Innate Immunity Flashcards
How does immediate innate immunity respond to infection?
Recognizes infection through pre-formed, non-specific and broadly specific effects
These remove infectious agents
How does early induced innate immunity respond to infection?
Recruits effector cells
Recognize infection by PAMPs then activating effector cells and inflammation
These remove infectious agents
How does adaptive immunity respond to infection?
Transport antigen to lymphoid organs
Recognition by naive B and T cells
Clonal expansion and differentiation of effector cells
Removal of infectious agents
Name 2 physical barriers to infection
Intact skin = when cut or burnt microbes can infect more easily
Mucus and cilia
What order are layers of the skin found?
Epidermis > dermis > hypodermis
From top to bottom layer
Role of mucus
Physical barrier to infection
Prevents pathogen colonization
What synthesizes and secretes mucus?
Goblet cells
What happens in cystic fibrosis?
Defective gene causes production of unusually thick and sticky mucus
Frequent lung infection because more difficult to get rid of pathogens so they colonize
Name chemical barriers to infection
Anti-microbial enzymes
Microbe-binding molecules
Acidic pH
Examples of anti-microbial enzymes
Phospholipase A2
Antimicrobial peptides
Lysozymes
Lysozyme mechanism of action?
Cleaves peptidoglycan bonds in bacterial cell walls
Cell wall is needed for bacteria to survive
Phospholipase A2 mechanism of action?
Enzyme able to insert into bacterial membrane and break it
The outside components can enter the cell = causing cell to burst
Name a microbe-binding molecule and its mechanism of action
Pulmonary surfactant = produced by alveolar type II cells
Binds to pathogen but is NON-specific
Antimicrobial peptides’ mechanism of action against virus?
Hindering virus attachment and virus-cell membrane fusion
Disrupting virus envelope
Inhibition of virus replication by interacting with viral polymerase
Name 3 anti-microbial peptides
Defensins
Cathlicidins
Histatins
What are the two defensin classes?
Alpha
Beta
Defensin mechanism of action?
One end positively charged other negatively
Bacterial cell membrane = negative so positive end of defensin is attracted and inserts itself
Then negative ends are hydrophobic so cluster together pulling membrane apart
Defensin functions in the body
Maintian a healthy gut= balancing gut microbiota
Modulate inflammation
Attract immune cells to site of infection
Cathelicidins action against microbes?
Damage microbial membrane
Inhibit bacterial DNA and protein synthesis
What are Histatins?
Anti-microbial peptides
Small and cationic
Hisitidine-rich peptides in human saliva
What microbe do histains fight against?
Anti-fungal activity
What feature does the microbiome demonstrate?
Competitive exclusion = microbiome occupies our body surface so that the pathogen find it hard to colonize
Compete for resources and space
What does clostridium difficile infection do to the body?
Diarrhea
Colitis = an inflammation of the colon)
What compounds does the microbiome produce?
Compounds toxic to pathogenic bacteria
What does the microbiome help mature?
Need microbiome when mucosal structure and immunity is not fully developed or established
Where are paneth cells found and what is their function?
Highly specialized secretory epithelial cells
Located in the small intestinal crypts of Lieberkühn.
What do paneth cells do?
Highly specialized secretory epithelial cells = secrete antimicrobial peptides
Located in the small intestinal crypts of Lieberkühn.
Where are M cells found?
Found overlying GALT lymphoid follicles, such as Peyer’s patches in the ileum
What do M cells do?
Microfold cells sample antigens
Clathrin-coated endocytic vesicles for larger antigens
Or via fluid phase pinocytosis for smaller antigens
What is the structure of an M cell?
Short microvilli or none
Allows antigens to come in close proximity to apical surface
Basolateral invagination allows for positioning of APCs and lymphocytes = close to lumen
M cells and antigen interaction?
M cells acquire antigens through apical surface
Antigens pass through M cells via vesicular transport to basolateral membrane
They are released from basolateral membrane
APCs uptake antigens and process them for presentation to T cells and other lymphocytes
What do absorptive endothelial progenitor cells do?
Secrete cytokines
What is the role of tight junctions?
Blocks movement of bacteria and PAMPs into lamina propria
What are germ-line encoded?
Pattern Recognition Receptors?
What does germ-line encoded mean?
Means that the information for PRRs is inherited = they have an innate ability to recognize certain patterns in pathogens
What is required for adaptive immunity activation?
Activation of innate immunity
Name 5 PRRs
Toll-like receptors
NOD-like receptors
RIG-I-like receptors
Mannose receptors
Phagocytic receptors
How many TLRs are there in humans vs mice?
10 in humans and 12 in mice
What is the ligand of TLR-3?
dsRNA
What is the ligand of TLR-4?
Lipopolysaccharide
What is lipopolysaaccharide?
Cell-wall component of gram-negative bacteria = sensed by TLR4
What is the ligand of TLR-5?
Flagellin
What is the ligand of TLR-7 and TLR-8?
ssRNA
What is the ligand of TLR-9?
CpG-ODN
What is CpG-ODN?
C linked to D oligodeoxynucleotides = single strand
Where are TLRs found?
Both on the cell membrane and in the endosome
What is the structure of TLRs?
Leucine rich repeat motif
Cysteine rich flanking motif
TIR domain
What part of the TLR sites in the cytoplasm?
TIR domain = tail
What is the TLR4 signalling pathway to activate gene expression of IL-6, TNFalpha etc?
When LPS is bound the receptor will dimerize
TIR domains are brought together = activating the domain
TIR domains recruits MyD88 = no enzyme activity
IRAK1/4 binds MyD88 at Death domain
IRAK1/4 go to activate MAPK and NFkB
What is the TLR4 signalling pathway to activate IFN-beta gene expression
When LPS is bound, the receptors will dimerize
TIR domains are brought together = activatingthe domain
TIR domains recruits TRIF
TRIF activates both kinases = IKK and TBK1
Which then activate IRF3 and NFkB
What two domains does MyD88 have?
TIR and Death domains
TIR binds to TLR4s TIR domain
Where are NOD-like receptors expressed?
Cytoplasm because they detect intracellular bacteria
What form are NOD proteins found in?
Inactive form
What is the structure of NOD-like receptors?
LRR
NOD
CARD
What are the differences between NOD1 & NOD2?
NOD1 has 1 CARD domain but NOD2 has 2
NOD
NOD1 activation triggered by iE-DAP in gram-negative bacteria
NOD2 activation triggered by MDP in both gram-positive and -negative bacteria.
What does NLR activation ultimately lead to?
Nuclear Factor kappa B (NFkB) activation by removing the inhibitor (IkB)
What happens when bacterial ligand binds to NOD protein?
Either iE-DAP or MDP binds
RIPK2 recruited and binds the CARD domain
TAK is phosphorylated by RIPK2
TAK is activated and then phosphorylates IKK
IKK phosphorylates IkB leading to its ubiquitination and subsequent degradation by the proteasome
NFkB is free to act as a transcription factor
Where are NOD2 strongly expressed?
In Paneth cells found in the small intestine
What does NOD2 induce?
Alpha-defensin expression
What mutation can cause Crohn’s disease?
Loss of function mutation in NOD2 = less anti-microbial production
More bacterial growth causing chronic gut inflammation
What mutation can cause Blau syndrome?
Gain of function mutation in NOD2 = activates signalling in absences of infection
Spontaneous inflammation in joints, eyes and skin
Where are RIG-I-like receptors found and why?
Expressed in cytoplasm because important to detect viral infection
What are the two types of RIG-I-like receptors?
RIG-I and MDA-5
What do the two RLRs recognize?
- RIG-I = unmodified 5’-tiphosphate end of ssRNA
- MDA – 5 = recognize dsRNA
What is the structure of RIG-I-like Receptors?
Repressor Domain
Helicase
CARD
