TLR (toll-like receptor)
- 1. induce transcription factors.
- 2. Where found:
- A. Found on cell membranes.
- B. Found free floating in the cytoplasm. (NLR’s)
- C. Found in endosome (organelle that processes and delivers molecules from cell surface to lysosome or vacuole)
- 3. Structure: Dimer
- 4. Reaction involved
- A. dimer activates a kinase.
- B. this leads to a series of phosphorylation reactions. A phosphate is passed back and forth activating these proteins!
- C. Finally P passed to IKK, inhibitor kappa kinase.
- D. IKK-P now attaches to NFKB
- E. NFKB originally too large to pass thru cell membrane. now IKk degrades one part of nfkb, and the remaining can pass thru cell membrane
- F. NFKb passes thru cell membrane to nucleus of macrophage.
- G. activates transcription of 5 proteins.
- 1. will bind to receptor.
- 2. Function:
- A. induces blood vessel opening.
- B. activates NK cells to produce interferon gamma.
- 1. classification: chemokine (a chemoattractant cytokine)
- 2. makes neutrophils follow chemical gradient to site of infected tissue (neutrophils orig. in blood)
- 3. Produced by: macrophage
- 4. attracts nk cells and neutrophils to tissue.
- 5. also slows neutrophil down to go thru diepidesis.
- 1. Functions:
- A. increases oxide production, which kills bacteria
- B. open blood vessels to allow other immunce cells in (neutrophils)
- C. promotes MAC to produce hydrolytic enzymes and TNF-α
- 1. Function: process that cytokines take to become activated and initiate a transcription factor
- 2. Cytokine to cyt. factor , activates kinase, then activates a transcription factor, which activates genes
- 3. structure: jak = kinase, stat = transcription factor
- 4. used by ALL cytokines.
- 1. family of 11 proteins; IL-1
- 2. Caused by:
- A. IL-1B -->
- B. IL1 production by MAC
- C. ion channels activated to lower K+ levels.
- D. ionic change activates protein formation of inflammasome, IL-1B
- 3. overall: MAC supercharged to produce and release large quantities of this IL-1B
- 4. Elevated levels of IL-1B creates inflammation
- 5. NLRP3 produced by this process
- 1. Functions:
- A. secretes: IL-12, TNF-alpha, IL-6, CXCL8, and IL-1B cytokines
- B. phagocytic. engulfs pathogens
- C. resident cell. first to respond.
- D. in lymph tissue, engulfs debris brought up by dendritic cells and other pathogens to avoid blood contamination from lympphs direct blood connection
- 2. dividing roles into two types:
- A. "M1 killers":
- i. activated by TNF-alpha
- ii. secrete IL-12
- B. M2 repair
- i. anti-imflammatory cytokines
- ii. (IL-4, TGF-B, IL-10)
- iii. has different transcripts than M1
- ** same cell just different phenotype***
- 1. alpha and beta
- A. f(x):
- i. interfere with viral replication by degrading viral DNA
- ii. IFN-a and beta act in paracrine fashion and attach to a nk cell receptor, they are activated and become drawn to infected tissue
- iii. increase expression of ligands for receptors on NK cells
- iV. increase proliferation and differentiation of nk cells if their receptors attach to ifn-a or b. **can be a problem such as ebola, nk cells takes out of epithelial cells, patient now leaks blood.**
- B. Beta: works in autocrine and paracrine fashion.
- C. these interferons are present in regular cells.
- D. jak-stat pathways initiate transcription factors that directly inhibit viral replication
- E: how they are produced:i. Through NK cells TLR3 and TLR7 for ds and ss viral RNA,
- ii. in regular cells' cytoplasm thru RIG-I-like receptors (RLRs)F. autocrine and paracrine relationship.
Autocrine: promotes MIC, what NK cells recognize.
- Paracrine. Decrease receptors, decrease viruses getting in.
- decrease metabolites , or virus food, production
- 2. gamma (on another card)
RIG -I like factors
- 1. F(x) :
- A. if viral RNA in cytoplasm of infected cell, RIG-I-like receptors (RLRs) detect them
- 2. Process:
- A. birus recognized by RLR. RLR acts as a helicase.
- B. binds to mitochondria protein MAVS
- C. produces IRF3 that goes into nucleus
- D. leads to transcription of IFNB
- E. this process also requires NFKB and AP-1
Role: bring in and activate NK cells. Also _____
Natural Killer Cells
- 1. F(X):destroy viral and tumor cells
- A. make intimate contact with patient cell and destroys it
- C. Secretes: IFN-Gamma for MAC longevity
- 2. activated by:
- A. IFN alpha and beta to proliferate and differentiate --> cytotoxic NK cell
- B. IL-12 from MAC--> effector NK cell (that continues communicates with mac and participate in inflammation)
- C. IL-15 from MAC --> ? NK cell
- 3. Chemical structures it produces: (to distinguish what is healthy and what it not)
- A. MIC: activating healthy cell has low of this.
- i. works by attaching to a cell signaling to NK cell that this infected cell needs to die. Nk cell releases cytotoxins/granules
- B. MHC: inhibitory. healthy cell has a normal level. unhealthy cell has low level.
- C. FasL: protein.
- i. attaches to FADD receptor of target cell
- D. perforin: prod. holes on target cell. leads to apoptosis.
- E. Granlysin, granzyme B (cytotoxins) leads to apoptosis.
- F. IFN-Gamma. makes MAC better.
- G produce ifn-a and beta (as well as activated by them)
- 4. interacts w/ dendritic c.
- A. Dc < nk, NK cells suppress dc f(x)
- B. dc > nk, body senses not enough protection. activates adaptive system.
- 1. 50-70% of all leukocytes
- 2. recruited by CXCL8
- 3. Activated by PAMPs , DAMPs, and cytokines.
- 3. Has 3 granules:
- A. primary-azurophilic: lysozyme, defensins, cathepsins.
- B. secondary:lysozyme, NADPH oxidase.:
- i. What gets ball rolling in ROS production.
- C. tertiary. gelatinase. activates proteins to sequester more Fe
- 3. PMN's : polymorphic nucleus
- 4.Major job : is to make gap in the “tight junctions” of blood vessel wall. This specific step is diepidesis.
- other jobs:when in inflamed tissue,
- B. releases granules
- C. phagocytic: a lot faster than MACs!
- D. produces NETs
- E. associates with NK cells. Nk cells then produce IL-18 which triggers IFN-γ production.
- F. recruits monocytes so they can differentiate into MAC
- 5. When neut. dies.,
- Has two fates:
- A.pus. (dead neutrophils)
- B.NET – necessary for degradation of mold.
- Releases DNA of chromatin.
- F. Granules: work with phagolysosome to make neutrophil more powerful.
- (produced by secondary granules of neutrophil)
- A. produce super radicals -> H2O2-> consume H ions
- B. increases pH which triggers synthesis of anit-microbial peptides.
- 1. phrase used to describe a neutrophil bursting instead of dying peacefully
- 2. "short increase in oxygen consumption"
- 3. enzymes activated to quell burst
- when contents release before apoptosis and before lysozome fuses.
- toxic granules and ROS leak out of cell
- cause of a lot of inflammatory diseases.
- 1. Role:
- A. "get rid of it"
- i. Smooth muscle contraction
- ii. fluid release
- iii. Granules have histamine in them. If this release did not work, they repopulate their granules with a little more toxic substance.
- iv. if antigen leaves GI ->blood, connective tissues mast cells
- B. also eosinophils and basophils will come into help
- 2. where: in all cells EXCEPT CNS and retina. considered the "the last resident cell". most common in airway.
- 3. Target: helminths and protozoa
- 4. Hypersensitivity: When a receptor binds to its molecular compound and immediately dumps histamines.
- 5. CONS:
- A.If mast cells get into lower airway, into bronchi, can lead to asthmatic symptoms.
- B. if cytokines and chemokines(especially these) recruit neutrophils, bad bc they arent trained to attack parasites.
- 6. Activation: has all the other receptors we have talked about (TLR, g protein, etc.)
- 7.**major source of inflammation**
- 1.Types: Two basic populations on these. Based mostly on stimulation from dif. Proteins
- 2. IL-4. Important in shift of immunoglobulin. Produced by basophil. *(Test 2 material)
- 3. Depending on which cytokine its activated by, depends on its pathology. Very much a hypothesis right now.
- 1.Hyper –eosinophil, when parasite is winning in host.
- 2.They actually depict how severe RSV is.
- 3. Extremely potent after granules
- Eosinophil comes along worm and it dumps its granules.
- A. First product is MBP, major product, a cytotoxin
- B. Has a variety of cytokines, chemokines, and cationic proteins.
- 1. ROLE: produces C3 convertase, which produces opsonin. also produces C5 convertase which makes membrane attack complex
- A. one of the first innate responses
- 2. what it is: proteases and > 30 proteins
- 3. Where: In epithelial, blood, lymph, and extracellular fluids
- 4. Made by: liver
- 5. Pathways:
- A. alternative pathway: first pathway taken
- B. classical pathway
- C. Mannose-lectin binding pathway
- 6. ALL:
- A. produce opsonin C3b (other pathways with C4bC2a prefer to use C3 bc it is more prevalent)
- B. all lead to membrane attack complex
- C. all lead to C3 convertase formation
- Def: gen. name for complement proteins and antibodies that coat pathogens and encourage phagocytosis by neutrophils or macrophages
- Structure: C3b
- 1. first pathway for complement activation
- A. activated thru spontaneous hydrolysis. iC3. (active form)
- 2. Reaction steps:
- B.Hydrolysis of C3
- C.Factor B
- D.Then factor D
- E.B splits and leave iC3Bb
- F.Another C3 attaches
- G.A. B factor leaves and C3b attaches to site of pathogen
- Or loops as C3 convertase and C3Bb attaches to pathogen to create a shortcut to produce C3b, called alternative C3 convertase (C3bBb)
The whole point of the complement…. Destruction of pathogen!
1.C3b surrounds and attaches to pathogen
2.CR1 binds to C3b on bacterium
3.Endocytosis of bacterium by macrophage
4.Engulfed pathogen is phagosome
- 5.Lysosome and phagosome join together to obliterate pathogen.
- *done by MAC!*
Membrane Attack Complex
- 1. Purpose: to drill holes into lipid bilayer membrane of bacterium.
- 2. Molecular steps:
- a. Alternative C5 convertase. : 2*C3b + Bb
- b. (2*C3b + Bb) + C5 -> C5b + C5a…. C5b initiates formation of MEMBRANE ATTACK COMPLEX.
- 3. C5 recruits innate cells
- 1. What is it: an acute inflammatory response in tissues due to C3a and C5a (c3a and C5a are receptors)
- 2. What they do:
- A.induce mast cells and basophils to release their granules.
- B. This releases histamine
- C. Act on blood vessels to increase vascular permeability so other cells can go to crime scene
Alternative C3 convertase: short cut version that produces a higher amount of C3b, opsonin. C3bBb
Classical C3 convertase: different molecules but same function. C4bC2a
- 1. Mannose binding lectin (MBL): a protein that binds to mannose containing carbs.
- A. a large surface area protein that allows for multiple binding sites
- 2. when binds to mannose of pathogen, initiates MBL binding pathway
- 3. Serves as opsonin that facilitates the uptake of bacteria by monocytes in the blood.
order of immune system
- Innate system: early, relatively non-specific, non-changing
- Adaptive system:
antiparasitic innate cells
- 1. mast cell
- 2. eosinophil
- 3. basophil
- 1. major family of human antimicrobial peptides
- 2. A. by destroying membranes of cells
- B. have positive charge to them (cells usually have negative charge)
- C. excreted at mucosal surfaces
- D. produced by skin, respiratory tract, urogenital tract, and neutrophils. in granules of neutrophils
- e. activated by neutrophils
- A. More specific for bacteria, form holes in bacteria cell membranes
- B. Neutrophils activate this
specialized one in salivary glands for pathogenic fungi.peptide not proten
- Degrade cell walls and some fungal cells
- found in tears
Stomach, pH 2
Vagina , pH 4.5
bacteria, gram - and positive
If has peptidoglycan wall, can be broken down by lysosome
1. destroys outer membrane first
pathogen will encounter two wbc
- 1. macrophage: the recruiter
- 2. dendritic cells: themessenger
- Dendritic cell
- B cell. Presents antigen to activate itself
a protein that acts on a cell
There are pro and non-inflammatory cytokines.
Tumor necrosis factor-alpha
acute phase proteins
- 1. early responding proteins
- 2. ROLE: designed to help resident cells remove pathogen more efficiently
- 2. Activate bone marrow, get more produced
- 3. Examples: MBL, C-reactive protein, surfactant proteins SP-A (protect lungs), complement
- 1. sebaceous glands (hari follicles)
- 2. contains fatty and lactic acids
- 3. inhibit bacterial growth on the skin surface
- 1. cytokines
- 2. dilation of blood capillaries (skin warm and red)
- B. chnage adhesive propertiesof epithelium
- 3. introduces gaps in endothelium
- 4. increases plasma leakage intotissue: (swelling or edema) due to leakage
- 5. pressure on nerve endings (pain)
- 1. ROLE: A. impede invasion and colonization of microbes
- 2. coagulation system: cascade of plasma enzymes. blood clots
- a. immobilize microbes
- b. platelets: release substance to aid antimicrobial defense
- c. protease inhibitors: many pathogens use protease.
Primary lymphoid organs
- 1. where lymphocytes develop and mature
- 2. these include
- A. bone marrow
- a. where b and t cells originate
- b. where b cells mature
- B. Thymus (muscle on heart)
- a. where T cells mature
two resident cells
- 1. macro: starts inflammatory response.
- 2. Dendritic: pick up bacteria through phagocytosis. takes draining lymph to nearest lymphoid tissue (2ndary lymph tissue)
- various parts:
- 1. b cells reside in lymphoid follicle.
- a. b cells replicate in germinal center.
secondary lymphoid site
- where B & T cells are activated
- Who: lymph nodes, adenoids, tonsils, isolated lymphoid follicles?
- A. isolated l. f. are in tissues, trachea, GI tract (peyer's patches)
- B. appendix
- C. spleen: involved in filtering blood. if you have a blood infection, will go to spleen
- 1.if you have blood infection, blood will go to spleen. filters the blood
- A. removes damaged red blood cells
- 2. if lymph nodes failed to drain tissue of microorganisms, spleen assists
- Two parts:
- 1. white pulp: b and t cell area
- 2. red pulp
Common lymphoid progenitor
- A. B cells: plasma cell
- B. NK/ T cell precursor
- i. Nk cell
- ii. T cell
Common myeloid progenitor
- branch of wbc
- 1. unknown precursor
- A. mast cells
- B. dendritic cells
- C. macrophage
- 2. Common granulocyte precursor
- A. neutrophils
- B. eosinophils
- C. basophils
common erythroid megakaryocyte
- 1. megakaryocyte
- a. platelets
- 2. erythroblast
- a. erythrocyte
common granulocytes precursor
- from myeloid progenitor
- have: Polymorphonuclear
- leukocytes (PMN) (the happy face nucleus ex/)
- granules in cytoplasm
- Cell surface receptor for
- pathogens =
- • Become plasma cells when
- • Secrete soluble Ig called
- – Bind to pathogens or toxic
- Cell surface receptor for
- pathogens = T cell receptors
- • Subdivided into 2 groups:
- 1. Cytotoxic (CTL)
- – Intracellular viruses or
- – Tumor-bearing cells
- 2. Helper
- – Activate effector cells
- – Secrete cytokines