Introduction to Innate Immunology Flashcards
What is the first line of defense in the innate immune system?
Physical barriers such as the skin, gut, lungs, and eyes/nose/oral cavity
What are 5 chemical barriers of infection?
Fatty acids/lactic acids such as sweat and sebum
Destructive enzymes in tears, and saliva for example
Acidic pH in the stomach and vagina and on the skin
Surfactant proteins A and D in the lung
Defensins (cells that make antimicrobial peptides) in the lung, GI tract, and skin
What are 3 types of granulocytes and what is their function?
Eosinophils, basophils, mast cells.
Function to secrete pharmacological mediators and are responsible for combating multi-cellular parasites. Additionally, they play a major role in diseases.
What is the one purpose that neutrophils serve?
To professionally kill.
Neutrophils are summoned by what cytokines?
IL-1, TNF-α, IL-8 (chemokine)
What are the 2 major functions of macrophages?
M1 classical macrophages are induced by innate immunity and play a role in inflammation.
M2 alternative macrophages are induced by IL-4, and IL-13, and play a role in tissue repair and control of inflammation
What do monocytes convert to once they have left the blood?
Macrophages
What is the function of macrophages in innate immunity?
Phagocytosis, cytokine production, inflammation, and wound healing
What is the function of macrophages in adaptive immunity?
Antigen presentation, regulatory cytokine secretion and are an effector cell since macrophage activity can be enhanced by Th cytokines
What is Chediak-Higashi syndrome?
Microtubule defect leading to decreased phagocytosis since there is no cytoskeleton to help bring in a phagosome. This can cause recurrent pyogenic infections due to macrophages and neutrophils not working correctly and partial oculocutaneous albinism since melanin cannot migrate the way that it should.
What are the professional APCs?
Dendritic cells
How to NK cells force a cell to commit suicide?
The 1-2 punch where perforin proteins deliver the suicide enzyme, granzyme B, into a target cell. Additionally, the Fas ligand that is expressed on NK cell surface binds to death receptor on target cell to induce apoptosis
Explain macrophage/NK cell reciprocal cytokine activation
Activated macrophages produce and secrete IL-12 which activates NK cells.
Activated NK cells produce and secrete IFN-γ which activates macrophages to become better killers.
What is the inhibitory ligand that prevents NK cells from killing healthy self cells?
MHC Class I
Distinguish between pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs)
PAMPs: molecules/structures that are shared by various classes of microbes but are not present on self cells. Typically target structures of microbes that are essential for survival and/or infectivity (such as LPS, mannose residues, dsDNA, etc.)
DAMPs: Molecules released by stressed cells undergoing necrosis which act as endogenous danger signals for surrounding tissue. The binding of PAMP ligands to PRRs induce intracellular signaling in the phagocytes leading to their activation.
What are the four endogenous toll-like receptors (TLRs) and what do they detect?
TLR-3: dsDNA
TLR-7: ssRNA
TLR-8: ssRNA
TLR-9: CpG DNA
What are the five exogenous TLRs and what do they detect?
TLR-1: Bacterial lipopeptides TLR-2: Bacterial lipopeptides and peptidoglycans TLR-4: LPS TLR-5: Bacterial flagellin TLR-6: Bacterial lipopeptides
Which cell types of innate immunity detect PAMPs via TLRs?
Macrophages, dendritic cells, and neutrophils
Binding of TLRs results in what? (5 things)
Phagocytosis
Production and secretion of cytokines
Increased cytokine receptor expression
Increased ROS production
Increased cytoskeletal changes
What is an inflammasome?
What does it produce?
Signaling system for detection of pathogens and stressors.
NLRP-3 (sensor) + ASC (adaptor) + inactive caspase-1 → NLRP-3 inflammasome + active caspase-1.
active Caspase-1 converts pro-IL1β to IL-1β , which is then secreted.
So produces IL-1 and IL-18, both are potent inflammatory cytokines
Where are complement (C’) proteins produced?
Produced in liver by hepatocytes
What is the purpose of C’?
Stimulates inflammation, facilitates Ag phagocytosis, and can lyse some cells directly.
What is the purpose of the ‘a’ and ‘b’ fragments in C’?
The ‘a’ fragment is an anaphylatoxin which diffuses from the site (w/ exception of C2a) and plays a role in initiating a localized inflammatory response.
The ‘b’ fragment is the active complement component which binds to the target near the site of activation (w/ exception of C2b)
During initiation of C’, what conversion is always occurring in the blood?
C3 is spontaneously being converted to C3a and C3b, which can be further cleaved to iC3b (for inhibitory)
Draw out the alternative/lectin C’ pathway in its entirety
C3 → C3a + C3b
C3b (bound to bacteria) recruits factor B.
Factor → (by C3b) → Ba + Bb
C3b + Bb → C3bBb (AKA C3 convertase)
C3bBb + C3b → C3bBbC3b (AKA C5 convertase)
C5 → (by C5 convertase) → C5a + C5b
C3bBbC3b + C5b → C3bBbC3bC5b + C5 + C6 + C7 + C8 + repeated C9 (which causes the hole)
What is properdin?
Properdin is added to complement to stabilize it since the half-life of the complement complex is incredibly short.
What is the job of the anaphylatoxins C3a, C4a, and C5a?
Which one has the most potent biologic activity?
All are soluble products that are highly inflammatory. They induce smooth muscle contraction and degranulation of mast cells/basophils causing release of inflammatory mediators histamine and vasodilators.
C5a
Phagocytes have membrane receptors for […], a product of C’, which enhances phagocytosis up to 4,000-fold
C3b
What cytokine is secreted primarily by macrophages, T cells, and mast cells?
TNF
IL-1 comes from primarily which types of cells? (5)
Macrophages, dendritic cells, endothelial cells, some epithelial cells, and mast cells
What are the principal targets of TNF and biologic effects of said targets? (6)
Endothelial cells: activation (inflammation, coagulation) Neutrophils: Activation Hypothalamus: fever Liver: synthesis of acute-phase proteins Muscle, fat: catabolism (cachexia) Many cell types: apoptosis
What are the principle cellular targets and biologic effects of IL-1? (4)
Endothelial cells: activation (inflammation, coagulation)
Hypothalamus: fever
Liver: synthesis of acute-phase proteins
T-cells: Th17 differentiation
What cytokine has a principal cellular target of leukocytes? What is the effect on this cell?
Chemokines
Increased integrin affinity, chemotaxis, and activation
What cells produce chemokines? (5)
Macrophages, dendritic cells, endothelial cells, T-cells, fibroblasts, platelets
What is the principle cell source of IL-12? (2)
Dendritic cells, macrophages
What is the principle cellular target and biologic effect of IL-12
NK and T cells: IFN-γ production, increased cytotoxic activity.
Th cells: Th1 differentiation
What cells secrete IFN-γ?
NK cells and T cells
What is the response on target cells of IFN-γ
Activation of macrophages
Stimulation of some Ab responses
Type I IFNs (α and β) principal cell source
IFN-α: Dendritic cells, macrophages
IFN-β: Fibroblasts
What is the principal cellular target and biologic effect of type I IFNs?
All cells: antiviral state, increased MHC class I expression. NK cells: activation
IL-10 principal cell source
Macrophages, dendritic cells, T cells
IL-10 principal cellular target and biologic effect
Macrophages and dendritic cells: inhibition of cytokine and chemokine production, reduced expression of costimulators and MHC class II
IL-6 principal cell source
Macrophages, endothelial cells, T cells
IL-6 principal cellular target and biologic effects
Liver: synthesis of acute-phase proteins
B-cells: proliferation of Ab-producing cells
IL-15 principle cell source
Macrophages, and others
IL-15 principal cellular targets and biologic effects
NK cells: proliferation
T cells: proliferation
IL-18 principal cell source
Macrophages
IL-18 cellular targets and effects
NK cells and T-cells: IFN-γ synthesis
TGF-β principal cell source
Many cell types
TGF-β target cell and effect
Inhibition of inflammation.
T-helper cells: differentiation of Th17, and Treg cells
What is the purpose of increasing body temperature during an infection?
Bacterial and viral replication decreased at higher temps
Ag processing is enhanced
Adaptive immunity becomes more potent
Human cells become more resistant to negative effects of TNF-α
How do type I interferons inhibit viral replication?
Degrade mRNA, and protects neighboring cells via IFN receptors. Additionally, activates NK cells.
What are the 3 functions of interferon?
- Induce resistance to viral replication in all cells
- Increase MHC class I expression and Ag presentation in all cells
- Activate NK cells to kill virally infected cells
What cytokines are considered the regulatory cytokines and cause contraction of the immune response and anti-inflammatory properties
TGF and IL-10
What cells secrete IL-10
Macrophages, dendritic cells, and Tregs
What cytokine allows for repair without regulatory immune cells in vicinity?
TGF-β
What is clinically important about C-reactive protein?
It is one of several proteins that increase rapidly due to infection, injury, inflammation, or trauma to tissue.
It functions in opsonization and complement activation
Most widely used indicator of acute inflammation
Draw out the steps involved during recruitment of leukocytes.
Seriously, do it. Don’t be a lazy fuck.
What are the three key processes involved in acute inflammatory response?
- Vasodilation
- Increased vascular permeability
- Emigration of leukocytes from blood into the damaged area.
What is the purpose of edema?
Brings plasma proteins into intimate contact with the damaged area
What 4 proteins are included in inflammatory exudate?
- Clotting proteins
- Complement
- Kinin cascade (for vasodilation and increased permeability of blood vessels along with stimulating pain receptors)
- Fibrinolytic protein (for degrading the clot when the wound has healed.
What is the result of a pathogenic overstimulation of the immune response when caused by non-infectious DAMPs?
What about if it is infectious in origin?
systemic inflammatory response syndrome (SIRS) → shock
Sepsis → Septic shock
What happens if we have a deficiency in phagocytes?
What about NK cells?
Increased susceptibility to extracellular bacteria and fungi
Increased susceptibility to viral infections, especially herpes simplex.
