What are the hallmarks of Innate Immunity?
- immediate response
-similar response to repeat encounters with a microbe
-respond to invariable structures
-receptors are encoded in the germline
-does not react against the host
What is the role of the epithelial barrier?
Physical barrer, killing microbes by locally produced anti-biotic peptides, killing of microbes and infected cells by intraepithelial lymphocytes
What are the characteristics of neutrophils?
-most abundant leukocyte in the blood, 4 to 10K per microliter, first responder to bacterial and fungal infections, and they ingest and destroy pathogens
-only live for a few hours in tissue
-dead neutrophils form pus
What stimulates neutrophils?
Increaed number of band neutrophils is a sign of what?
What is Severe Congenital Neutropenia and how is it currently treated?
hereditary disorders with recurrent sever bacterial and fungal infections and sepsis.
-due to dysfunction in neutrophil generation
-marked neutropenia (low neutrophil count)
-current treatment is with G-CSF (the reason you have to stimulate neutropihl production and not just add them is because neutropihls are short lived where G-CSF will produce long acting stimulation. It is possible in another disease a patient could not respond to G-CSF so therefore that therapy would not work.
How can you determine between increaed neutrophil destruction vs. decreased production in the bone marrow.
-if you look at the bone marrow and see lots of band neutrophils then you know there is a problem with destruction and not production
What is the role of monocytes and macrophages in innate immunity?
They ingest and destroy microbes and produce cytokines to regulate other cells. Monocyte turn into macrophage when it enters the tissue. there are 500 to 1000 circulating per microliter of blood
What is the importance of PAMPs
these are structures shared by classes of microbes and are not present in normal cells. These are required for surivival and infectivity of that the pathogenic cell.
What are some examples of PAMPs
-Terminal Mannose Residues
-Unmethylated CG-rich DNA
What does TLR-2 recognize?
TLR-2 = bacterial lipoglycans; peptidoglycans
(these are on the cell surface, while others are in the endosomes)
What does TLR-4 recognize and what is interesting about it?
TLR-4 recognizes LPS both on the cell surface and within the endosomes
What does TLR-5 recognize?
What does TLR-9 recognize?
Unmethylated CpG oligonucleotides
What is the TLF signaling pathway?
Membrane receptor leads to activation of MyD88 that interacts with IRAK/TRAF6 which leads to activation of NF-KappaB. NF-kB creates is a transcript for inflammatory cytokines
What is the NLR pathway (NOD-like Receptors)?
NLRs are within the cell.
NLRP-3 (Inflammasome) activates caspase-1 by cleavage, which will then cleave Pro-IL-1beta to IL-1beta which will activate acute inflammation specifically it is the cytokine that induces fever
What are the way to activate complement?
What does complement lead to?
Complement is an enzymatic cascade, where activated proteins cleave other proteins and rapidly amplify the signal.
-early step is C3b leads to opsonization of the microbe
-late stage is C5a leads to MAC which will punch holes in the membrane and lead to cell death
What is responsible for the acute phase response? and what is the acute phase response?
The acute phase response is an increase in circulating levels of plasma proteins rapidly with infection. It is stimulated by IL-6 from the macrophages.
-IL-6 from the macrophages induces C-reactive Protein and Collectins
-CRP is a pentraxin with 5 heads that can activate complement, and help opsonization
-Collectins are soluble PRRs
-TNF alpha and IL-1 also help produce the acute phase response and IL-6 is a cytokine made in the liver
What is the function of IL-1 and what is it secreted by?
Secreted by Macrophages and activates acute inflammation especially fever
What are the functions of chemokines and what are they secreted by?
Chemokines are secreted by macrophages, DCs, endothelial cells and fibroblasts. They increase integrin affinity that will influence extravasation
What is teh role of IL-6 ?
IL-6 is synthesized in the liver and helps with acute phase proteins and B cell proliferation of antibody producing cells
What is the sequence of extravasation?
1. macrophages respond to microbe and secrete TNF, IL-1
2. These secreted cytokines will increase selectins affinity for leukocyte selectin ligand
3. rolling of leukocyte increases integrin affinity
4. Integrins of Leukocyte bind with endothelial ligand
5. leukocyte will enter the extracellular matrix
What are the signs of inflammation?
Heat, Redness (due to vasodilation)
Swelling, pain, loss of function (due to increased vascular permeability)
Pain (swelling and stimulation of pain receptors)
What is opsonization?
Marking of a pathogen for ingestion or destruction by a phagocyte
What are LADs?
Leukocyte Adhesion Deficiencies
-inherited deficiencies in integrins and selectin ligands
-defective leukocyte extravasation and recruitment
-increaed susceptibility to bacterial infections, defects in wound healing
What is the process of microbial destruction by phagocytosis?
Complement initiates MAC
-Microbe is ingested and is fused with lysosome to create phagolysosome that destorys pathogen
What is a NET?
Nuetrophil Extracellular Trap that is laid down when a neutropihl dies, it empties out all of its contents that can trap microbes
What is the structural cellular driving componenet of phagocytosis?
Actin clusters the receptors closer together
What are the important enzymes for phagocytosis?
NAPDH oxidase - creates ROS
iNOS- creates NO lysosomal proteases
What is CGD?
Chronic Granulomatous Disease
-inherited deficiency of NADPH oxidase enzyme, makes it difficult to destroy the microbe
What is the role of NK cells with microbes?
These respond to macrophages that have eaten up microbes. The macrophages secrete IL-12 which signals the NK cell to help out. The NK cell will then secrete IFNgamma which will lead to further killing and activation of the macrophage
What is the role of IFN gamma?
Secreted by NK cells to signal to macrophages to kill ingested microbes
How are viruses detected?
By TLRs called MDA5, RIG-1, MAVS, and STING.
important is that this is not just on the cell surface but within the cytosol to recognizeing DNA and RNA like sensors
What are type I interferons and what do they do?
IFN-alpha and IFN-beta they
-induce resistance to viral replication in all cells
-increase expression of ligands for receptors on NK cells
-activate NK cells to kill virus-infected cells
What type of interferon is IFN-gamma?
Type II IFN
WHAT is Recurrent HSE? What would be a therapy for it?
Herpes Simplex Encephalitis
-caused by a defect in the production or response to Type I IFNs
-defect in TLR-3 signaling are associated with increased susceptibility and recurrent HSE
Therapy would to add IFN-alpha because then you will not have to worry about the problem with TLR-3 signaling that normally would be producing IFN-alpha
What is the signal NK cells receive from macrophages?
What leads to inactivation of NK cells?
MHC class I signaling (this would be inhibitory)
What are the two ways a NK cell can kill a target cell?
By granule dependent killing
By Killing by death ligand (NK cell upregulates death ligan receptor and binding causing the cell to undergo apoptosis)
What are the two ways to stimulate a NK cell?
-lack of MHC-1 or if you upregulate the stimulatory receptor
What is one of the best known activating (stimulatory) receptors on NK cells?
NKG2D and ADCC
What is the anti-inflammatory signal?
IL-10 is the anti-inflammatory cytokine, the antagonist of IL-1
What are some mechanisms of microbial evasion?
1. resistance of phagocyte destruction (like in listeria monocyttogenes which escape the phagocytic vesicles)
2. cell walls that are resistant to complement (MAC)
3. Degradation of NKG2D ligands (like in cytomegalovirus)
How is gout an example of innate immunity gone bad?
recognition of urate crystals and inflammation mediated by inflammasome.
-treat with IL-1 antagonist like IL-10
What is SIRs and its characteristics?
Systemic Inflammatory Response Syndrome. Fever of more than 38, heart rate higher than 90 bpm, high respiratory rate, and low CO2, abnormal white blood count (high or low)
What is a cause of Septic Shock?
Septic shock is Sepsis induced hypotension caused by high levels of TNF-alpha promotes thrombus formation on the endothelium, reduced myocardial contractility, and vascular dilation and leakiness
What are dectins?
Dectin 1 and dectin 2 are dendritic cell receptors that serve as pattern recognition receptors for two life-cycle stages of fungal organisms
What are defensins?
Antimicrobial peptides that are produced by the epithelial cells of mucosal tissue
What is the role of C-reactive protein?
Opsonin; fixes complement and facilitates phagocytosis