Innate Immunity Flashcards
Components of the Mechanical First Line of Defense
Epithelial cells joined by tight junctions
Movement of mucus by cilia
Air flow, fluid flow
Tears, Nasal Cilia
Components of the Chemical First Line of Defense
Fatty acids, lactic acid (sweat, sebum)
Acidic pH, enzymes
Pulmonary surfactant proteins A and D
Tear enzymes, Saliva
Defensins!
Components of the Microbiological First Line of Defense
Purpose?
Normal Microbiota
Prevent bad bacteria from taking root
Overview of Innate Immunity.
What happens when you get a paper cut?
Mast cells initiate the response. They get degranulated with the cut since they are in the tissue. Histamine is released. Start to get macrophages that recognize what is coming through the breach by things that are binding to Toll-like receptors.
What happens when TLRs are ligated? Activation of Macrophages, Induction of inflammasomes, Cytokine production, Increased reactive O2 species, NO prod.
Macrophage starts secreting cytokines IL-1, IL-6, and TNF, along with chemokine IL-8. IL-6 initiates the big pro inflammatory response. The cytokines and chemokine will tell the cells in circulation to come to site of infection.
Neutrophils are circulating in the blood. They have ligands to adhesion molecules on the endothelium. Those adhesion molecules (selectins) are in an inactive form until activated by cyto/chemokines. IL-1 and TNF increase expression and activation of selectins on endothelium within 1-2 hrs. Ns start binding and rolling down endothelium. Chemokines have bound to proteoglycans. The chemokine receptor on neutrophil will bind to the chemokine. This binding will change the intern receptor form low affinity to high affinity state for its ligand.
Now neutrophil is firmly bound. TNF has made the endothelium leaky. The integrin adhesion molecule on the neutrophil is LFA1 (late-functioning Ag) and it binds to ICAM. The cytoskeleton will flatten and the neutrophil will travel b/w the endothelium into periphery.
Next wave = macrophages (24 hrs). Coming from response to different chemokines. Also using different integrin (VLA4) binding to VCAM. They have chemokine receptor 2, which is binding to CCL2 (chemokine)
What is Macrophage function in innate immunity?
Phagocytosis
Cytokine production
Inflammation
Wound healing
What is Macrophage (MO) function in adaptive immunity?
Ag presentation
Regulatory cytokines
Effector cell (can be enhanced by Th cytokines)
Characteristics of Activated MOs
Increase phagocytic activity
Increased ability to activate Th cells
Higher levels of Class 2 MHC/HLA on cell surface
What happens during phagocytosis?
Phagocyte membrane isolates microbe and is ingested into a phagosome.
Phagosome fuses with lysosome to become a phagolysosome
There the microbe is digested with the help of ROS, NO, and enzymes.
Describe Chediak-Higashi Syndrome
Autosomal recessive (LYST gene)
Microtubule defect inhibiting fusion
Decreased phagocytic activity - less phagosomes
Recurrent pyogenic infection, albinism
Function of NK cells in Adaptive Immunity
Principle mediator of ADCC (antibody dependent cellular cytotoxicity)
Activating receptor IgG Fc
How do NK cells destroy infected cells?
FAS ligand on cell surface binds “death” receptor on target cell
Perforin proteins deliver “suicide” enzyme, granzyme B, into target cell
APOPTOSIS
How do NK cells know not to target healthy cells?
Healthy cells express HLA/MHC Class 1 ligand which is an inhibitory ligand. If it is not present, NK cell can’t bind to it and will kill the infected cell.
What are PAMPs?
Pathogen-associated molecular patterns
These are structures shared by various classes of microbes that are essential for survival and infectivity but are not present on self.
What are DAMPs?
Damage-associated molecular patterns
There are molecules released by stressed cells undergoing necrosis that act as endogenous danger signals to promote and exacerbate the inflammatory response.
AKA Alarmins
Causes: Non-Infectious, cell damage, radiation, surgery, burns, UV light
What are PRRs and what binds to them?
Pattern Recognition Receptors.
PAMP ligands bind to PRRs to induce intracellular signaling in phagocytes leading to ACTIVATION
What are Toll-Like Receptors?
Specific receptors for different microbial products
What does TLR4 recognize?
LPS (part of gram negative bacterial wall)
Also LPS is a Co-receptor for CD14 (Macrophages)
What does TLR2 recognize?
Bacterial peptidoglycan (part of gram positive bacteria)
What do TLR3, 7, 8, 9 recognize?
Located in Endosomes, into which microbes are ingested
Respond only to nucleic acids
What are the responses to PRR binding?
Phagocytosis
Production and secretion of cytokines
Increased cytoskeleton changes
Increased ROS
What is an Inflammasome?
Signaling system for detection of pathogens and stressors Assembly of: NLR3P (sensor) ASC (adaptor) Caspase-1 (inactive enzyme)
What does the Inflammasome increase expression of?
How does it do this?
IL-1 and IL-18 - Both potent inflammatory cytokines
Signals (from TLR?) already activated the production of pro-IL1 (zymogen). The active caspase will cleave the zymogen and the active IL-1 is secreted.
What are complements?
Serum proteins that are produced by LIVER
They are NOT Ag-specific
Most of the time, part of innate (classical pathway is part of humoral)
Functions of Complements
Stimulate inflammation (chemotactic anaphylatoxins - C3a, C4a, C5a, etc.)
Facilitate Ag phagocytosis (C3b - opsonization)
Cell Lysis (MAC - Membrane Attack Complex)
Describe the Alternative Complement Pathway.
Protects form pathogens in absence of Ab
Initiations: C3 –> C3a + C3b
Identifies and binds to non-self membrane
How are Self cells unhurt from Alternative pathway?
C3b is inactivated by sialic acid, which self membrane have high levels of
On non-self, low levels lead to longer activated C3b, enough for phagocytosis by macrophage
Describe the Lectin Binding Pathway.
Mannan Binding Lectin binds to Mannose on the bacterial cell wall
What are anaphylatoxins?
They are the “a” fragments of the C components (C3a, C4a, C5a, etc)
Highly inflammatory - C5a most potent
Induce smooth muscle contraction and degranulation of mast cells/basophils
What is Opsonization?
Another way to recognize and respond to pathogens
Phagocytes have membrane receptors for IgG (adaptive) and C3b (complement) - enhance phagocytosis
What are the 3 Acute phase Cytokines?
TNF (tumor necrosis factor)
IL-1, IL-6
Name the Cytokines involved in Innate Immunity other than the 3 acute ones.
Chemokines (IL-8)
IL-12, IL-10, IL-15, IL-18
IFN-y, Type 1 IFNs
TGF-B
Describe Type 1 Cytokine Receptor Family
Part of the hematopoietic receptor family
Majority of the Cytokines
Describe Type 2 Cytokine Receptor Family
For all interferons + IL-10, 20, 22
Describe TNF Cytokine Receptor Family
For all TNFs
Can induce adaptors that lead to activation of Caspase-8, apoptotic
FAS
Describe G-protein Cytokine Receptors
For mainly chemokines
Can cause cell to undergo cytoskeletal changes
IL-1 vs. Hypotalamus
IL-1 is a pyrogen
It works on the hypothalamus to increase body temperature.
This decreases viral and bacterial replication, increases Ag processing, & facilitates adaptive immune response
IL-6 vs. Liver
IL-6 is the main cytokine that works in the liver to induce synthesis of acute-phase proteins (MBL, fibrinogen, C-reactive protein) that are required for the activation of complement.
TNF-a vs. Dendritic cells
TNF stimulates the migrate of DCs to lymph nodes - initiation of adaptive immune response
Why is a fever helpful?
Bacteria like body temperature and their viability decreases at higher temperatures.
Ag precessing is enhanced
Adaptive immunity becomes more potent
Human cells become more resistant to negative effects of TNF when temp increases
What are some of the systemic pathological effects that acute phase cytokines create?
Heart = TNF can vasodilate you to the point of low output
Vessels = TNF can cause clots (thrombus)
TNF can lead to insulin resistance in tissues
Describe Type 1 IFNs
IFN-a and B, inhibit viral replication
IFN-a produced by leukocytes, IFN-B produced by fibroblasts
They degrade mRNA leading to inhibition of protein synthesis
What are the function of IFNs?
Induce resistance to viral replication in all cells
Increase MHC class 1 expression and Ag presentation in all cells
Activate NK cells to kill virus-infected cells
What the the regulatory cytokines?
TGF-B and IL-10 - anti inflammatories
TFG-B secreted by many cells - allows for repair without regulatory immune cells
IL-10 secreted by Macrophages, dendritic cells, and Tregs
What is the C-reactive protein?
It is an acute phase protein activated by IL-6
Increases due to infection, injury, inflammation, or trauma to tissue
Function in C’ activation and opsonization
Widely used indicator of acute inflammation - used clinically to follow disease progression and treatment
What are the 3 key processes of the acute inflammatory processes?
- Vasodilation
- Increased vascular permeability
- Emigration of leukocytes form blood to damaged area
What are the proteins in the inflammatory exudate?
Clotting proteins
Complement
Kinin cascade - vasodilation, increase permeability of blood vessels, stimulate pain receptors
Fibrinolytic protein - degrades clot when wound has healed
What happens at the end of the immune response?
Type 2 Macrophages clean up cell debris
Clearance of injurious stimuli, mediator, and acute inflammation
PRR: scavenger receptors
Specialized cytokines (IL-10, TGF-B)
What are SIRS?
Systemic Inflammatory Response Syndrome
This is pathogenic OVER stimulation of the immune response
Non-infections (DAMPS) leads to shock
Infectious = Sepsis –> septic shock
What do the cytokine profiles look like during SIRS?
IL-1, IL-6, and TNF involved
Stimulate liver to overproduce acute phase proteins
Anaphylatoxin C5a storms that confuse immune system
Name some deficiencies in the cells of innate immunity.
Phagocytes are susceptible to extracellular bacteria and fungi
NK cells are susceptible to viral infections (ex: Herpes)
How does Pneumococci evade the immune system?
Capsular polysaccharides - Resistance to phagocytosis
How does Staphylococci evade the immune system?
Production of catalase - resistance to ROS in phagocyte
How does Nisseria and Streptococci evade the immune system respectively?
Both - Resistance to C’ activation (alternative pathway)
Sialic acid expression inhibits C3 and C5 convertases
M protein blocks binding of C3 and C3b
How does Pseudomonas evade the immune system?
Synthesis of modified LPS that resists action of peptide hormones
Anti-viral Innate immune response is mediate by?
Type 1 IFNs that block viral replication and NK cells which kill virus-infected host cells
What are the 2 signals of lymphocyte activation?
Signal 1 - recognition of antigen
Signal 2 - response to microbes by substances produced during innate immune response
Signal 3 may be provided by cytokines
