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Flashcards in Immune Response to Microbes Deck (29):
1

General features of immune response to microbes?

1. defense against microbes is mediated by the effector mechanisms of innate and adaptive immunity

2. immune system responds in distinct and specialized ways to different types of microbes to most effectively combat these agents

3. the survival and pathogenicity of microbes in a host are critically influenced by the ability of microbes to evade or resist the effector mechanisms of immunity

4. in many infections, tissue injury and disease may be caused by the host response to microbe and its products rather than the microbe itself (granuloma)

2

Overview of responses? (5)

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3

What do Type 1 interferons (a and b) do? (9)

-inhibit viral replication via intracellular mechanisms

-regulate immune responsiveness -activate NK cells

-upregulate MHC 1 (up regulates CTL activation)

-mice lacking a/b receptor are more susceptible to viral infection

4

Interferon gamma (type 2) function? (9)

-produced by T cells and NK cells

-enhances MHC class 2 expression

-upregulates CD 4 T cell activation

-activate macrophage and NK cells

-augment MHC1 on cell surface

-makes changes to proteasome to digest more

-increase antigen on surface

-activates strong cell mediated immunity

5

NK cells function?

1. detectable within 2 days of infection

2. incredibly responsive to cytokines (Type 1 IFN, IFN gamma, IL-2, IL-15, IL-12)

3. recognize target cells via KARs and KIRs

-regulate lytic activity

4. lysis proceeds:

-perforins/granzymes

-ADCC- antibody dependent cell mediated cytotoxicity (NK cells have Fc receptors for IgG)

6

Macrophages function?

-act on viruses at three levels:

1. phagocytosis of virus and virally infected cells

2. killing of virally infected cells

3. release of antiviral molecules

-IFN alpha

-TNF alpha

-Nitric Oxide

7

Specific immune responses to viral infection?

1. virus specific antibodies control viruses when they are extracellular

-major mechanism for prevention of viral spread between cells and tissues

-important for restricting viremia (especially IgG)

-IgA at mucosal surfaces prevents re-infection (remember that viruses often enter via mucosal surfaces)

-70% of all antibodies are IgA (mostly in GI tract)

8

Antiviral effects of antibody? (14)

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9

CD 4 T cells function?

1. antiviral antibody production is usually T dependent (CD 4 TH1 cells)

-class switching and affinity maturation

2. help in induction of CD 8 CTLs

-production of cytokines (IL-2, IFN-gamma)

3. recruit and activate macrophages (CD40L and IFNgamma)

10

CD 8 T cells function?

1. kills virally infected cells in a class 1 MHC restricted antigen specific manner

-kill via perforin/granzymes

-Fas/FasL

-cytokine production

11

Innate and adaptive immunity working together on a virus? (17)

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12

Host defenses affected by certain viruses? (18)

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13

How do extracellular bacteria cause disease?

1. invasiveness

2. inflammatory response

3. secretion of exotoxins

-Extoxoin A (pseudomonas aeruginosa)

-lethal factor (bacillus anthracis)

4. Gram negative bacteria also make endotoxins

-potent stimulator of TNF alpha production

14

How does the immune response fight extracellular bacteria?

1. clearance of organisms

2. neutralization of toxins

15

Immunity in some important bacterial infections? (21)

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16

Natural immunity to extracellular bacteria?

-the principal mechanisms of innate immunity to extracellular bacteria are:

1. complement activation

2. phagocytosis

3. inflammation

17

Complement activation in immunity against extracellular bacteria?

1. activation of alternate complement cascade

-direct activation by peptidoglycan (Gram +) or LPS (Gram -)

-generation of C3b- opsonization and enhanced phagocytosis

-generation of membrane attack complex- bacterial lysis (can occur via the classical or alternative path)

2. Mannose pathway initiated by bacterial expression of mannose

-complement byproducts (C3a and C5a)- participate in inflammation by recruiting and activating leukocytes

18

Phagocytosis in immunity against extracellular bacteria?

1. phagocytosis/stimulation of microbicidal activity

-phagocytes recognize extracellular bacteria via surface receptors (mannose receptors, scavenger receptors)

-phagocytes use Fc receptors and complement receptors to recognize opsonized bacteria

-TLRs contribute to activation of phagocytes

19

Inflammation in immunity against extracellular bacteria?

1. activated phagocytes secrete cytokines

-proinflammatory cytokines:

-IL-1

-TNF

-IL-6

-chemokines

20

Cytokine effects in infection by extracellular bacteria?

1. stimulate inflammation

2. induce adhesion of neutrophils and monocytes to vascular endothelium

3. induce migration, local accumulation and activation of inflammatory cells

-eliminate bacteria, but induce normal tissue injury

4. fever

5. stimulation of acute phase reactants

6. regulate specific immunity through effects on B lymphocytes, T lymphocytes, APC

21

Bad things that cytokines do?

1. septic shock

-severe, often fatal, pathologic consequence of disseminated infection by Gram negative and some Gram positive bacteria

-sepsis is caused by cytokines:

-TNF alpha (maybe IL-1 and IL-6)

-IFN gamma

-IL-12

22

Virchow's classic triad in sepsis?

1. changes in coagulation: disseminated intravascular coagulation

2. endothelial cell injury

3. abnormal blood flow

-all three are present in sepsis and culminate in:

-reduced blood flow to vital organs (end organ failure)

-shock

-death

23

Adaptive immunity against extracellular bacteria? (33)

1. humoral immunity is the principal protective immune response against extracellular bacteria

2. functions to:

-block infection

-eliminate microbes

-neutralize toxins

3. neutralizing antibody

-may be all that is needed for protection if the organism is pathogenic only because of a single toxin or adhesion molecule

-IgA, IgG

4. activation of complement (classical)

-IgM and certain subclasses of IgG

5. opsonizing antibody

-together with complement can kill bacteria with an outer exposed lipid bilayer (Gram negative bacteria)

-IgG

6. most extracellular bacteria are removed by phagocytes

24

Immune evasion by extracellular bacteria? (34)

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25

Immune evasion by intracellular bacteria? (35)

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26

Innate immunity to intracellular bacteria? (38)

1. innate immune response to intracellular bacteria is mediated mainly by phagocytes and NK cells

2. intracellular bacteria are resistant to degradation within phagocytes

3. key player: activation of NK cells

-intracellular infection induces NK cell activating ligands on the infected cell surface

-or by stimulating production of IL 12 by macrophages and/or dendritic cells

-results in production of IFN gamma by NK cells

-activates macrophages (promotes killing of phagocytize bacteria)

-importance of IL-12 and IFN gamma underscored in studies using KO mice (very susceptible to infection by mycobacteria)

27

Adaptive immunity to intracellular bacteria? (42)

1. major protective immune response against intracellular bacteria is T cell mediated immunity (produce IFN gamma), mostly CD4 T cells, activate CD8 T cells

-people with AIDS are extremely susceptible to infection by intracellular bacteria

-NK cells and cytokines only transiently control infection

2. T cell activation of macrophages

-mediated by CD4 TH1, under influence of IL12

-TH1 cells activate macrophages to kill phagocytize bacteria through IFN gamma, CD40L

-macrophages then produce microbicidal products like ROS, NO, lysosomal enzymes

3. CTL

-phagocytized bacteria leak into cytosol

-or bacteria escape from phagosomes and enter cytosol

-cytosolic organisms no longer accessible to microbicidal activity to phagocytes

-so killing is accomplished by CTL

28

Control of infection? both arms? (43)

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29

Tissue injury caused by intracellular bacteria? (45)

1. due to macrophage activation

-because intracellular bacteria have evolved to resist killing within phagocytes:

-often persist for long periods

-cause chronic antigenic stimulation

-prolonged T cell and macrophage activation

-formation of granulomas:

-granulomatous inflammation hallmark of infection by intracellular bacteria