Into To Innate Immuno Flashcards
(33 cards)
Define Innate Immunity
Protection against infections before infections begin, are capable of rapid responses to microbes, and react in essentially the same way to repeat infections
Characteristics of Innate Immunity
Responds rapidly to the presence of microorganisms or foreign Ag (inactive without infection, in EVERY vascularized tissue
Not Ag specific, limited diversity (recognizes structures shared by many microbes)
No immunologic memory
Stimulates the adaptive immune system
Benefits of innate and adaptive immunity
chart
If you are lacking innate immunity only in only a short time the number of microorganisms is out of control
If you are lacking adaptive immunity only the duration of the infection lasts a little longer until the number of microorganisms is too large
Perfect balance is having both to bring the number of microorganisms down again
Components of Innate Immunity
Barrier (skin, secretions)
Cytokines
Adhesion molecules, 3=SIS
Selections, integrins, superfamily Ig
Phagocytes= PMN
Macrophages
(Antigen-presenting cells, APC)
First Line of Defense
Mechanical- skin, gut, lungs, and eyes/nose/oral cavity
Chemical- skin, etc.
Fatty acids, lactic acid (seat and sebum), Destructive enzymes (lysozyme and phospholipase)(tears saliva, nasal secretion), acidic pH (stomach, skin, vagina), Sufactant proteins A and D (lung), Defensins (lung, GI tract, skin)
Microbiological- etc.
Granulocytes
Eosinophils- 1-3% of WBC
Basophils- <1% WBC
Mast Cells- tissue residents
All release pharmacological mediators responsible for combating multicellular parasites (histamines)
Play a major role in atopic diseases (histamines)
Neutrophils
Professional Killers
Summoned from bloodstream (about 30 min) by Il-1, TNF-a, IL-8
Endothelial cells near site of infection begin expressing selection proteins (adhesion molecules) that help capture the neutrophils attention
When die they form pus (pyogenic)
*think kamikaze pilots with these guys
Macrophages
Monocytes circulate, macrophages in the tissues
Prolonged defense
2 major functions:
M1- classical macrophages induced by innate immunity play a role in inflammation
M2- alternative macrophages induced by IL-4 and IL-13 and play a role in tissue repair and control of inflammation “shut it down”
Macrophages function
Phagocytosis
Cytokines production Inflammation
Wound healing
Antigen presentation
Regulatory cytokines
Effector cell
- Mo activity can be enhanced by Th cytokines
- activated Mo more efficient at elongating pathogens than resting Mo
- activated Mo have
A. Increased phagocytic activity, increased ability to activate Th cells, higher levels of Class II MHC/HLA on the cell surface
As it phagocytizes it fuses with lysosome, becomes phagolysosome and uses reactive oxygen and nitric oxide- degradation is what it’s all about
Clinical Blue Box
Chediak-Higashi Syndrome
AR
Partial oculocutaenous albinism
Recurrent pyogenic infections
Presence of giant granules in leukocytes
Dendritic Cells
Profession Ag presenting cell (APC) (along with B cell and macrophage)
Constitutively express high levels of Class II HLA and CD80, why they are professional
After capturing Ag in the tissues, migrate into blood or lymph and circulate to various lymphoid organs where they present Ag to T cells
APCs- BRIDGE between innate and adaptive immunity
NK cells
Part of Innate immunity
Large granulated circulation lymphocytes CD16+ CD56+
Effector mechanisms similar to cytotoxic T cells- cell killing and seceretion of cytokines (performing and granzymes induce apoptosis)
Secrete IFN-y (activates macrophages)
Activated by Il-12 (secreted by macrophages), IL-15, Type I IFNs
Adaptive immunity- principle mediator of ADCC: activating receptor IgG Fc
NK Destruction of Infected Cells
Destroy bacteria, artistes, fungi, tumor cells, and virus infected cells
Force cells to commit suicide- perforin proteins that deliver granzymes B into target cell, Fas ligand expressed on their cell surface (binds “death receptor” on target cell to induce apoptosis)
Macrophage and NK cell support
Reciprocal cytokine activation
Activated macrophages produce and secrete IL-12 which activate NK cells which produce IFN-y which activate macrophages to become better killers
Why do NK cells not target healthy cells?
NK must interpret “kill” on surface of the cell when their inhibitory receptor is not engaged by the MHC class I inhibitory ligand
Recognition of Microbes: pattern recognition receptors (PRR)
PAMPS- molecules/structures tat are shared by various classes of microbes, but not present on self (LBS, mannose, dsRNA, etc)
DAMPS- molecules released by stressed cells undergoing necrosis that act as endogenous danger signal
Binding of PAMP Logan’s to PRRs induce IC signaling in the phagocytes leading to their ACTIVATION
TLR and Inflammasome
TLR1, 2 and 6- Bacterial lipopetides
TLR2- bacterial peptidoglycan
TLR4- LPS
TLR5- bacterial flagellin
TLR3,7,8,9- endogenous Ag
CD14 and TLR4- macrophages
Binding of ligand to TLRs- phagocytosis production and secretion of cytokines, increased ROS, (superoxide and nitric oxide) and increased cytoskeletal changes
TLR- increased cytokine expression
—> inflammasome leads to the assembly of a sensor (NLRP-3) and adaptor and the inactive caspase into the inflammasome. THe inflammasome activates the caspase which in turn results in the expression of IL-1 and 18 (potent inflammatory cytokines)
DAMPS
Non-infections, cell damage/necrosis that is caused by radiation, surgery, burns, UV light, etc. Leads to HMGB1 (high mobility box 1- RAGE) and HSP (heat shock protein)
Complement and Opsonization
Serum proteins created by hepatocytes
NOT Ag specific- innate immunity (more immediate)
AB activates classical pathway
Stimulates inflammation, facilitates Ag phagocytosis and can lyse some cells directly
Under tight regulation
Component activated by cleavage into peptide fragments- smaller fragments being “a” and larger being “b”
“B” activates complement component, binds to the target near the site of activation (except C2b)
“A” anaphylatoxins, diffuses from the site (except C2a), plays a role in initiating a localized inflammatory response
Alternative pathway
Protects from pathogens in absence of Ab- slower, less efficient
Initiates through spontaneous conversion of C3 to C3b (and a), identity and bind to non-self membranes
Sialic acid on self membranes rapidly inactivates bound C3b
Alternative/Lectin C’ pathway
Alternate- spontaneous lysis of C3, if binds to bacteria, initiate pathway
Lectin- mannose binding Lectin
Anaphylatoxins: C3a, C4a, and C5a are soluble products that are highly inflammatory
Induce smooth muscle contraction and degranulation of mast cells/basophils causing release the inflammatory mediators histamine and vasodialators which increase capillary permeability
C5a has the most potent biologic activity
Opsonization- phagocytes have membrane receptors for IgG (adaptive) and C3b- makes more “tasty” —> enhances phagocytosis
Cytokines of Innate Immunity
TNF- comes from macrophages, T cells, and mast cells. Targets endothelial cell activation, neutrophil activation, fever from hypothalamus, liver- synthesis of acute phase proteins, catabolism of muscle and fat, apoptosis for many cells
IL-1- comes from macrophages, DC, endothelial cells, some epithelial cells, mast cells. Targets endothelial cells, hypothalamus, liver, and T cells- Th17 differentiation
Chemokines- comes from macrophages, DC, endothelial cells, T lymphocytes, fibroblasts, platelets. Target leukocytes- increased integrity affinity, chemotaxis activation
IL-12- comes DC, macrophages. Targets NK cells and T cells, IFN-y production, increased cytotoxic activity, T cells-Th1 differentiation
IFN-y- comes from NK cells, T lymphocytes. Targets Activation of macrophages and simulation of some Ab responses
Type I IFNs (a and b)- comes from IFN-a: DC, macrophages; IFN-b: fibroblasts. Targets all cells, antiviral state increases class I MHC expression, NK cell activation
IL-10- comes from macrophages, DC, T cells. Targets macrophages, DC, INB of cytokine and chemokines production, reduced expression of costimulators and class II MHC molecules
IL-6- comes from macrophages, endothelial cells, T cells. Targets liver (acute phase proteins) and B cells- proliferation of Ab producing cells
IL-15- Macrophages, others. Targets NK cells and T cells to proliferate
IL-18- macrophages, targets NK and T cells- IFNy synthesis
TGF-b- many cells, targets INB of inflammation, T cells- differentiation of Th17, regulatory T cells
Cytokine Receptor families
Type 1- hematopoietic receptor family (majority of cytokines)
Type 2- all IFN plus IL-10, 20 and 22
TNF receptor family- TNF: can induce adaptors that lead to activation of caspase-8 (apoptotic)
Fas
G protein- mainly chemokines
Endogenous pyrogens
Why fever?
IL-1, IL-6, and TNF-a work on liver, BM endothelium, hypothalamus, fat, muscle, DC
Decreases Ag processing, decreased bacterial and viral replication
Human cells become more resistant to negative effects of TNF-a
Innate antiviral state and functions of IFN
Type I interferons
Interferons a and b, directly inhibit viral replication
IFN-a- produced by leukocytes
IFN-b- produced by fibroblasts
Degrade mRNA- INB of protein synthesis
Produced by vial infected cell/protects neighboring cells via IFN receptors
Functions
Induce resistance to viral replication in all cells
Increases MHC class I expression and Ag presentation in all cells-?
Activate NK cells to kill virus infected cells-?
TGF and IL-10
Regulatory cytokines (and regulatory T cells)
Anti-inflammatory properties
TGF-b secreted by may types of cells. Allows for repair Sioux regulatory immune cells in vicinity
IL-10 secreted by macrophages, DC, and Tregs
