Innate immunity, NKcells, Inflammation Flashcards
What are the physical barriers of the innate immune system?
Mechanical
Chemical
Microbiological
Mechanical barriers of the innate immune system
Skin Ciliary movement Peristaltic movement Washing by tears and saliva Mucous layers
Chemical barriers of the innate immune system
Sweat- fatty acids inhibit bacterial growth
Tears and saliva- lysozyme and phospholipidae inhibits growth of infectious agents
Low pH of sweat and gastric juices
Surfactants - opsonins
What are the humoral barriers of the innate immune system?
Complement system Coagulative system Latoferin and transferin Lysozyme Interferons Interleukin 1
Some molecules of the coagulateive system may act as _________________ factors, attracting other cells to the site of damage
Chemotatic
Beta -lysine is produced by __________ and has what effect against G+ bacteria during coagulation?
Platelets
Bactericidal effects
Lactoferin and transferring _______ __________ to inhibit bacteria growth
Bind iron
What role do interferons play in innate immunity
Inhibit infection and replication of viruses
Interleukin 1 plays what role in the innate immune response?
Increase temp during inflammation and induce acute phase proteins which are bactericidal
Neutrofiels are identified by expression of ______ on their cell surface
CD66
What two types of granules do neutrophils contain?
Azurophilic -defensins, proteolytic enzymes (elastase, cathespin G), lysozyme, and myeloperoxidase
Secondary granules - lysozyme, lactoferin, and NADPH oxidase components
Macrophages are identified by expression of what three surface proteins?
CD4, CD11b, or F4/80
Macrophages react to danger signals such as?
N-formal-methionine- secreted by bacteria
Peptides of coagulative system
Complement protein
Cytokines - secreted by tissue macrophages
What receptors are used for the initiation of phagocytosis?
- Fc receptors on macrophages: bind to antibody Fc region
- Complement receptors : Bind C3b complement component (which is bound to antigen)
- Scavenger receptors (SRA, CD68, Lox-1, or CD36) bind polyamines on bacterial surface
- Toll like receptors - recognize PAMP
What is the process of phagocytosis
- Chemotaxis
- Detect and bind to target object through receptors
- Endocytosis
- Enclosed in phagosome
- Fuses with lysosome to become phagolysosome
- Digestion
What are the two killing pathways of neutrophils, monocytes, and macrophages?
Oxidative - reactive oxygen species and reactive nitrogen species
Non oxidative - lysosomal toxic substances
What is referred to as the respiratory burst during phagocytosis?
Increased use of oxygen and glucose
Leads to the formation of ROS which are toxic to microorganisms
What is the process of ROS generation?
- Glucose metabolized to NADPH and Pentose
- NADPH activated by cytochrome oxidase
- NADPH uses O2 to produce superoxide anion (O2-)
- O2- reduced to H2O2 and 1O2 by superoxide dismustase
- O2- and H202 reduced to OH- and hydroxyl radical OH
What is the antimicrobial action of NO?
Bacteria bound by phagocyte through TLR
Secrete TNFa -> induce expression of inducible nitric oxide synthetase (iNOS)
L-Arginine to make L-citrulline and NO
NO is toxic to microorganisms
What are the mechanisms of non-oxidative intracellular killing?
Cationic proteins= damage cell wall
Lysozyme =damage mucopeptide in cell wall
Lactoferrin =sequester iron
Proteolytic and hydrolytic enzyme =kill bacteria
What are PAMPS and on what cells are they found?
Pathogen-associated molecular patter
-found on pathogen
Eg lipoplysaccharide, peptidogylan, lipoteichoic acids, mannan
What are DAMPs and on what cells are they found?
Damage-associated molecular patterns
From damaged host cells
What host molecules can recognized PAMPS
PRR (pattern recognition receptors)
What are the 5 classes of PRR?
- Toll-like
- NOD-like
- Rig-like
- C-type lectin
- Peptidoglycan-recognition protein
Binding of PAMP through TLR causes ?
Signals transcription and translation of proinflammatory cytokines
(MyD88 is central to signaling)
NOD-like receptors detect what kind of pathogens and cause what response?
Pathogens in cytoplasm (PAMP and DAMP)
NOD1- bacterial peptidoglycans
NOD2- muramyl dipeptides
Activates NF-kB transcription -> transcription of pro inflammatory cytokines
Activates IRF3/7 to -> Type 1 interferons
RIG like receptors detect ________ in the cytoplasm and induce production of?
Detect viral RNA
Induce IFN and inflammatory cytokines production
C type lectin receptors bind to ____________ to recognize fungal infections
Carbohydrates
Expressed on macrophages and dendritic cells
Peptidogylcan recognition receptors bond to ________ and induce production of _________
Peptidogycan Defensins (antimicrobial peptides)
What is the acute phase response?
Change in serum proteins during and infection
The proteins that change in level are called acute phase response proteins
Where are acute phase response proteins produced? And how is production induced?
Liver
Pro-inflammatory cytokines produced by phagocytes (tNFa, IL-1, IL-6)
C-reactive proteins bind to __________ to promote uptake by _________ and activate complement mediated attack
Polysaccharides/phosphorylcholine
Phagocytes
Eg. Mannose-binding lectin
Natural Killer cells are also known as?
Large granular lymphocytes
What is the role of NK cells in the innate immune response?
- Kill cells which are stressed, infected with virus or tumor cells (following cytokines activation Il2 and IFNy, they become lymphokine activated killer cell)
- Cytokines and chemokine production - IFNy, TNFa, IL7, and IL22, MIP1a, MIP1B
How do NK cells recognize abnormal cells?
Infected cells- suppressed expression of MHCI
High expression of MHC I chain related A(MICA), MICB, Rae-1, and H60
What two types of receptors are on NK cells?
Activating and inhibitory receptors
Activation of NK cells is regulated by a balance between signals from activating and inhibitory receptors
Eg high level of activating cells- > killing of target
High level of Inhibitory signals ->no killing
If MHCis is expressed on a cell and binds to an inhibitory receptor on the NKcell, will the cell live or be killed?
Live
A cell has an MHCI bound to and inhibitory receptor and an activating receptor is bound to a stress protein, does the cell live or is it killed?
Killed
A non-self MHC I molecule signals and NK cell to ?
Kills
Allogenic cells
Express and MHC molecule that doesnt agree with the inhibitory cell on the NK cell
What are the two types of NKcell inhibitory and activating signals?
Immunoglobulin like receptors (KIR)
Lectin like receptors (KLR)
What are the features of Killer immunoglobulin-like receptors
Transmembrne
Polymorphic
Expressed on NK cells and lymphocytes
Include:
Leukocyte immunoglobulin-like receptor (LILRs) - NK cell and leukocytes
NK46k - NKcells
What type of NK cell recognizes stress proteins such as MICA, MICB, ILBP, Rae1, MULT1 and H60?
Killer-lectin like receptor
NKG2D expressed on NK cells - binds to stress proteins
After activation of NK cells, how do they function to overcome infections
Lysis of infected cells (cytotoxicity mechanisms)
Activate machrophages by secretion of cytokines
What are the cytotoxicity mechanisms of NKcells?
Perforin-dependent
CD95/CD95L mechanism
CD16 killing pathway
What is the process of perforin-dependent mechanism of NKcells?
NK cell releases perforin in granules
Creates a lesion in target cell membrane AKA perforin channel
Granzymes and proteases enter cell and induce apoptosis
What is the CD95/ CD95L (Fas/FasL) mechanism of NKcells?
NKcells normally express CD95L (FasL)
Target cells increase expression of CD95
Binding induce apoptosis of target cell
What is the CD16 killing pathway of NKcells?
Recognize target cell through antibody dependent pathway with CD16
CD16 is a Fc receptor
Antibody binds to antigen, NK cell binds to antibody through Fc receptor -> cytotoxicity
How is NKcell activity regulated?
Cytokines (interleukins and interferons)
Cytokines induce NKcells to lymphocyte activated killer cells (LAK) which have increased cytotoxic activity
What are NK Tcells?
Cells with properties similar to NK and T ymphocytes
Specificity against few pathogens
Thymic origin
NKT cells express a _________that recognize glycolipid antigens on bacteria
TCR
NK1.1 (KLR family receptor)
How are NKTcells activated
IL-5
What are NK DCs? What do they express? And what is their main function?
Natural killer dendritic cells
Express NK1.1 an CD11c
Spontaneously lyse tumor cells
Present antigen to native Tcells
produce large amounts of IFNy
Link innate and adaptive immunity
What are the two types of inflammation?
Acute or chronic
____________ inflammation fights the early stages of infection and prepares the process that leas to tissue repair
Acute
_____________ inflammation is characterized by the dominating presence of macrophages in the injured tissue
Chronic
What are the causes of inflammation
Physical agents
- mechanical
- thermal
Chemical agents
-toxic gases, acids, bases
Biological agents
-bacteria, virus, parasites, fungi
Endogenous
- circulation disorder
- Metabolic products
What are the 5 signs of inflammation?
Calor (heat) Rubor (redness) Tumor (swelling) Dolor (pain) Functio laesa (loss of function)
What leads to the development of heat, redness, and swelling during inflammation
Vasodilation increasing blood in the area
Large volume of blood is responsible for redness and heat
Vascular permeability =leaking of fluids =swelling
What is responsible pain during inflammation?
Leukocyte phagocytose invading pathogens and release mediators
What are the pro-inflammatory cytokines?
TNFa, IL-1, IL-2, IL-6, and IL-8
TNFa and IL-1 induce _______ , ___________, and ___________ production
Fever; stress hormone; and synthesis of IL-6, IL-8, and interferon gamma
IL-6 stimulates the release of ________________ proteins
Acute phase (eg. C-reactive protein)
What is the function of pro-inflammatory cytokines?
Coagulation cascade, release of NO, platelet-activating factor, prostaglandins, and leukotrienes
What promotes chemotaxis, induces extravasation of granulocytes, and degranualtion of neutrophils?
IL-1, IL-6, and Il-8
What role do the complement proteins C3a and C5a play in inflammation?
Increase vascular permeability
Stimulate chemotaxis of neutrophils, eosinophils, and monocytes
What are the functions of prostaglandins?
Vasodilation, capillary permeability, pain, and fever
Low BP
Enhance effects of histamine
Promote platelet aggregation and vasoconstriction
What are leukotrienes and what are they produced by?
Eicosanoid inflammatory mediators produced in leukocytes
LTB4, LTC4, LTD4, LTE4
What leukotrienes are smooth muscle contraction
LTC4, LTD4, LTD4
What leukotriene is a chemoattractant of neutrophils
LTB4
What factor is generated from lipid in cell membranes and induces platelet aggregation?
Platelet-activating factor (PAF)
Also activates neutrophils and is a chemoattractant to eosinophils
What plasma protease increases capillary permeability
Kinin (particularly bradykinin)
What plasma protease produces fibrin peptides during the clotting process?
Clotting factors
What are the two stages of inflammation ?
Vascular response and cellular response
The vascular response has three phases, what are they?
Phase I- vasoconstriction : momentary with few vessels
Phase II- active vasodilation: dilation of arterioles and capillaries, increased blood flow, and increased cellular metabolism
Phase III- passive vasodilation : blood vessels stop reacting to nervous and humoral stimuli, increase vascular permeability
Cellular response is the movement of ________ into the area of injury?
Leukocytes
Mainly granulocytes and monocytes
What is the sequence by which leukocytes move from the blood to an area of injury during the cellular response?
Chemotaxis - leukocytes migrate to chemical signal
Rolling - leukocytes slow down and increase expression of adhesion molecules
Migration - migrate into tissue spaces
Phagocytosis -neutrophils and macrophages engulf and degrade the bacteria and cellular debris
For immune system cells to migrate into tissues they must express ________, allowing them to roll and migrate into the tissues.
CAM (cell adhesion molecules) -> adhesion to the endothelium
What are the 4 families of cell adhesion molecules?
Selectins,
Mucins
Integrins
Ig-superfamily CAM
A CAM that is a membrane glycoproteins containing lectin binding domains that bind to carbohydrates of mucins
Selectins
Most important selectins are selectin E and L
What selectin is expressed on leukocytes?
Selectin L
What selectins are expressed on eduothelium during inflammation?
Selectin P and Selectin E
What CAM is heavily glycosylated, has Ernie and threonine-rich proteins that bind to selectins?
Mucins
What CAM is a heterdimeric protein consisting of a and B chains that are covalently joined at the cell surface
Integrins
What cells express integrins with a B2 chain (Cd18)
Leukocytes
Integrins bind to ?
Ig-superfamily (CAM)
What CAM has an immunoglobulin domain and a fibronectin domain
Ig-superfamily
Ig-superfamily CAMS are expressed on __________cells
Endothelial
What are the 4 phases of leukocytes extravasation?
Rolling
Activation
Adhesion (strict adhesion)
Diapedesis (transendothelial migration)
What occurs in the rolling phase of leukocyte extravasation ?
Loose binding of leukocytes (CAM mucin) to the endothelial cells (selectin E and P)
Slows down movement
What occurs in the activation phase of leukocyte extravasion?
Increased cytokines -> increased receptor expression on leukocytes
What occurs in the adhesion phase of leukocyte extravasation?
Strict adhesion
Activation produces conformational changes in cells
Integrins on leukocytes bind firmly to the endothelium
What occurs in the diapedesis phase of leukocyte extravasation?
Leukocyte slides between two neighboring endothelial cells
Leukocytes use Homotypic binding of platelet-endothelial-cell adhesion molecule 1
What are systemic manifestations of inflammation
Acute phase response
Alterations of WBC
High fever
Sepsis and septic shock-
How is inflammation terminated
Upregulation of anti-inflammatory molecules such as IL-1 receptor antigen and soluble TNF
Apoptosis of pro-inflammatory cells
Production of which anti-inflammatory lipoxins will initiate the termination sequence for inflammation
Arachionic acid-derived lipoxin
