Inflammation 1 Flashcards
why do we need homeostasis? what happens when abnormal response?
- 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
two types of inflammation?
- acute: quick and intensive
- chronic: slow and smoldering
- there is overlap between them
how tell difference between acute & chronic inflammation?
- how signals are acquired for inflamm response
- kinetics/ time course of resolution
- histological features
- diff active responders
- diff effector cells
what are the two triggers for innate immunity?
1) exogenous stimuli (infection/toxins/anything that can cause cell damage)
2) endogenous stimuli (release of cell debris & chem mediators from tissue injury)
what comprises the innate immune system?
- nearly every cell in the body
- have intrinsic (innate) sensors for exogenous and endogenous triggers
- the sensors+ trigger pathways= innate immune system
what is innate immunity? where present?
- genome encoded defensive responses to infections & other injurious agents
- has no memory/recall response
- ancient system present in all animals & pants
Innate immunity & PAMPs?
-can be triggered by recognition of PAMPs, so are also called Patter Recognition Receptors
PAMPs?
- 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
Magnitude of innate immune response?
- far greater than any potential toxicity of the actual PAMPs
- ex: septic shock, can be lethal before bacteria has chance to do real harm
innate immune system receptors?
- 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
innate different from adaptive immune receptors?
- 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
how do innate and adaptive differ in immune memory??
-adaptive= memory (recall responses); innate= no memory
how do innate and adaptive differ in target ligands?
- innate: common molecule patterns (PAMPs), stress, injury
- adaptive: can respond to any conformational determinant
desensitization vs immune tolerance?
- innate= desensitization, allows you to walk down street and now respond aggressively to every pathogen
- adaptive= immune tolerance
- different mechanisms*
6 elements of innate immunity?
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
Why are neutrophils and macrophages considered part of innate immunity?
-their activity is intrinsic and doesn’t require specific receptor recombination for antigens
exogenous triggers of innate immunity?
- 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
How can innate immune response tell bacteria/ infectious eukaryotes from self?
- 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
2 main components of bacteria that are different than humans?
1) cell wall & capsule
2) flagella
bacteria flagella
- produced by polymer of flagellen which humans don’t
- have same function as human though
bacteria cell wall & capsule structure?
- 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
gram + bacteria 2 unique features ?
1) lipoteichoic acid
2) lots of peptidoglycan
- strong cell walls
gram - bacteria 2 unique features?
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
lipopolysaccharide
- glycolipid composed of a lipid and sugar component
- universal in gram negative bacteria
Flagellin
- 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
Bacterial DNA vs Mammalian DNA 2 key difference?
1) CG seqeunces
bacteria=many; mammals= rare
2) Cytosine methylation
bacteria=no; mammals= yes
how innate immunity protect against viruses?
- 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
how are such diverse pathogenic molecules detected and activating the innate immune system?
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)
2 innate immune receptor classes we need to know?
1) NOD-like receptors
- NLRs, NALPs, intracell receptor for PAMPs
2) Toll-Like receptors (TLRS)
what do innate immune receptors recognize?
- pathogen associated proteins, carbohydrates, and nucleic acid
- but also self molecules associated with inflammation and cell death
recognition of PAMPs
- pathogen associated molecules (PAMPs) can be recognized at the cell surface in cytoplasmic vesicles or in cytoplasm
- PAMP recognition signals inflammation alarm
what happens once PAMP is recognized?
- signals alarm
- activates NF-kB trxn factor which causes expression of inflammation associated genes
how do PAMP recognition and dendritic cell process differ?
- PAMP recognition is designed to raise an alarm
- dendritic cell capture of antigen is for processing and presentation
What state is NF-kB usually in the cell in healthy conditions
-NF-kB is always present in the cell, but kept inactive so when it is needed can be activated and used rapidly
NF-kB
- a system for rapid gene activation that relies on preexisting components
- involved in adaptive & innate responses
- invovled in tissue/wound repair & remodeling
NF-kB activation 4 general steps?
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
Process of phosphorylated IkB
-has a cascade of kinases from the membrane bound receptor down to IKK that get activate din step wise fashion
What happens when NF-kB (p65/p50) enters the nucleus?
- it activates gene expression
- recognizes sequences that activates pro- inflammation molecules:
1) cytokines
2) adhesions
3) antiviral
4) immunostimulation
anti-inflammatory drugs target what??
- 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
Toll like receptors (TLR)
- 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
Diff species and TLR? 2 common features of all TLR?
-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
How get TLR specificity?
- Heterodimers
- recognition domains built from leucine rich repeated (LRR)
- can recognize wide range of things like gram +/- bacteria, dsRNA, flagellin etc
What do recognition domains recognize?
-PAMPs both inside and outside the cell
TLR distribution
-can be apical, basolateral, or cytoplasmic
TLR transduction pathways?
- can be complex
- use MyD88 for NFkB activation
NOD2
- (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
cytoplasm activators of NOD2?
1) MDP
2) ssRNA/viral RNA that binds mitochondrial anti-viral signaling protein (MAVS) & activate NOD 2
What can NOD2 sense in the cell?
-both bacteria & viruses
MDP
- Cytoplasmic muramyl dipeptide
- a PAMP from gram+ bacteria
NOD2 binding to MDP?
-causes NF-kB activation by degrading IkB kinase, driving inflammatory cytokine gene expression like Caspase 1
Caspase 1 activation ?
- activation causes cleavage/maturation and release of pro-inflammatory cytokines IL-1b and IL-18
- distinct from apoptosis caspase 9
inflammasome
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
Inflammasome activators?
- various cytoplasmic activators
1) microbial components & pore forming toxins
2) cytoplasmic DNA fragments (indicate cell damage)
what happens when inflammasome complex is activated by a ligand?
- causes assembly of complex which activates Caspase-1, which in turn causes maturation and release of pro-inflammatory cytokines IL-1B and IL-18
Inflammasome and NF-kB
- NF-kB activation drives inflammatory inflammasome component gene expression
- therefore activates inflamamsome complex more and releases more IL-1B and IL-18 inflammatory cytokines,
NOD2 and Inflammatory Bowel Disease
-Genetic studies found several variants of NOD2 are associated w/ increased susceptibility (>20x) to Crohn’s Disease
diseased variants of NOD2 showed what in inflamamtory bowl disease?
- reduced NF-kB activation and production of TNFa, IL-6, IL-1b after stimulation with MDP
Two hypotheses in how decreased response of NF-kB can lead to paradoxically increased inflammation response in the intestine in nflamamtory bowl disease?
1) Impaired bacterial clearance, increased invasion
2) Loss of NOD2 negative regulation of TLR signaling, leading to hyper-responsiveness, Th1 responses to TLR agonists
What allows specificity in the innate immune/ inflamamtory response?
1) broad array of innate immune receptors that recognize pathogens and damaged tissue
Commensal bacteria and the immune response?
- 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
how else does innate immune ligands from microbes help in the body?
- innate immune signaling also regulates tissue homeostasis
- ex: TLR2 ligands promote mucosal epithelium tight junction formation
What do innate immune receptors activate? (x5)
- 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
