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Host Defense Exam 2 > Immune Complex Diseases > Flashcards

Immune Complex Diseases Flashcards

1
Q

Define hypersensitivity reaction.

A
  • immune system has an exaggerated response to an antigen it has already encountered before
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2
Q

Define hypersensitivity Type 1.

A
  • immediate
  • seen in allergies and asthma
  • mediated by IgE and Th2 cells
  • injury due to mast cells and eosinophils releasing inflammatory cytokines => swelling, vasoactivity, anaphylaxis
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3
Q

Define hypersensitivity Type 2.

A
  • antibody-mediated
  • seen in antibodies specific to cell surfaces and ECM proteins
  • antibody binds to protein => opsonization => phagocytosis => tissue injury
  • antibody activates complement => innate immunity activation
  • can interrupt signaling
  • ex: immune thrombocytopenia
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4
Q

Define hypersensitivity Type 3.

A
  • immune complex mediated
  • caused by circulating antigen:antibody complexes (IgM or IgG)
  • several antibodies bind to the antigen => deposition of large immune complexes
  • ex: lupus erythematosus
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5
Q

Define hypersensitivity Type 4.

A
  • AKA delayed hypersensitivity
  • T cell mediated
  • mediated by CD4 (Th1 and Th17) and CD8 CTLs
  • mediated by cytokines and direct killing
  • involves FcR and complement
  • ex: PPD test, poison ivy
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6
Q

Define lupus erythematosus.

A
  • most likely due to an abnormal activation of TLRs
  • faulty T cell regulation
  • leads to excess immune complex production
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7
Q

Define sarcoidosis.

A
  • involves CD8 and Th17
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8
Q

What are some reasons you might get hypersensitivity?

A
  • allergen
  • autoimmunity
  • overwhelming infection
  • repeated exposure to antigen leads to increased intensity of adaptive response
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9
Q

What is IC formation based on?

A

intensity of antigen stimulation

  • type of antigen
  • length of host exposure
  • site of exposure
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10
Q

What is rate of IC formation based on?

A
  • valency
  • affinity
  • avidity
  • rate of antibody formation (primary vs secondary response)
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11
Q

What is the vigor of an immune response based on?

A
  • antigenic properties
  • gender
  • age
  • MHC
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12
Q

Define valency. How does it affect IC formation?

A

valency - # of identical epitopes on an antigen

- the more epitopes, the more antibodies will bind, the more immunogenic => increased IC formation

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13
Q

Define avidity. How does it affect IC formation?

A

avidity - strength of overall attachment of antibody to antigen

  • affected by valency and affinity
  • increased avidity = increased IC formation
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14
Q

Define affinity. How does it affect IC formation?

A

affinity - strength of antigen-binding site on the antibody and its attachment to the epitope

  • improves with time (somatic hypermutation)
  • increased affinity = increased IC formation
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15
Q

How are immune complexes formed?

A

soluble Ig binds to soluble, circulating antigen

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16
Q

List the stages of immune complex formation (zones).

A
  • zone of antibody excess
  • zone of equivalence
  • zone of antigen excess
17
Q

Describe the zone of antibody excess.

A
  • small complexes
  • antibody > antigen
  • possibly associated with secondary response (lots of antibody production)
  • easily cleared, antigen sequestered
18
Q

Describe the zone of equivalence.

A
  • large ring complexes
  • antibody = antigen
  • antigen is sequestered, but large size can impair clearance and lead to deposition
19
Q

Describe the zone of antigen excess.

A
  • small complexes

- antibody

20
Q

Review the classical complement pathway.

A
  1. antibody binds to antigen, opening up a site on the Fc for C1q
  2. 2 C1q globular heads must simultaneously bind to the antibody
  3. Once bound, C1r cleaves C1s => C1s is active
  4. Activation of C1s and MASP2 (see previous cards)
  5. C1s/MASP2 cleave C4 => C4a and C4b
  6. C4b binds to the pathogen surface
  7. C2 binds to C4b
  8. C1s/MASP2 cleave C2 => C2b and C4b2a
  9. C4b2a is a C3 convertase => cleave C3 => C3a and C4b2a3b
  10. C4b2a3b is a C5 convertase => cleaves C5 => C5a and C5b
  11. C5a is a soluble inflammatory mediator
  12. C5b complexes with C6, 7, 8, and 9 to create the MAC
21
Q

Review the alternative complement pathway.

A
  1. C3 is hydrolyzed to form C3(H2O)
  2. C3(H2O) binds to Factor B
  3. Factor D cleaves C3(H2O)-B => Ba and C3(H2O)Bb
  4. C3(H2O)Bb is a C3 convertase => C3a and C3b
  5. Most C3b is degraded, but some attaches to the pathogen surface
  6. Factor B binds to C3b on the surface
  7. Factor D cleaves Factor B => Ba and C3bBb
  8. Properdin (Factor P) binds to C3bBb and stabilizes it
  9. C3bBb is a C3 convertase => C3a and C3bBb3b
  10. C3bBb3b is a C5 convertase => C5a and C5b
  11. C5b complexes with C6, 7, 8, 9 to form MAC
22
Q

What are the functions of C3a and C5a?

A
  • potent anaphylaxatoxins
  • ## recruit neutrophils
23
Q

What is the function of C3b?

A

opsonization

- binds to CR1 on phagocytes

24
Q

What are the disadvantages to small IC complexes?

A
  • found in zone of antibody excess or antigen excess
  • can get trapped in blood vessels and tissue => injury
  • escape phagocytosis
  • can escape removal by the spleen and kidney and bind to FcR and C3b receptors in other tissues/organs leading to inflammatory response at other sites
25
Q

What are the advantages of large IC complexes?

A

easily phagocytosed

26
Q

How can you prevent IC excess?

A
  • get rid of the antigen via antibiotics or lymph drainage
  • get rid of the ICs by recruiting neutrophils and macrophages to phagocytose via FcR
  • Cr1-mediated removal in the spleen and liver
27
Q

Review CR1-mediated removal of ICs.

A
  • C3b binds to Cr1 on RBC surface

- removed in the spleen and liver by macrophages

28
Q

Contrast neutrophil/macrophage-mediated and RBC-mediated IC removal.

A
  • neutrophils/macrophages bind to FcR of antibody:antigen complex at the site of infection
  • RBCs are required for antigen:antibody complexes that are not phagocytosed at the site of infection; bind to C3b via Cr1 and transport to the spleen and liver
29
Q

Which organ is the most efficient at IC removal?

A

liver due to high blood flow and prevalence of Kupffer cells (macrophages)
- spleen removes IC for the purpose of activating B cell response

30
Q

What are some reasons why production of IC would exceed disposal, leading to pathological response?

A
  • intensity and duration of antigen leads to prolonged antibody production stimulation
  • impaired disposal due to receptor saturation, CR1 deficiency, deposition
31
Q

Define ITAM and its mechanism.

A

ITAM = Immunoreceptor Tyrosine-based Activation Motif

  • found on innate cells (NK cells, neutrophils, macrophages)
  • stimulated by IC binding => conformational change => phosphorylation => Ca2+ mobilization
32
Q

Define ITIM and its mechanism.

A

ITIM = Immunoreceptor Tyrosine-based Inhibition Motif

  • found on B cells
  • associated with BCR and inhibitory FcR
  • stimulated by IC
  • binds Fc and causes downstream dephosphorylation to inhibit immune activation
33
Q

Differentiate the binding affinities of FcR.

A
  • FcGRI has high affinity: when a small amount of IC is present, an immune response will occur (found on innate cells => immune response => phagocytosis)
  • FcGRII has a low affinity: when there is an overabundance of IC, this will inhibit the immune response (found on B cells => if this receptor is being activated, the cell knows to stop proliferating)
34
Q

Define Rh alloimmunization.

A
  1. Rh- mother has an Rh+ fetus
  2. fetal RBCs with Rh+ can trickle into maternal circulation
  3. Rh- mother makes anti-Rh antibody (in very small amounts)
  4. the baby is born without issue because the anti-Rh is in small dose (primary response)
  5. However, if the second fetus is also Rh+ => secondary response => increased production of anti-Rh antibody => anemia due to RBC destruction => miscarriage
35
Q

Explain how Rhogam prevents Rh immune response.

A
  1. administer passive anti-Rh immunity
  2. anti-Rh antibodies bind to fetal RBCs found in maternal circulation before antigen can stimulate B cells
  3. antibody:antigen complexes can also bind to ITIM/FcGRII and inhibit immune activation
    - by giving a large dose, you overwhelm the B cells => activate ITIM => cell thinks it doesn’t need to make more
36
Q

How do immune complexes cause pathology?

A
  1. ICs bind to FcGR and cause release of IL-8
  2. IL-8 recruits neutrophils to the site of infection
  3. ICs stimulate complement pathway, which amplifies neutrophil recruitment via C3a and C5a
  4. RBCs cannot effectively remove ICs from the infection site
  5. neutrophils release destructive enzymes
  6. IL-8 and other vasoactive mediators lead to local swelling, pain, redness,
37
Q

Describe the Arthus reaction.

A
  1. Patient has been previously immunized against the antigen = has enough antibodies in serum
  2. Patient becomes immunized again
  3. increased presence of antibody leads to increased IC formation
  4. RBC-CR1 system gets overwhelmed
  5. IC binds to C3bR and FcR on other cells and recruits neutrophils
  6. massive neutrophil recruitment leads to excess IL8 production
  7. localize inflammation

Host Defense Exam 2 (11 decks)

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