Innate Imunity Flashcards
Under host defenses, we have innate and adaptive immunity. What 3 subsets lie under innate immunity?
Barriers (skin, cilia, pH, sebum)
Humoral (ROI, Complement, ACPs, Interferons)
Cellular (Neutrophils, basophils, eosinophils, NK, monocytes, macrophage, dendritic, mast)
Under host defenses, we have innate and adaptive immunity. What 2 subsets lie under adaptive?
Humoral (antibodies)
Cellular (B cells, helper T cells, cytotoxic T cells)
What includes the barriers in innate
Skin Mucous epithelia Ciliated epithelia Lysozyme pH Sebum Etc.
What’s included in innate humoral immunity
Bactericidal substances ROI Complement system ACPs (acute phase proteins) Transport proteins Coagulation proteins Interferons
Innately, “I, Allergic To Cats, Cant Really Breathe”
What’s included in cellular innate immunity
Blood: Neutrophils Eosinophils Basophils Monocytes NK cells
Tissue:
Macrophages
Dendritic cells
Mast cells
What’s included in humoral adaptive immunity
Antibodies
What’s included in cellular adaptive immunity
B cells
Helper T cells
Cytotoxic T cells
What is sebum made of and how does it inhibit microbe growth?
Made up of lactic and fatty acids. Reduces skin pH to 3-5, inhibiting microbe growth
Which specific organs contain IgA (plays a critical role in opsonization of organisms and blocking adherence of pathogens to epithelial surfaces)
Mucous membranes (urinary tract, vagina) Other (tears, saliva, nasal and bronchial tissues)
What are the 4 cardinal signs of inflammation
Tumor (swelling) Rubor (redness) Calor (heat) Dolor (pain) *Lasea ( loss of function)
What are the vasoactive mediators involved in inflammation?
Prostaglandins and leukotrines
Histamine
Bradykinin
Prostaglandins, Leukotrienes, and Histamine are what kind of cells
MAST CELLS
What are the 7 steps of the acute inflammatory response
- Injury, barrier break, microbe entry
- Microbes/injury activates sentinel cells (dendritic, mast, macrophages)
- Sentinel cells secrete inflammatory mediators (prostaglandin, leukotrienes, histamine, bradykinin)
- There is increased vascular permeability; fluid and proteins enter the tissues
- Complement, antibodies, and anti-microbial proteins kill microbes
- Adhesion molecules and chemokines cause leukocyte migration into tissue
- Phagocytosis and killing of microbes
Why do we get pain w/ inflammation?
The inflammatory mediations (bradykinin, prostaglandin, histamine, leukotrienes) stimulate the nerves, causing pain
Is fever caused directly by pathogens?
No. Bacterial constituents trigger the production of cytokines TNK, IL-1, IL-6 in macrophages which are potent inducers of the fever response controlled by the hypothalamus.
what kind of receptors are helpful in the innate immune system differentiating between self and non-self
PAMPs (pathogen-associated molecular patterns)
*PAMPs are often required for survival of pathogens so that PAMPs cannot be altered, suppressed, or hidden from the pathogen surface
What are the 8 exampled of PAMPs
- Porins
- Lipoproteins
- Lipopolysaccharides
- Lipoteichoic acid
- Teichoic acid
- Mannoproteins
- Beta-glycan
- Lipoarabinomannan
“Manny Beto Teich care of L4 Po”
What is a PRR?
Pattern Recognition Receptor
what does the PRR mannose receptor recognize?
Mannose PRR recognizes glycan w/ a terminal glycose/ This is important because mannose-tailed glycans are essential surface molecules of bacteria, fungi, and viruses. There are NO mannose-tailed glycans in humans.
which receptors are encoded in the germ-line and therefor have limited diversity?
Toll-like Receptor (TLR)
N-formyl methionyl receptor
Mannose receptor
How are receptors distributed? Non-clonal or clonal?
Non-clonal. This means that all cells have receptors with identical specificities. This is different than clonal because the B and T cells will have antigen-specific receptors.
How do TLRs work?
After recognizing the PAMPs on a microbe, the TLR begins a series of chemical rxns that allows signals to enter the INNATE IMMUNE CELL and allow it to function in the killing of the microbe.
Which TLRs recognize extracellular pathogens?
TLR 1,2,4,5,6 ( EXtra is up to SIX…minus the 3!)
Which TLRs recognize intracellular pathogens?
TLR 3,7,8,9 (3 skip 3, 7, 8, nINe)
Which signals are produced by NF-KB transcription factor
Various cytokines, adhesion molecules, and costimulators. Leading to acute inflammation and stimulation of the adaptive immune system.
What does the transcription factor IRF (interferon regulatory factors) produce?
Antiviral cytokines IFN alpha/beta called type 1 interferons leading to the antiviral state
What are the steps of TLR signaling
- TLR engagement by bacterial or viral molecules
- Recruitment of adaptor proteins carried out by Tol-IL-1 Receptor signaling domain
- Activation of transcription factors (NF-KB and IRFs)
- Increased expression of cytokines, adhesion molecules, costimulators from NF-KB and IFN alpha, beta from IRF)
- Acute inflammation, adaptive stimulation, antiviral state
What is MyD88
myeloid differentiation primary response gene 88. MyD88 is an adaptor protein.
Bacteria use TLR1/2, TLR2/6, TLR4, and TLR5 which stimulate MyD88 which activates the transcription factor NF-KB
What is the most important transcription factor (TF) for inflammation?
NF-KB (nuclear factor kappa B)
Interleukin-1 Receptor Associated Kinase (IRAK) is activated by ____
MyD88. MyD88 activates IRAK after the TLR interacts with LPS, viruses, or gram neg bacteria.
What 2 actions can be carried out by TRAF, an adaptor protein (TNF receptor-associated Factor 6)
It can 1. Inactivate IKB or 2. Induce MAPK kinases.
What does the inactivation of IKB or the induction of MAPK kinases lead to?
The translocation of NF-KB and the activation of genes in the nucleus.
What are some responses of the immunomodulatory genes activated by NF-KB?
Influence adaptive response by harnessing T-cells for cell-mediated immunity
Direct antimicrobial response (bacterial death)
Tissue injury (apoptosis of host cells, septic shock)
What is the presentation of patients with MyD88 and IRAK-4 deficiency?
Susceptibility to infection with either bacteria or viruses.
Inflammasomes containing NLRs (nod like receptors) are activated by ____
PAMPs activate these cytoplasmic complexes
What do NLRs do?
They act as scaffolding proteins that assemble signaling platforms that triggers activation of NF-KB and mitogen-activated protein kinase (MAPK) pathways
What do inflammasomes activate and what do these things do?
THey activate protein caspase-1. Protein caspase-1 processes the inactive cytoplasmic precursor forms into secreted forms of IL-beta and IL-18.
What do secreted forms of IL-1beta and IL-18 (produced in the inflammasome) do?
They act as potent inflammatory cytokines which drive inflammation
What is used to treat gout patients?
Anti-IL-1 therapy. IL-1beta is a regulatory key PROinflammatory in gout because it causes the neutrophil influx into the synovial and joint fluid.
What are DAMPs
DAMPs are endogenous danger molecules released from damaged or dying cells. DAMPs induce non-infectious inflammation by activating the innate immune system by interacting with PRRs (pattern recognition receptors)
What are DAMPs recognized by?
They are recognized by macrophages via TLRs
What are some PRRs
TLR
NLR
C-type lectin
etc.
Why is necrosis a dirty type of cell death?
It is characterized by the swelling and rupture of cell membrane which causes inflammation.
Nucleus: HMGB1, Histones, U1snRNP, DNA/RNA
Mitochondria: ATP, DNA
Cytosol: Urate, S100 Proteins, HSPs, RNA
Does apoptosis cause inflammation?
No, the apoptotic bodies containing DAMPs are removed by macrophages.
What does HMGB-1 signal?
Activates NF-KB via TLR3/4 signaling
What doe urate signal?
Activates NK-KB via NLRP3
What do heat shock proteins activate?
Activate NF-KB via TLR2/4.
What do all DAMPs stimulate the production and release of?
TNF-alpha and IL-1
How are DAMPs related to autoimmune diseases?
DAMPs instigate innate immune pathways that promote adaptive autoimmune responses against self-Ags which manifests as severe clinical sx.
Ex. MS, DMi, Lupus, RA
Which ligands are recognized by the TLR1/2 heterodimer
Lipopeptides and GPI
What are mast cell activators? There are 8
IgE +Ag PAMPs Cytokines Chemokines C3a & C5a complement Temperature Pressure Cell-cell contact
What do cytokines mediate?
Inflammation, immunity, hematopoiesis
Are cytokines a part of humoral or cell-mediated immunity?
Humoral. Participate in endocrine, paracrine, and autocrine signaling.
What do chemokines help with?
Chemokines are small protein chemoattractants important for trafficking immune cells.
Chemokine=chemotaxis
Which cytokines are anti-inflammatories
IL-10
TGF-beta
What is the principal cell source for inflammatory cytokines?
Macrophages
which cytokine activates NK cells?
IL-12. IL-12 acts on NK and T cell, which goes to IFN-gamma to activate macrophages (slide 51)
What are the 5 components on the complement system/
MAC C3b, C3bi C3a, C4a, C5a C3b C4d
What does the MAC (complement system) do?
Lysis of foreign bacteria and cells
What do C3b and C3bi do? (complement system)
Opsonization and bacterial phagocytosis
What do C3a, C4a, and C5a (complement system) do?
Chemotactic anaphylaxtoin and vasodilation (inflammation)
What does C3b do? (complement system)
Solubilization and clearance of immunocomplexes
What does C3d do? (complement system)
Enhancement of immune response
When neutrophils are coming into the tissue, the endothelial cells must be activated. What are they activated by?
Proinflammatory cytokines TNF-alpha and IL-1 produced by active mast cells and tissue-resident macrophages activate endothelial cells, which go on to increase surface expression of P selectin and E selectin adhesion molecules.
What is the location of Leukocyte function-associated Antigen 1 (LFA-1) and Very Late Antigen 4 (VLA-4) (how neutrophils come into tissue)
They are integrins expressed on neutrophils and monocytes in a low-affinity state
What does a chemokine receptor do to LFA-1 and VLA-4 (how neutrophils come into tissue)
Chemokine receptors signal to activate LFA-1 and VLA-4 to increase affinity and bind selectively to intracellular adhesion molecule (ICAM-1) and Vascular Cell Adhesion Molecule (VCAM-1) on activated endothelial cells.
