Innate Immunity Flashcards by Kyra Porter

peripheral (secondary) immune system organs

lymph nodes & spleen
*where cells RESIDE

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central (primary) lymphoid organs

bone marrow & thymus
*where immune cells are MADE

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cells of innate immunity

NK cells
neutrophils
eosinophils
basophils
dendritic cells
mast cells
monocytes
mast cells

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cells of adaptive immunity

lymphocytes (B & T cells)
plasma cells

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lymphocytes

production of antibodies (B cells) or cytotoxic and helper functions (T cells)

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plasma cells

fully differentiated form of B cell that secretes antibodies
*live in the spleen and bone marrow

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natural killer (NK) cells

*use perforin and granzymes to induce apoptosis of virally infected cells and tumor cells
*activity enhanced by IL-2, IL-12, IFN-alpha, and IFN-beta
*cell surface proteins: CD16 (binds Fc of IgG), CD56 (suggestive marker for NK cells)

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neutrophils

phagocytosis and killing of microorganisms (especially BACTERIA)

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eosinophils

killing of antibody-coated parasites through release of granule contents

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basophils

controlling immune response to parasites

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mast cells

expulsion of parasites from body through release of granules containing histamine and other active agents

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monocytes

circulating precursor to macrophage

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macrophages

phagocytosis and killing of microorganisms; activation of T cells and initiation of immune response

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dendritic cells

responsible for T cell activation and initiation of adaptive immune responses
*interaction between innate and adaptive immunity

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innate immunity

-physical barriers (skin, mucous membranes)
-cells (neutrophils, macrophages, dendritic cells)
-complement
-rapid in onset
-antigen-nonspecific
-initiates events required for adaptive immune response
-no memory

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adaptive immunity

-cell mediated immunity (T cells)
-antibody producing B cells
-requires several days
-highly antigen-specific
-exhibits immunologic (antigen-specific) memory

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3 main functions of innate immunity

1) initiate a rapid response against the pathogen
2) limit the spread of infection
3) initiate the adaptive immune response at secondary lymphoid site (e.g. draining a lymph node

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how does the innate immune system initiate the adaptive immune system

innate antigen-presenting cells (dendritic cells & macrophages) will:
1) carry the antigen from the site of infection to a secondary lymphoid site, like a nearby draining lymph node
2) present the antigen to clones of T and B lymphocytes that reside in secondary lymphoid site
3) once T cells are activated, they can traffic to the site of infection from lymph nodes and the bloodstream in order to help clear the pathogen

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acute inflammation

reaction of the innate immune system that serves as a transient, early response to infection or injury
s/s include:
-rubor (redness)
-calor (heat)
-tumor (swelling)
-dolor (pain)

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components of acute inflammation

a) vascular: vasodilation and increased endothelial permeability (allows cells out of blood into the infected tissue)
b) cellular: extravasation of leukocytes (4 steps: margination and rolling, adhesion, diapedesis, migration)

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when will neutrophils peak during acute inflammation

at about 24 hours

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when will macrophages peak during acute inflammation

at about 2-3 days

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possible outcomes of acute inflammation, influenced by cytokines from macrophages

1) resolution and healing (IL-10 and TGF beta)
2) persistent acute inflammation (IL-8: pro-inflammatory)
3) abscess - acute inflammation walled off by fibrosis
4) chronic inflammation - APCs activate CD4+ Th cells
5) scarring

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type I interferons

*proteins made by the innate immune system
*bind to IFNAR (interferon alpha/beta receptor), expressed by almost every cell
*puts the cell into an anti-viral state: downregulate protein synthesis to resist potential viral replication

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effectors of innate immunity

cytokines acute phase reactants phagocytes natural killer cells innate lymphoid cells (ILCs)

cytokines

proteins that communicate between cells of the immune system and between immune cells and other cells of the body *interferons are a type of cytokine

acute phase reactants

facilitate a range of processes involved in pathogen clearance *produced by the liver

phagocytes (neutrophils, macrophages, dendritic cells) as effectors of innate immunity

engulf and destroy bacterial pathogens

innate lymphoid cells (ILCs)

lymphoid cells that lack an antigen receptor; produce cytokines

positive acute phase reactants

*tend to be increased during inflammation ferritin fibrinogen serum amyloid A hepcidin C-reactive protein

ferritin

positive acute phase reactant *binds and sequesters IRON

negative acute phase reactants

*tend to be downregulated during infection albumin transferrin

transferrin

negative acute phase reactant *internalized by macrophages to sequester IRON

4 part response of innate immunity to BACTERIA

1. activation of the complement system 2. recruitment of neutrophils and macrophages 3. induction of cytokine synthesis by resident macrophages, endothelial and epithelial cells 4. maturation of dendritic cells

C3a

anaphylatoxin *recruits inflammatory components from vascular space

C3b

opsonin *coats bacterium to enhance phagocytosis

functions of C3b

1. a component of the C3 convertase 2. **opsonin**: a modified form of C3b termed iC3b **promotes phagocytosis** by macrophages and neutrophils 3. a component of the C5 convertase

C5b

component of the membrane attack complex

C5a

the most potent anaphylatoxin *a chemotactic factor for neutrophils

C3a and C5a

anaphylatoxins *result in: -increased flow of circulating complement components to the site of infection -recruitment of phagocytes via adhesion molecules

decay accelerating factor (DAF)

*expressed by host cells *competes with Factor B for binding to C3b ***prevents positive feedback loop of C3 convertase formation (helping us not be attacked by our own complement system)**

factor H

*preferentially binds host cell due to sialic acid on surface *can displace Factor B from C3b, making C3b available for proteolysis *Factor I lyses (degrades) free C3b (helping us not be attacked by our own complement system)

paroxysmal nocturnal hemoglobinuria - disease overview

*complement-mediated intravascular RBC lysis → decreased haptoglobin, dark urine *due to a **defect in the PIGA gene**

paroxysmal nocturnal hemoglobinuria - pathophysiology

***defect in PIGA gene → prevents formation of GPI anchors → impaired DAF/CD55 → RBC membrane unprotected from complement** *causes complement-mediated intravascular hemolysis of RBCs

paroxysmal nocturnal hemoglobinuria - labs

CD55 (-) RBCs on flow cytometry

paroxysmal nocturnal hemoglobinuria - treatment

eculizumab - inhibits terminal complement formation

factor I deficiency

leads to low levels of circulating C3 *consumptive deficiency: without factor I, C3 convertase is uninhibited, leading to a high rate of C3 consumption, leading to increased pyogenic infections

toll-like receptors

*family of cell surface proteins that are involved in the RECOGNITION of microbial pathogens and activation of the innate immune response ***recognize PAMPs (pathogen-associated molecular patterns) → activation of NF-kappaB** (patterns, rather than unique ligands)

molecules recognized by TLR1 and TLR 6

components of gram-positive bacteria

molecules recognized by TLR 2

components of gram-positive bacteria

molecules recognized by TLR 3

double stranded RNA

molecules recognized by TLR 4

LPS (lipopolysaccharide), pili, RSV F protein

molecules recognized by TLR 5

gram-negative flagellin

molecules recognized by TLR 9

unmethylated CpG DNA (abundant in bacteria)

TLR signaling

1) TLR agonists bind to receptors on macrophages and neutrophils at the site of infection 2) agonist stimulates the cells to make pyrogens (IL-1, IL-6, and TNF alpha) and chemokines 3) pyrogens cause increased expression of ADHESION MOLECULES on the circulating neutrophils, monocytes, and endothelial cells 4) adhesion, together with the chemokines, causes increases in neutrophil and monocyte infiltration at the site of infection 5) the neutrophils use C3b to enhance their ability to phagocytose bacteria

respiratory burst

KEY ENZYME: NADPH oxidase *the destruction of internalized bacteria is mediated by reactive oxygen species (ROS), including nitric oxide (NO), superoxide, hydrogen peroxide, and hypochlorite *ROS are produced in phagocytes like neutrophils and kill the bacteria

chronic granulomatous disease (CGD)

***deficiency in NADPH oxidase, causing failure of the respiratory burst** to kill bacterial pathogens] *patients at increased risk for infection with CATALASE-positive organisms

TNF-alpha functions

fever, sepsis, WBC recruitment; maintains granulomas is TB; causes cachexia in malignancy

IL-1 functions

fever, acute inflammation (aka osteoclast-activating factor)

IL-6 functions

fever, acute phase reactants

IL-8 functions

major chemotactic factor for neutrophils

IL-12 functions

induces Th1 cells; activates NK cells

why are pyrogens beneficial for our immune response

increased body temperature helps the immune cells work better, as well as hindering pathogen functions

dendritic cell maturation

TLR ligands bind to TLRs on dendritic cells, inducing MATURATION and MIGRATION of the dendritic cells to secondary lymphoid sites (spleen, lymph nodes), where they promote antigen-specific activation of T cells

4 part response of innate immunity to VIRUSES

1) production of Type I interferons* 2) recruitment of natural killer cells* 3) induction of cytokine synthesis by resident macrophages, endothelial and epithelial cells 4) maturation of dendritic cells

innate immune response to a virus

*type I interferons (IFN-alpha and IFN-beta) are produced by infected cells, leading to dendritic cell maturation and NK cell recruitment *specific viral proteins and double-stranded RNA can signal via TLRs *double-stranded viral RNA can also signal through cytoplasmic pattern recognition receptors such as RIG-1 and MDA5

how do interferons work to put a cell in the anti-viral state

1) **downregulate protein synthesis** to resist potential viral replication 2) **upregulate MHC expression** to facilitate recognition of infected cells *protects the NEIGHBORING cells, not really the infected cell

activation of NK cells

1) exposed to nonspecific activation signal on target cell or MIC ligand 2) exposed to ABSENCE of MHC1 on target cell surface 3) antibody-dependent cell-mediated cytotoxicity; CD16 of NK binds Fc region of antibody to activate NK cell

how do NK cells kill infected cells

induce apoptosis in virally-infected cells with: *perforin (perforate the membrane) *granzymes (proteases, which cleave cellular proteins, especially pro-caspase 9)

which bacterial pathogens are people with CGD most susceptible to

catalase-positive organisms