Innate Immunity Flashcards
peripheral (secondary) immune system organs
lymph nodes & spleen
*where cells RESIDE
central (primary) lymphoid organs
bone marrow & thymus
*where immune cells are MADE
cells of innate immunity
NK cells
neutrophils
eosinophils
basophils
dendritic cells
mast cells
monocytes
mast cells
cells of adaptive immunity
lymphocytes (B & T cells)
plasma cells
lymphocytes
production of antibodies (B cells) or cytotoxic and helper functions (T cells)
plasma cells
fully differentiated form of B cell that secretes antibodies
*live in the spleen and bone marrow
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)
neutrophils
phagocytosis and killing of microorganisms (especially BACTERIA)
eosinophils
killing of antibody-coated parasites through release of granule contents
basophils
controlling immune response to parasites
mast cells
expulsion of parasites from body through release of granules containing histamine and other active agents
monocytes
circulating precursor to macrophage
macrophages
phagocytosis and killing of microorganisms; activation of T cells and initiation of immune response
dendritic cells
responsible for T cell activation and initiation of adaptive immune responses
*interaction between innate and adaptive immunity
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
adaptive immunity
-cell mediated immunity (T cells)
-antibody producing B cells
-requires several days
-highly antigen-specific
-exhibits immunologic (antigen-specific) memory
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
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
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)
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)
when will neutrophils peak during acute inflammation
at about 24 hours
when will macrophages peak during acute inflammation
at about 2-3 days
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
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
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
- activation of the complement system
- recruitment of neutrophils and macrophages
- induction of cytokine synthesis by resident macrophages, endothelial and epithelial cells
- maturation of dendritic cells
C3a
anaphylatoxin
*recruits inflammatory components from vascular space
C3b
opsonin
*coats bacterium to enhance phagocytosis
functions of C3b
- a component of the C3 convertase
- opsonin: a modified form of C3b termed iC3b promotes phagocytosis by macrophages and neutrophils
- 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
