L9: Host Defense

Question 1

Five classes of pathogens that the human body encounters

Answer 1

1. ) Extracellular bacteria
2. ) Intracellular bacteria
3. ) Fungi
4. ) Viruses
5. ) Parasites

Question 2

Extracellular bacteria. Innate and adaptive responses to these pathogens?

Answer 2

1. ) Innate immunity:
   a. ) phagocytosis = 1st line of defense,
   b. ) alternative complement activation via bacterial cell wall components (C3b) not antibody to lyse or opsonize
2. ) Adaptive immunity: humoral immunity
   a. ) IgG opsonizes
   b. ) toxin-specific antibodies neutralize,
   c. ) IgM and IgG activate classical complement to lyse

Question 3

How to extracellular bacteria attempt to evade the immune system?

Answer 3

• polysaccharide capsules resist phagocytosis and inhibit alternative complement activation

Question 4

Deleterious effects of the immune response against extracellular bacteria?

Answer 4

1. ) septic shock: gram negative, some gram positive bacteria induce macrophages to release TNF-alpha and IL-1 (and others), leading to negative systemic effects of such cytokines such as hypotension, low output from heart, clot formation etc.
2. ) superantigens: some bacterial toxins bind class II MHC on APCs and also alpha and beta variable regions on T cells causing their activation. This leads to cytokine storm and a septic shock-like condition (example: TSS)
3. ) disease causing antibodies:
   a. ) Rheumatic fever: streptococcal M-protein cause formation of cross-reactive antibodies to sarcolemma protein in heart leading to carditis
   b. ) Glomerulonephritis: streptococcal infection leads to antibodies that form complexes that lodge in kidney leading to nephritis

Question 5

Conceptually, what is problematic with intracellular bacterium?

Answer 5

• They survive and multiply within our cells and attempt to escape immune system

Question 6

Intracellular bacteria. Innate and adaptive responses to these pathogens?

Answer 6

1. ) Innate immunity:
   - Macrophages with intracellular bacteria (not destroyed) will release IL-12 (stimulating TH1 response). NK cells under IL-12 produce IFN-gamma to activate macrophages further, which can partially respond by killing the intracellular microbe, but must elicit TH1 response for full eradication
2. ) Adaptive immunity:
   - Type IV (DTH) reaction occurs: TH1 cells under IL-12 become activated, release IFN-gamma and cause macrophages to eliminate intracellular bacteria. Macrophages unable to completely eradicate pathogen will form granuloma to wall off living bacteria and prevent spread

Question 7

How do intracellular bacteria attempt to evade the immune system?

Answer 7

a. ) mycobacterium inhibits fusion of phagosomes and lysosome, also scavenge ROS intermediates to prevent killing
b. ) Listeria disrupts phagosome and escapes into cytosol

Question 8

One of the mechanisms for Listeria to evade the immune system is to disrupt the phagosome. How can this lead to CTL activation?

Answer 8

• Listeria in the cytoplasm can be processed down the endogenous pathway and loaded onto class I MHC causing CD8+ CTL activation

Question 9

Describe deleterious effects of the immune response caused by intracellular bacterial infections

Answer 9

• Granuloma formation may severely compromise tissue function (esp in lungs) as it encroaches on parenchyma

Question 10

Viruses. Innate and adaptive immune responses to these pathogens?

Answer 10

1. ) Innate immunity:
   - Production of type 1 IFN (alpha and beta) by virally-infected cells causes upregulation of class I MHC and activation of NK cells. Class I MHC drives upregulation of CTLs. In event that virus downregulates class I MHC, NK cells destroys those cells as the inhibitory signal (by MHC 1 presence) is absent.
   - Within cells, type I IFN causes inhibition of viral protein synthesis, degradation of viral RNA and inhibition of viral gene expression and virion assembly
2. ) Adaptive immunity:
   - Humoral immunity is important EARLY in viral immunity if antibodies are present. These antibodies prevent virus from binding, opsonize virus and activate complement to lyse viral envelopes
   - CTLs are the principle component during ESTABLISHED viral infections – virus antigen processed and presented on class I MHC

Question 11

How to viruses attempt to evade the immune system?

Answer 11

• HIV: contains error-prone reverse transcriptase therefore introducing point mutations in it’s proteins. HIV infects and destroys CD4+ T cells therefore preventing immune response
• Influenza: reassortments produce antigenic alterations
• Several viruses prevent class I MHC expression of viral peptides, therefore not lysed by CTLs

Question 12

What are the deleterious effects of the immune response against viruses?

Answer 12

• CTLs mediate pathologic lesions in some viral disease states, example Hep B infection – liver destroyed by CTL response
• Some viruses express proteins with homology for host cell proteins – cross-reaction/molecular mimicry

Question 13

Fungi. Innate and adaptive immune response to these pathogens

Answer 13

1. ) Innate response: neutrophils are main mediators, fungi are phagocytosed and destroyed via lysomal enzymes and ROS intermediates.
2. ) Adaptive response: TH1 mediated response (cell-mediated including via CTLs), antibody response not established, granulomas also formed

Question 14

What infections are neutropenic pts highly susceptible to?

Answer 14

• Fungal infections

Question 15

What pathogens can induce granuloma formation?

Answer 15

• Intracellular bacteria

- Fungi

Question 16

Parasites. Innate and adaptive immune responses to these pathogens

Answer 16

1. ) Innate response:
   - Macrophages phagocytoze protozoa (many resistant to killing)
   - Outer layer of helminthes activate alternative complement pathway, resistant to effects of activation
2. ) Adaptive response:
   - Response is TH1 mediated (production of IFN-gamma):
   - macrophages cause activation of CD4+ T cells and production of IFN-gamma, which activates more macrophages
   - plasmodium lead to activation of TH1 CTLs
   - Helminthic infestations lead to IgE and eosinophil production/activation during ADCC – TH2 response

Question 17

How to parasites attempt to evade the immune system?

Answer 17

• Thick integuments of helminths are resistant to neutrophils and macrophages
• Reside in intestinal lumen or cysts
• Coat with host proteins so identified as self
• Outer surfaces inhibit complement-mediated damage
• Extracellular enzymes cleave membrane-bound antibody
• Variation of surface antigen
• Shed their antigens spontaneously

Question 18

What are deleterious effects of the immune response in combatting parasitic infections?

Answer 18

1. Chronic parasite infestations lead to immune complexes that lodge in vessels and kidneys leading to vasculitis and nephritis
2. Eggs lead to liver fibrosis that disrupts venous return leading to portal HTN and cirrhosis
3. Filaria worms lodge in lymphatics leading to severe fibrosis restricting lymph flow and severe lymphedema

Question 19

A 5-year old child is suffering from a virus infection. The child has never had a natural exposure to the virus. No vaccine is available to prevent this virus infection. Which cell type from adaptive immunity would be needed to eradicate the virus? Which cell type from adaptive immunity likely would be involved if the child had prior exposure to the virus?

1. Basophil
2. B lymphocyte
3. Cytotoxic T lymphocyte
4. Natural killer cell
5. Neutrophil

Answer 19

• CTL if no prior exposure

- B lymphocyte if child had prior exposure

Question 20

What is the main difference between the ADCC of a virus-infected cell and the opsonization and phagocytosis of an extracellular bacteria?

1. Different antibody isotypes are used
2. Different immune cells are involved
3. Opsonization only utilizes C3b
4. Size of the targeted cell varies

Answer 20

• 4

Question 21

Why don’t cytotoxic T lymphocytes (CTL’s) kill infected red blood cells (RBC’s)?

1. No microbes infected RBC’s.
2. RBC’s don’t express class I MHC.
3. RBC’s don’t express class II MHC.
4. RBC’s reside in a different location than CTL’s

Answer 21

• 2

Question 22

NK cells require the absence of class I MHC molecules to become activated. RBC’s don’t express class I MHC molecules. Why don’t peripheral blood NK cells kill RBC’s?

1. I don’t have the foggiest notion!
2. Because no interferon is available.
3. RBC’s can’t be infected by viruses.
4. RBC’s don’t express activating signals.
5. Regulatory T cells keep NK cells controlled.

Answer 22

• 4