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Block 1 Week 5 > Inflammation 1 > Flashcards

Inflammation 1 Flashcards

1
Q

why do we need homeostasis? what happens when abnormal response?

A
  • we have high cell turnover even in tissues that have continuity through life
  • homeostasis retires normal tissue relationships and function after injury

-get scaring/altered function when have pathogen tissue response

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2
Q

two types of inflammation?

A
  • acute: quick and intensive
  • chronic: slow and smoldering
  • there is overlap between them
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3
Q

how tell difference between acute & chronic inflammation?

A
  • how signals are acquired for inflamm response
  • kinetics/ time course of resolution
  • histological features
  • diff active responders
  • diff effector cells
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4
Q

what are the two triggers for innate immunity?

A

1) exogenous stimuli (infection/toxins/anything that can cause cell damage)
2) endogenous stimuli (release of cell debris & chem mediators from tissue injury)

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5
Q

what comprises the innate immune system?

A
  • nearly every cell in the body
  • have intrinsic (innate) sensors for exogenous and endogenous triggers
  • the sensors+ trigger pathways= innate immune system
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6
Q

what is innate immunity? where present?

A
  • genome encoded defensive responses to infections & other injurious agents
  • has no memory/recall response
  • ancient system present in all animals & pants
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7
Q

Innate immunity & PAMPs?

A

-can be triggered by recognition of PAMPs, so are also called Patter Recognition Receptors

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8
Q

PAMPs?

A
  • molecular entities that are characteristic of pathogens but not present or released by normal self tissue
  • are signals/red flags for infection but do not do the actual damage
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9
Q

Magnitude of innate immune response?

A
  • far greater than any potential toxicity of the actual PAMPs
  • ex: septic shock, can be lethal before bacteria has chance to do real harm
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10
Q

innate immune system receptors?

A
  • receptors/sensor molecules already encoded in the genome through evolution
  • is an evolved system responding to insults we’ve encountered as a species over time
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11
Q

innate different from adaptive immune receptors?

A
  • adaptive uses lymphocytes which undergo gene rearrangments to make various types of receptors to respond to future potential antigens (make repertoire)
  • innate receptors are genetically encoded w/ preexisting specificity for target molecules
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12
Q

how do innate and adaptive differ in immune memory??

A

-adaptive= memory (recall responses); innate= no memory

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13
Q

how do innate and adaptive differ in target ligands?

A
  • innate: common molecule patterns (PAMPs), stress, injury

- adaptive: can respond to any conformational determinant

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14
Q

desensitization vs immune tolerance?

A
  • innate= desensitization, allows you to walk down street and now respond aggressively to every pathogen
  • adaptive= immune tolerance
  • different mechanisms*
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15
Q

6 elements of innate immunity?

A

1) physical barriers
2) chemical barriers
3) antimicrobial peptides in mucus
4) sensors of microbes & tissue injury, signaling substances
4) phagocytes & natural killer cells
5) complement

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16
Q

Why are neutrophils and macrophages considered part of innate immunity?

A

-their activity is intrinsic and doesn’t require specific receptor recombination for antigens

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17
Q

exogenous triggers of innate immunity?

A
  • innate needs to determine what molecules are typical of pathogens, but not present in normal self tissue or PAMPs, stress, or injury
  • this is the self vs non self question in innate
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18
Q

How can innate immune response tell bacteria/ infectious eukaryotes from self?

A
  • most eukaryotic organisms are similar, but have distinct difference
  • ex: flagella, bacteria have similar shape/function but produced by unique non-human cells
    • is way to ID as pathogenic
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19
Q

2 main components of bacteria that are different than humans?

A

1) cell wall & capsule

2) flagella

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20
Q

bacteria flagella

A
  • produced by polymer of flagellen which humans don’t

- have same function as human though

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21
Q

bacteria cell wall & capsule structure?

A
  • unique to bacteria, all have it
  • good candidates for innate immune response deciphering self vs non self
  • have cross linked glycopeptides
  • have gram +/- bacteria w/ different cell wall compositions
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22
Q

gram + bacteria 2 unique features ?

A

1) lipoteichoic acid
2) lots of peptidoglycan
- strong cell walls

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23
Q

gram - bacteria 2 unique features?

A

1) less peptidoglycan
2) lipopolysaccharide (LPS)
LPS provides unique essential function for bacteria, so are in all gram - bacteria and good candidate for innate immunity

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24
Q

lipopolysaccharide

A
  • glycolipid composed of a lipid and sugar component

- universal in gram negative bacteria

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25
Q

Flagellin

A
  • flagellin monomer polymerizes into bacterial flagella
  • flagela produced from 11 protofilaments wound together that spin which allow bacteria mobility
  • humans flagella has completely different mechanism
26
Q

Bacterial DNA vs Mammalian DNA 2 key difference?

A

1) CG seqeunces
bacteria=many; mammals= rare

2) Cytosine methylation
bacteria=no; mammals= yes

27
Q

how innate immunity protect against viruses?

A
  • rarely viruses have dsRNA genomes, most have ssRNA but produce dsRNA during replication & mRNA synthesis
  • mammals do make some dsRNA but very low concentration, if have a large concentration then assume viral infection & innate immunity attacks
28
Q

how are such diverse pathogenic molecules detected and activating the innate immune system?

A

1) several classes of receptors encoded in the genome
2) receptors present at cell surface & cytoplasm
- various pathogens triger these receptors and activate common alarm system (innate immunity)

29
Q

2 innate immune receptor classes we need to know?

A

1) NOD-like receptors
- NLRs, NALPs, intracell receptor for PAMPs
2) Toll-Like receptors (TLRS)

30
Q

what do innate immune receptors recognize?

A
  • pathogen associated proteins, carbohydrates, and nucleic acid
  • but also self molecules associated with inflammation and cell death
31
Q

recognition of PAMPs

A
  • pathogen associated molecules (PAMPs) can be recognized at the cell surface in cytoplasmic vesicles or in cytoplasm
  • PAMP recognition signals inflammation alarm
32
Q

what happens once PAMP is recognized?

A
  • signals alarm

- activates NF-kB trxn factor which causes expression of inflammation associated genes

33
Q

how do PAMP recognition and dendritic cell process differ?

A
  • PAMP recognition is designed to raise an alarm

- dendritic cell capture of antigen is for processing and presentation

34
Q

What state is NF-kB usually in the cell in healthy conditions

A

-NF-kB is always present in the cell, but kept inactive so when it is needed can be activated and used rapidly

35
Q

NF-kB

A
  • a system for rapid gene activation that relies on preexisting components
  • involved in adaptive & innate responses
  • invovled in tissue/wound repair & remodeling
36
Q

NF-kB activation 4 general steps?

A

1) inactive NF-kB has heterodimer (p65/p50) held in cytoplasm in complex w/ IkB
2) signaling by ligand leads to activation of kinase (IKK) that phosphorylate IkB
3) phosph. IkB is ubiquitinylated, degraded by proteasome
4) released p65/p50 dimer now free to enter nucleus & activate gene trxn

37
Q

Process of phosphorylated IkB

A

-has a cascade of kinases from the membrane bound receptor down to IKK that get activate din step wise fashion

38
Q

What happens when NF-kB (p65/p50) enters the nucleus?

A
  • it activates gene expression
  • recognizes sequences that activates pro- inflammation molecules:
    1) cytokines
    2) adhesions
    3) antiviral
    4) immunostimulation
39
Q

anti-inflammatory drugs target what??

A
  • Corticosteroids for example
  • work by blocking NF-kB mediaited induction of proinflammatory molecules
  • can target:
    1) trxn factor activity
    2) suppress expression of NF-kB components
    3) inhibit kinase cascade
40
Q

Toll like receptors (TLR)

A
  • originally IDed in mutant fruit flies
  • are 1-13 in humans
  • have expression on many different cell types
  • essential to immunity, composed of several diff families
  • recognize wide range of pathogens
41
Q

Diff species and TLR? 2 common features of all TLR?

A

-diff species have different # of TLK and diff ways they recognize target molecules

1) leucine rich repeats, can adapt to fit a diverse array of target molecules (specificity)
2) intracell domain that interacts w/ molecules (MyD88) & activate a kinase cascade that leads to NF-kB activation

42
Q

How get TLR specificity?

A
  • Heterodimers
  • recognition domains built from leucine rich repeated (LRR)
  • can recognize wide range of things like gram +/- bacteria, dsRNA, flagellin etc
43
Q

What do recognition domains recognize?

A

-PAMPs both inside and outside the cell

44
Q

TLR distribution

A

-can be apical, basolateral, or cytoplasmic

45
Q

TLR transduction pathways?

A
  • can be complex

- use MyD88 for NFkB activation

46
Q

NOD2

A
  • (and NOD1) part of NLR family, with leucine rich repeated (LRR) and caspase recruitment domains (CARD)
  • have various cytoplamsic activators
  • NOD2 binding MDP cause activate NF-kB
47
Q

cytoplasm activators of NOD2?

A

1) MDP

2) ssRNA/viral RNA that binds mitochondrial anti-viral signaling protein (MAVS) & activate NOD 2

48
Q

What can NOD2 sense in the cell?

A

-both bacteria & viruses

49
Q

MDP

A
  • Cytoplasmic muramyl dipeptide

- a PAMP from gram+ bacteria

50
Q

NOD2 binding to MDP?

A

-causes NF-kB activation by degrading IkB kinase, driving inflammatory cytokine gene expression like Caspase 1

51
Q

Caspase 1 activation ?

A
  • activation causes cleavage/maturation and release of pro-inflammatory cytokines IL-1b and IL-18
  • distinct from apoptosis caspase 9
52
Q

inflammasome

A

cytoplasmic complex includes 3 components:

1) NLR family members (related to NOD2): Recognition component
2) ASC/PYCARD: scaffolding component
3) Caspase-1: at center of molecule

53
Q

Inflammasome activators?

A
  • various cytoplasmic activators
    1) microbial components & pore forming toxins
    2) cytoplasmic DNA fragments (indicate cell damage)
54
Q

what happens when inflammasome complex is activated by a ligand?

A
  • causes assembly of complex which activates Caspase-1, which in turn causes maturation and release of pro-inflammatory cytokines IL-1B and IL-18
55
Q

Inflammasome and NF-kB

A
  • NF-kB activation drives inflammatory inflammasome component gene expression
  • therefore activates inflamamsome complex more and releases more IL-1B and IL-18 inflammatory cytokines,
56
Q

NOD2 and Inflammatory Bowel Disease

A

-Genetic studies found several variants of NOD2 are associated w/ increased susceptibility (>20x) to Crohn’s Disease

57
Q

diseased variants of NOD2 showed what in inflamamtory bowl disease?

A
  • reduced NF-kB activation and production of TNFa, IL-6, IL-1b after stimulation with MDP
58
Q

Two hypotheses in how decreased response of NF-kB can lead to paradoxically increased inflammation response in the intestine in nflamamtory bowl disease?

A

1) Impaired bacterial clearance, increased invasion

2) Loss of NOD2 negative regulation of TLR signaling, leading to hyper-responsiveness, Th1 responses to TLR agonists

59
Q

What allows specificity in the innate immune/ inflamamtory response?

A

1) broad array of innate immune receptors that recognize pathogens and damaged tissue

60
Q

Commensal bacteria and the immune response?

A
  • tolerance to commensal bacteria not well understood, beneficial bacteria also not well understood
  • if put commensal bacteria from one part of body in other part, now can be pathogenic
61
Q

how else does innate immune ligands from microbes help in the body?

A
  • innate immune signaling also regulates tissue homeostasis

- ex: TLR2 ligands promote mucosal epithelium tight junction formation

62
Q

What do innate immune receptors activate? (x5)

A
  • trigger ADAPTIVE IMMUNITY*
    1) pro-inflammtory cytokines/chemokines
    2) recruitment of inflammatory cells (neutrophils, macrophages)
    3) myeloid cell activation (macrophages, dendritic cells)
    4) Increased phagocytosis, cytokines
    5) migration to lymphoid tissues

Block 1 Week 5 (8 decks)

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