Section 3: Innate Immunity (Recognition and Response) Flashcards
defensins
are antimicrobial peptides that contribute to the innate immune response
-there are two classes alpha and beta
-their molecular structure allows them to penetrate microbial membranes and disrupt their integrity
-the set of defensins made by a person is highly variable in the population
a-defensins
expressed by neutrophils and Paneth cells
b-defensins
expressed by a broad range of epithelial cells
pathogen associated molecular pattern (PAMP)
pathogenic microorganisms have fundamental, structural, and biochemical differences that set them apart from eukaryotic cells
-set of conserved motifs that exist on bacterial cell walls or part of viral replication (ex: double-stranded RNA)
-macrophages express a variety of receptors that recognize these differences
-many of the ligands for these receptors are carbohydrates and lipids of microorganisms
receptor mediated endocytosis
the binding of macrophage receptors to their microbial ligands initiates engulfment
endosome/phagosome
pathogen internalized into a membrane bound vesicle
phagolysosomes
the phagosomes fuse with cellular organisms called lysosomes to form these and result in the destruction of the pathogen
Innate-surface receptors
-initiate receptor mediated endocytosis
-transduce signals to the nucleus causing gene activation and the release of cytokines
Toll-like receptor (TLR)
-example of an innate-surface receptor
-are expressed by a variety of cells and recognize numerous PAMPS
-not all located on the surface some are in vesicles
-activation of TLR during these initial stages of infection is not only important to the innate immune response but also provides the conditions necessary for the adaptive immune response
TLR4
-specifically binds to lipopolysaccharide (LPS), a key component of the gram negative cell wall
-upon binding LPS sends signals into the cell nucleus activating genes to release inflammatory cytokines
What are some inflammatory cytokines
-in sensing a pathogen by innate immune receptors resident macrophages are stimulated to secrete a variety of cytokines depending on the signal transduced
-can determine immune response
1. IL-1 (interleukin)
2. IL-6
3. CXCL8 (chemokine ligand 8)
4. IL-12
5. Tumor necrosis factor-a (TNF-a)
What are some antiviral type I interferons?
- IFN-a
- IFN-b
IL-6 systemic effects**
- fever
- induces acute phase protein production by hepatocytes
TNF-a local effects (tumor-necrosis factor)**
-activates vascular endothelium and increases vascular permeability, which leads to the increased entry of complement and cells to tissue and increase fluid drainage to lymph nodes
-best way of knocking down inflammation used in a lot of medicine
-main thing responsible for inducing shock when you get septic infection
TNF-a systemic effects**
-fever
-mobilization of metabolites
-shock
IL-1B local effects
-activates vascular endothelium, activates lymphocytes, local tissue destruction, increase access of effector cells
IL-1B systemic effects
-fever
-production of IL-6
CXCL8 local effects
-chemotactic factor , recruits neutrophils and basophils to site of infection
IL-12 local effects
activates NK cells
Tumor necrosis factor alpha (TNF-a)
-released by macrophages in response to TLR activation/stimulation
-helps to limit local infections but if the infection spreads leading to sepsis, TNF-a can have bad results
acute phase response
further systemic effect of IL-6, IL-1, and TNF-a changing the spectrum of plasma proteins secreted by the liver (acute phase proteins)
-MBL
-CRP
- fibrinogen (helps with clotting)
* proteins made in response to the cytokines
leukocyte extravasation
inflammatory cytokines mobilize populations of circulating neutrophils to the site of infection (homing)
-occurring initially from inflammation and neutrophils are big player that move across in that manner
Neutrophils
-a specialized phagocytic cell that use innate immune receptors top phagocytose invading pathogens
-they use a battery of degradative enzymes to destroy pathogens that are contained in internal granule
-depend on enzyme NADPH oxidase which is crucial to the production of several toxic oxygen species
(respiratory burst)
-big primary innate responders
-cells can be induced to change into other cells like monocytes –> dendritic cell (there is plasticity) `
chronic granulomatous disease
people who posses defective mutations in the NADPH oxidase gene have a severe disease state
neutrophil innate receptors
-neutrophils express receptors for many bacterial and fungal constitutes
-they bind bacteria, engulf them, and destroy them with toxic contents of the neutrophil granules
-they have all these receptors that help them phagocytose or endocytosis
macrophage innate receptor
-the macrophage expresses several receptors specific for bacterial constituents
-bacteria bind to macrophage receptors
-engulf and digest bound bacteria
Neutrophil and respiratory burst
- bacteria is phagocytosed by neutrophil
- phagosome fuses with azurophilic and specific granules
- pH of phagosome rises , antimicrobial response is activated and bacterium is killed
- pH of phagosome decreases, fusion with lysosome allows acid hydrolases to degrade the bacterium completely
- neutrophil dies by apoptosis and is phagocytosed by macrophage
Type I interferons
are proteins that are produced when a cell is infected by a virus (intracellular pathogen)
-interferon- a (INF-a)
- interferon- b (INF-b)
-these proteins immediately start to interfere with viral replication and signal other cells to the viral replication
-stimulate NK cells which are innate immune cells specialized in killing virus-infected cells
interferon-producing cells (IPCs)
are specialized cells that produce large amounts of IFNs
-eventually, these cells differentiate and mature into plasmacytoid dendritic cells
-important to the initial innate immune response
What is the interferon response?
- induce resistance to viral replication in all cells
- increased expression of ligands for receptors on NK cells
- activate NK cells to kill virus-infected cells (provide early response)
- IFN-a, b, TNF-a, and IL-12 activate and trigger proliferation of NK cells
-the NK cell response bides time until the adaptive T cell response can clear the infection
- has an autocrine and paracrine response
-tells the neighbors I’m infected you should shut down but also produce more interferons to make a zone of warning
toll-like receptors: signaling
-TLR4 can send signals two ways either through the TRIF-TRAM pathway or MYD88-IRAK4 pathway
-NFkB can lead to the secretion and synthesis of TNF-a and other inflammatory cytokines (MYD88-IRAK4 pathway)
-IRF3 can lead to the synthesis and secretion of type I interferons: IFN-a and IFN-b (for viral and anti-viral)
IL-1/IL-6/TNF-a response in liver
-acute phase proteins (CRP, MBL)
-activation of complement
-oposination
IL-1/IL-6/TNF-a response in bone marrow endothelium
-neutrophil mobilization
-phagocytosis
IL-1/IL-6/TNF-a response in hypothalamus
-increased body temperature
-decreased viral and bacterial replication
IL-1/IL-6/TNF-a response in fat. muscle
-protein and energy mobilization to generate an increased body temperature
-decreased viral and bacterial replication
primary granules
-primary (azurophilic)- pre-formed waiting around
secondary granules
-secondary (specific)- need to be induced, more potent
enzymatic reactions involving superoxide and hydrogen peroxide
NADPH + 2 O2 –NADPH oxidase–>NADPH + 2 O2- + H+
2 H+ +2 O2—superoxide dimutase–> H2O2 + O2
2 H2O2 –catalase–> 2 H2O + O2
Natural killer cells are
-main innate response to viral infection
-involved in modulating some innate immune response (ex: T-regulatory cells)
-provide early response to virus infection
-NK cell goes around and bops on cells and pick who to bind to determine healthy cells from not
-when it goes on an infected cell the ligands are expressed by that cell and the NK cell sends a signal
