Lecture 2: Intro To Innate Immunity Flashcards
The mechanical barriers involved in innate immunity include epithelial cells joined by _______ ________, along with the longitudinal flow of air or fluid, movement of mucus by ___________, as well as tears and nasal cilia.
Tight junctions; cilia
What chemical barrier defenses exist in the skin?
Fatty acids
Beta-defensins
Lamellar bodies
Cathelicidin
What chemical barriers exist in the gut?
Low pH (pepsin)
Alpha-defensins (cryptidins)
RegIII (lecticidin)
Cathelicidin
What chemical defenses exist in the lungs?
Alpha-defensins
Cathelicidin
Pulmonary surfactant
What chemical defenses exist in the eyes/nose/oral cavity?
Enzymes in tears and saliva = lysozyme
Histatins, beta-defensins
What is the microbiological barrier associated with the first line of defense against pathogens?
Normal microbiota
___________ is a peptide that comes from neutrophils, mast cells, epithelia (skin, lung, GI, GU, oral), sweat, and seminal fluid that has antimicrobial and chemotactic action
Cathelicidin
____________ are peptides that come from neutrophils and have antimicrobial action
Alpha-defensins
__________ are peptides that come from neutrophils and epithelia (skin, oral, mammary, lung, urinary, eccrine, occular), and participate in antimicrobial, chemotactic and histamine release
Beta-defensins
Fatty acids and lactic acid are chemical barriers to infection that are primarily found in what bodily fluids?
Sweat
Sebum
Destructive enzymes like lysozyme and phospholipase are primarily found in what bodily secretions?
Tears
Saliva
Nasal secretions
Where does an acidic pH play a role as a chemical barrier to infection?
Stomach
Skin
Vagina
The lungs secrete surfactant proteins ___ and ___ as chemical barriers to infection
A
D
Defensins are found in what 3 major areas?
Lungs
GI tract
Skin
What are the 3 types of granulocytes?
Eosinophils
Basophils
Mast cells (tissue residents)
The main role of granulocytes in general is in _______ disease
Atopic
Natural killer cells express which 2 CD molecules?
CD16
CD56
NK cells provide innate immunity against __________ infections like viruses and cancer
Intracellular
What cell type is also known as polymorphonuclear cells and makes up 54-62% of white blood cells?
Neutrophils
Neutrophils are released from _______ ________ into the blood and migrate 7-10 hours then home to the tissue where they have a ______ day lifespan
Bone marrow
3
In response to an infection, neutrophils will be released from bone marrow in greater numbers in a process called ___________ ___________
Neutrophil leukocytosis
True or false: Neutrophils are the FIRST to the site of the infection, and are HIGHLY phagocytic
True
Neutrophils are a large component of pus/abscesses, meaning they are ___________
They express ______ and ______ CD markers
Pyogenic
CD15
CD16b
Neutrophils serve one purpose: professional killers. They are summoned from the bloodstream by what 3 cytokines?
IL-1
TNF-a
IL-8
Once neutrophils have been recruited by IL-1, TNF-a, and IL-8, endothelial cells near the site of infection begin expressing __________ proteins (adhesion molecules) that help capture the neutrophils attention
Selectin
_________ is the cell surface marker of macrophages, which recognizes and binds ________
CD14 (TLR4)
LPS
__________ respond to sites of inflammation in 1-2 days, but survive longer than neutrophils. Levels may be inreased in chronic inflammation, various immune-mediated diseases, stress response, and necrosis
Monocytes/macrophages
What are the 3 primary functions of monocytes/macrophages?
Garbage collecters (resting) APCs (activated/primed) Vicious killers (hyperactivated)
True or false: M1 macrophages have anti-inflammatory effects and participate in wound repair and fibrosis
False, this is a description of M2 (alternative) macrophages
M2 macrophages are induced by _____ and ______
IL-4
IL-13
Macrophage activity can be enhanced by ___ cytokines
T Helper cell
Activated macrophages have:
Increased phagocytic activity.
Increased ability to activate _____ cells.
Higher levels of _______on the cell surface
T helper
Class II MHC
What type of cell constitutively expresses high levels of class II HLA/MHC and CD80?
Dendritic cells
What makes dendritic cells an important bridge between innate and adaptive immunity?
They are professional APCs
What makes dendritic cells better APCs than macrophages and B cells?
Their constitutive expression of class II MHC and CD80
__________ are molecules/structures that are shared by various classes of microbes but are not present on self
PAMPs (pathogen associated molecular patterns)
__________ are molecules released by stressed cells undergoing necrosis that act as endogenous danger signals to promote and exacerbate the inflammatory response
DAMPs (damage associated molecular patterns)
Binding of PAMP ligands to _______ induces intracellular signaling in the phagocytes leading to their ___________
PRRs
Activation
The largest family of PRRs are the __________, which have receptors with specificities for different microbial products, respond to both exogenous and endogenous antigens, and are present on macrophages, dendritic cells, and neutrophils
TLRs
Is the following TLR intracellular or extracellular and what type of PAMP does it recognize:
TLR-8
Intracellular
ssRNA
Is the following TLR intracellular or extracellular and what type of PAMP does it recognize:
TLR-2
Extracellular
Peptidoglycan
Is the following TLR intracellular or extracellular and what type of PAMP does it recognize:
TLR-1:TLR-2
Extracellular
Bacterial Lipopeptides
Is the following TLR intracellular or extracellular and what type of PAMP does it recognize:
TLR-3
Intracellular
dsRNA
Is the following TLR intracellular or extracellular and what type of PAMP does it recognize:
TLR-2:TLR-6
Extracellular
Bacterial Lipopeptides
Is the following TLR intracellular or extracellular and what type of PAMP does it recognize:
TLR-4
Extracellular
LPS
Is the following TLR intracellular or extracellular and what type of PAMP does it recognize:
TLR-5
Extracellular
Bacterial flagellin
Is the following TLR intracellular or extracellular and what type of PAMP does it recognize:
TLR-7
Intracellular
ssRNA
Is the following TLR intracellular or extracellular and what type of PAMP does it recognize:
TLR-9
Intracellular
TLR-9
Binding of ligand to a TLR results in phagocytosis, production and secretion of _____________, increased ________, and increased cytoskeletal changes
Cytokines
ROS
______________ is another way to recognize and respond to pathogens. Phagocytes have membrane receptors for IgG and C3b which facilitate the enhancement of phagocytosis up to 4000-fold
Opsonization
What are the 2 primary intracellular killing mechanisms?
Oxygen-independent killing
Oxygen-dependent killing
What is the oxygen-independent killing mechanism?
Lysozyme, defensins, lactoferrin, and hydrolytic enzymes contained in the lysosome
What 2 enzymes does the oxygen-dependent killing mechanism depend on?
NADPH oxidase
Myeloperoxidase
Chediak-Higashi syndrome results from microtubule defect affecting phagosome-lysosome fusion.
Genetically, it is _____________ ____________.
It is characterized by partial oculocutaneous ____________, recurrent _____________ infections, and the presence of giant _________ in leukocytes.
Autosomal recessive
Albinism
Pyogenic
Granules
Chronic granulomatous disease results from an inherited deficiency in __________ _____________, leading to decreased production of reactive oxygen species.
Clinically, it results in chronic, recurrent infections with ____________-______________ microorganisms like Staphylococcus, Klebsiella, Serratia, and Aspergillus.
Chronic inflammatory symptoms like gingivitis, enlarged lymph nodes, and tumor-like ___________ masses.
NADPH oxidase
Catalase-positive
Granuloma
What neonatal finding may be indicative of chronic granulomatous disease?
Omphalatis (failed or delayed separation of the umbilical cord)
If chronic granulomatous disease results from a deficiency in NADPH oxidase, why is immunity only affected in terms of catalase-positive organisms?
The patient still has adequate myeloperoxidase, which is able to continue killing most bacteria.
However, catalase-positive organisms can neutralize H2O2 species that your body is trying to utilize to kill them, and thus survive in the phagosome.
What are the 3 principle cell sources of tumor necrosis factor (TNF)?
Macrophages
T cells
Mast cells
What effect does TNF have on the following:
Endothelial cells
Neutrophils
Hypothalamus
Endothelial cells: activation (inflammation, coagulation)
Neutrophils: Activation
Hypothalamus: fever
What effect does TNF have on the following:
Liver
Muscle
Many cell types
Liver: synthesis of APPs
Muscle: fat catabolism (cachexia)
Many cell types: apoptosis
What 5 cell types secrete IL-1?
Macrophages Dendritic cells Endothelial cells Epithelial cells Mast cells
What effect does IL-1 have on the following:
Endothelial cells
Hypothalamus
Liver
T cells
Endothelial cells: activation (inflammation, coagulation)
Hypothalamus: fever
Liver: synthesis of APPs
T cells: Th17 differentiation
What 6 cell types secrete chemokines?
Macrophages Dendritic cells Endothelial cells T lymphocytes Fibroblasts Platelets
What effect do chemokines have on leukocytes?
Increased integrin affinity, chemotaxis, activation
What 2 cell types secrete IL-12?
Dendritic cells
Macrophages
What effect does IL-12 have on the following cell types:
NK cells and T cells
T cells
NK cells and T cells: IFN-y production, increased cytotoxic activity
T cells: Th1 differentiation
What 2 cell types secrete IFN-y?
NK cells
T cells
What effect does IFN-y have on its cellular targets?
Activation of macrophages
Stimulation of some antibody responses
What are the 2 principle cell sources for IFN-alpha?
Dendritic cells
Macrophages
What is the principle cell source for IFN-beta?
Fibroblasts
What effects do IFN-alpha and IFN-beta have on the following:
All cells
NK cells
All cells: antiviral state = increased class I MHC expression
NK cells: activation
What are the 3 cell sources of IL-10?
Macrophages
Dendritic cells
T cells
What effect does IL-10 have on macrophages and dendritic cells?
Inhibition of cytokine and chemokine production, reduced expression of costimulators and class II MHC molecules
What are the 3 principle cell sources of IL-6?
Macrophages
Endothelial cells
T cells
What effect does IL-6 have on the following:
Liver
B cells
Liver: synthesis of APPs
B cells: proliferation of antibody-producing cells
What is the principle cell source of IL-15?
Macrophages
What effect does IL-15 have on the following:
NK cells
T cells
NK cells: proliferation
T cells: proliferation
What is the principle cell source of IL-18?
Macrophages
What effect does IL-18 have on NK cells and T cells?
IFN-y synthesis
TGF beta is secreted by many cell types. What is its generalized effect and what effect does it have on T cells?
Inhibition of inflammation
T cells: differentiation of Th17, regulatory T cells
What cytokines are responsible for directly inhibiting viral replication?
Type I interferons (alpha and beta)
How do type I interferons go about inhibiting viral replication?
They degrade viral mRNA which nonspecifically shuts down cellular protein synthesis
What other role do type I interferons play in the protection of the cells surrounding an infected cell?
IFNs produced by virally infected cell protect neighboring cells via IFN receptors
Natural Killer cells express _______ and ______, and provide innate immunity against intracellular infections (especially viral) and cancer
CD16; CD56
NK cells have effector mechanisms similar to cytotoxic T cells in that they perform cell killing and secretion of cytokines.
They also secrete __________ and _________ which induce apoptosis in the target cell
Perforin
Granzymes
What 3 cytokines serve to activate NK cells?
IL-12 (from macrophages)
IL-15
Type I IFNs
What cytokine do NK cells secrete that is responsible for activating macrophages?
IFN-y
NK cells destroy bacteria, parasites, fungi, tumor cells, and virus-infected cells by forcing them into apoptosis.
This is done by first secreting _________ proteins that deliver “suicide” enzyme _____________ into the target cell.
_____ ligand expressed on their cell surface binds death receptor on target cell to induce apoptosis
Perforin; granzyme B
Fas
How do macrophages and NK cells work together to fight infection?
Macrophages that have phagocytosed microbes find NK cells and secrete IL-12 to activate them
Those NK cells then secrete IFN-y to further activate macrophages
Why don’t NK cells target healthy cells?
They have an inhibitory receptor that binds to MHC class I (an indicator of healthy cells)
Viruses inhibit class I MHC expression, so the NK cell inhibitory receptor is not engaged and thus the infected cell will be killed.
What would be the general result in a phagocyte deficiency?
Increased susceptibility to extracellular bacteria and fungi
What would be the general result of an NK cell deficiency?
Increased susceptibility to viral infections, especially Herpes Simplex
What type of deficiency would lead to widespread pyogenic bacterial infections?
Leukocyte adhesion deficiency
What disease leads to intracellular and extracellular infections as well as large collections of cells that cannot be cleared?
Chronic Granulomatous Disease
What deficiency results in defective respiratory burst and chronic infections?
G6PD deficiency
What deficiency leads to defective intracellular killing and chronic infections?
Myeloperoxidase deficiency
What syndrome results in intracellular and extracellular infections as well as granulomas, other than CGD?
Chediak-Higashi syndrome
