Term
| Distinguish between the major receptor types of the innate and adaptive immune systems. |
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Definition
Innate- Pattern-recognition receptors (PRRs)
Adaptive- TCRs and BCRs |
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Term
| What are the 4 steps involved in neutrophils recruitment to sites of inflammation? |
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Definition
Remember, Neutrophils release ROS, RNS and antimicrobial peptides!
1) Rolling (selectins)
2) Activation (selectins)
3) Adhesion (ICAM)
4) Diapedesis (PECAM) |
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Term
What is the major function of Natural Killer Cells (NKCs) in innate immunological responsiveness.
How does this function differ from Dendritic Cells (DCs)? |
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Definition
1) NKCs look for lymphocytes (but not antigen-specific) and poke holes in cells that lack MHC or that are either virally infected or tumorous.
NKCs target viruses and cancer because these conditions turn off MHC, which alerts the NK cells and causes them to release granules into the holes that they poke.
2) DCs are resident win most tissues, whether they phagocytically capture antigens and bring to to T-cells in lymph nodes. |
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Term
| The innate immune system recognizes and attacks a variety of danger signals using "pattern recognition." Explain 6 types of pattern recognition and the molecules that each targets. |
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Definition
1) TLRs recognize, LPS, LOS, DNA and viral RNA
2) NFkB is activated by TLRs and induces inflammatory gene expression
3) NOD receptors collaborate with TLRs to induce IL-1 secretion
4) Non-TLR sensors of viruses (RNA helicases)
5) Interferons mediate anti-viral responses and responses to "other" cells.
6) C-type lectins recognize fungal and bacterial carbohydrates. |
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Term
| What is the "acute phase" response , where does it occur and what are the major players? |
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Definition
Acute Phase response occurs when localized responses are enhanced.
IL-1, IL-6 and TNF-a acts
-Mainly on the LIVER to induce the expression of anti-microbial proteins (defensins), complement, fibrinogen, C-reactive proteins, ect)
-On the BONE MARROW to increase WBCs
-On the BRAIN to increase prostaglandins and fever |
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Term
| Provide 3 examples of how the innate immune system alerts the adaptive immune system that something is wrong. |
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Definition
1) TLRs release cytokines that up-regulate "co-stimulatory" molecules, which are necessary to activate T-cells.
2) Phagocytosed organisms are presented by Macrophages and DCs to T-cells.
3) Cytokines released from Macrophages and DCs induce expression of adhesion molecules on vascular endothelium, which recruit lymphocytes to infected tissue. |
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Term
| What is the major cytokine that is up-regulated during viral infections? |
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Definition
| Interferon (direct and indirect antiviral properties). |
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Term
| Explain how neutrophil activation can link the primary and adaptive immune responses. |
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Definition
| Antibodies can "mark" microbes, which enhancing neutrophil-mediated phagocytosis of microbes. |
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Term
| Explain how TLRs can induce an Acute Phase inflammatory response. |
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Definition
1) LPS (TLR4), LOS, CpG DNA and viral RNA can all bind TLRs
2) TLR activation kicks phosphorylated IkB off of NFKB (P50/RelA), which then travels to the nucleus and acts as a t-factor
3) IL-1, IL-6 and TNF-a transcription is up-regulated (remember, IL-1 also requires NLR/caspase-1 mediated cleavage to be released).
4) Acute-phase reactants act on the Liver (C-reactive protein, complement, fibrinogen), the Brain (prostaglandins and ACTH) and the Bone Marrow (increase WBC and CSF production) |
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Term
| Why might you give antibody against TLR4 to patients with Sepsis? |
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Definition
| Sepsis is a form of SIRS associated with bacterial infection. You could prevent inflammation by prevents TLR4 interactions with LPS on gram (-) bacteria |
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Term
| Explain why you need both TLR and NOD-like receptors (NLRs) to activate IL-1. |
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Definition
1) TLR acts through NFKB to up-regulate pro-IL-1b transcription
2) NLR activates caspase 1 which cleaves and activates pro-IL-1b into IL-1b. |
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Term
| Explain how non-TLR sensors of virus (i.e. RNA helicases) fight viral infections. |
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Definition
1) RNA helicases activate NFKB, leading to an increase in Interferon (IFN) transcription.
2) Interferon-y induces macrophages and the JAK/STAT pathway, which degrades poly mRNA and inhibits viral RNA translation |
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Term
| What do C-type lectin receptors (CLRs) recognize and how do they act? |
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Definition
Fungal and bacterial carbohydrates in walls.
CLRs act through NFKB to increase inflammation and act on the adaptive immune system. |
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Term
| Explain the meaning of "pleiotropy," "synergism," "antagonism," "redundancy," and "cascade," in the context of cytokines. |
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Definition
Pleiotropy- many different targets
Synergism- some cytokines work together to maximize a response
Antagonism- IL-10 inhibits the action of pro-inflammatory cytokines
Redundancy- Some cytokines achieve the same response
Cascade- think about IL-12/TNF-y signaling with macrophages and T-cells. |
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Term
True or False:
Cytokine responses are 1) Transient, 2) local, 3) involve unstable RNAs, 4) can never be stored and 5) act through autocrine, paracrine and endocrine (least likely) pathways. |
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Definition
False
All are true except 4. Sometimes cytokines are stored. |
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Term
| Explain the importance of TNF and the results of medium and high amounts of TNF in the blood and tissues |
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Definition
TNF-a is an acute phase reactant that is important in inflammation against bacteria, PMN recruitment, cytokine/chemokine production and apoptosis
Medium amounts of TNF lead to fever and high WBC counts from the brain and bone marrow, respectively
High amounts can cause shock by acting on the heart, vessels and liver. |
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Term
| Why is IL-1 called a "leaderless" cytokine and how is it activated? |
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Definition
1) No secretory signal
2) TLRs induce NFKB through MyD88 adapter
NFKB transcribes the "pro-form" of IL-1b
NLRs induce caspase-1 to cleave and activate into "active form."
** IL-18 and IL-33 work similarly ** |
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Term
| How does IL-6 activate inflammation in an acute-phase response. |
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Definition
JACK/STAT NOT NFkB!
TNF-a and IL-1 = NFkB
IL-6 and RNA-helicase= JACK/STAT
1) IL-6 is a major regulator of the acute phase response and it is pleiotropic (B/T/macrophages/vascular endothelium). It binds to a receptor
2) IL-6-binding brings JAKs closer together and causes CROSS-PHOSPHORYLATION of tyrosine residues on adjacent receptors.
3) Now 1000X more active, Phosphorylated receptor recruits SH2-contaiing STAT proteins
4) STAT proteins get phosphorylated and then dimerize
5) STAT dimers act as transcription factors to up-regulate cytokine-response gene transcription. |
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Term
What are 2 ways that drugs can influence cytokine signaling?
What viruses utilize these mechanisms? |
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Definition
1) Cytokine/Receptor interaction (TNF-a, IL-1 and IL-6)
2) Neutralize cytokine by providing a soluble receptor
3) Vaccinia (pox) has soluble IL-1B receptor
EBV has IL-10 homolog
CMB has chemokine receptor homologs |
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