraded in liver

= SYSTEMIC INFLAMMATION via neutrophil recruitment by IL-8 and other vasoactive mediators

20
Q

Give the 4 basic steps to IC

A
  1. Locally injected Antigen in immune individual with IgG antibody
  2. Local immune-complex formation
  3. Activation of complement releases inflammatory mediators
    C5a, C3a, C4a.

C5a induces mast-cell degranulation

  1. Local inflammation, movement of fluid and protein into tissue and blood vessel OCCLUSION
    - within 1-2 hours
21
Q

What is the resulting disease of IV dose in the following areas:

  1. Blood vessel walls
  2. Renal glomeruli
  3. Joint Spaces
  4. Subcutaneous Perivascular Area
  5. Inhaled Alveolar/Capillar interface
A
  1. Blood vessel walls - Vasculitis
  2. Renal glomeruli - Nephritis
  3. Joint Spaces - Arthritis
  4. Subcutaneous Perivascular Area - Arthus REACTION***
  5. Inhaled Alveolar/Capillar interface - Farmer’s Lung
22
Q

Systemic Lupus: A systemic Immune Complex Disease

How does it occur?

Where do IC bind?

How can it be detected?

A
  1. Immune complexes bind to Fc and C3b receptors on glomerular basement membrane
  2. Detect by DIRECT immunofluorescence using ISOTYPE specific antisera
23
Q

Diagnosis of IC Disease:

  1. Detection/Quantitation of Circulating Complexes (does/does not) predict Disease
  2. The large Number of clinical assays available to measure IC are a clue to the above fact***
  3. Quantitation of Complement Components is/isn’t helpful in most cases either

How can it be tested?

A
  1. DOES NOT
  2. IS NOT helpful

Newer assays measure Activated C3 may be useful

24
Q

True or False:

In diagnosing IC, decreased levels of C3 and C4 in serum should suggest that a direct activation of complement pathway has occurred.

What does TX depend on?

A

TRUE IN THEORY, BUT FALSE in real life

  • TX depends on reduction of antigen load by antibiotics, surgical drainage of abcess, etc..
25
Q

What 3 ways can IC disease be Treated?

A
  1. Eliminate the antigen:
    a) drainage of an abcess,
    b) antibiotics
  2. Inhibit antibody formation- can be dangerous
  3. Suppress inflammation- also can be dangerous
26
Q

IC and bound complement fragments delivered to the SPLEEN/LYMPH NODES, or formed in situ in lymphoid tissue, are potent stimuli for what?

A

for Ab production!!

27
Q

When IgG-IC targets an antigen to an FcGamma R on an APC (macrophage, monocyte, neutrophil, or dendritic cell) it is prompted to phagocytose the complex by what signal?

What happens when an IgG - IC targets an antigen to an FCGamma R on its B CELL?
What is the result?

A
  1. ITAM (immunoreceptor tyrosine - bases activation motif)
  2. Activates ITIM
    - immunoreceptor based tyrosine inhibitory motif
    - SHUTS DOWN FURTHER B cell proliferation
28
Q

What is the different between an APC activating an ITAM and a B cell activating ITIM?

A

Difference is RECEPTOR AFFINITY:

APC:

  1. high affinity
  2. receptor can be activated by small amounts of IC

B cell:

  1. Low affinity
  2. Need ALOT of IC to be activated
    - B cell senses high density of bound antigen-antibody complex that “tell” it to stop making more of this particular IgG antibody
29
Q

FcR will not recognize free antigen, will only recognize it if it is bound to_______

A

ANTIBODY

-on APC:
there are FcG receptors -when they cross link they activate an ITAM sequence

  • ACTIVATING MOTIF TELLING CELL TO TURN ON = FcGamma on APCs!!!!!!
30
Q

What happens when there is a substantial amount of Antigen X bound to IgG anti x?

A

when there is a SUBSTANTIAL AMOUNT of Antigen X bound to IgG anti X

ANTIGEN BINDS TO BCR BUT AT THE SAME TIME It begins to cross link the FcGamma

telling the B cell YOU’VE MADE A LOT OF IgG antibody (start to see complexed antibody)
= negative signal = ITIM

ONLY ON B CELLS

31
Q

When does the Rh problem arise?

Mother & father have what phenotype?

First or Second Pregnancy?

A
  1. Mother = Rh-
    Father = Rh+

1st Baby is Rh+ and mother begins to make antibody against RH+ (primary response)

problem during the SECOND pregnancy–> mothers Anti-Rh antibodies can cross into placenta and start killing fetal RBC’s
( if significant maternal gG antibody formation and memory cell formation occurs, the anti-Rh IgG will cross the placenta and destroy fetal red cells)

SECONDARY RESPONSE!

IgG = only one to cross the placenta!

32
Q

What is the answer to the Rh problem?

A

Immunoregulation by FcGamma R

  • Give mother a ton of IgG antibody at certain time to fool her into thinking there is another fetus with Rh+ cells
  • The antibody combines with fetal RBC and that complex binds to a B cell with anti-fetal RBC specificity that
  • when “dense” enough on B cells, turns them off by crosslinking their FcR and BCR (fools system into shutting off B cells)

–> antigen specific

33
Q

What would happen if you gave IgM anti-Rh?

A
  1. Would not inhibit IgG anti-Rh antibody synthesis
    - mother will become sensitized to the Rh antigen on the fetal RBC’s that she was exposed to at time of birth

Prediction: probable that the long-lasting inhibition is based on development of CD4,25, FoxP3 Tregs

Immunology (26 decks)

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