Chapter 2: Innate Immunity, The First Lines of Defense Flashcards
What is the order of the innate immune system’s defenses?
Anatomic barriers: Skin, mucosa
Complement/antimicrobial proteins: C3, defensins, RegIIIy
Innate immune cells: Macrophages, granulocytes, NK cells, epithelial cells
Adaptive immune response: B cells/antibodies, T cells
What are the three mechanisms by which bacteria can directly damage tissue?
- Exotoxin Production
- Proteins secreted by bacteria
- Endotoxin
- Proteins that are liberated when bacteria dies
- Direct cytopathic effect
What are the three mechanisms by which bacteria can indirectly damage tissue?
- Immune complexes
- Formation of complex can lead to complement activation and inflammation leading to tissue damage
- Anti-host antibodies
- Cell-mediated immunity
- When an immune response is triggered a Helper T cell (CD8+) may kill infected cells
How does infection by a pathogen usually occur?
- Pathogen usually enter the body via mucosa
- Can sometimes enter via epithelium after cut or damage
Outline the general steps of an immune response
- Pathogen must attach, infect, or cross epithelium
- Local immune response tries to eliminate pathogen or stop spread via inflammation (recruiting WBC and effectors)
- If innate immune system cannot eliminate, adaptive immune response will kick in
Describe the features of anatomical barriers and initial chemical defenses.
- Epithelial surfaces are the first barrier held by tight junctions allowing for (Mech, chem, micro)
Mechanical barriers: - Cilia move mucus trapping pathogens
- Airflow pushes mucus away
- Peristalsis also pushes microbes away
Chemical: - Mucus secretion
- Antimicrobial peptides or enzymes
Microbiological: - Normal flora excrete antimicrobial compounds and cause competition
Why is skin important? Explain the layers of epithelium.
- It is the first line of defense and is multilayered
- Stratum corneum: dead layer that sheds periodically
- Stratum spinosum and granulosum: secrete lamellar bodies to form watertight lipid layer which secrete antimicrobial molecules
How are pores, sweat glands, and hair follicles protected from infection?
Sebum (oil) - has antimicrobial compounds
Sweat glands - release antimicrobial compound (Dermcidin)
Commensal microbes
How is the epidermis in the lungs protected? (Bronchial epithelium)
- Goblet cells and mucous glands create mucous layer
- Cilia transport mucus out of lung
- Alveolar cells produce defensins
- Commensal microbes provide their own microbial protection
What is the difference in a normal airway vs the airway of someone with cystic fibrosis?
- Normal airway has watery mucus while a cystic fibrosis patient will have sticky mucus which traps germs
Describe the features of the gut epithelium.
- Mucus layer (colon has two layers)
- Paneth cells secrete antimicrobial molecules
- Commensals (microbiome makes antibiotic proteins)
- Peristalsis moves pathogens trapped in mucus
- Bile salts and digestive enzymes
- Acid and pepsin in stomach
What are two important enzymes that are produced by epithelial cells and phagocytes?
Lysosomes
- Degrade bacterial cell wall by cleaving peptidoglycan layer
Phospholipase A2
- Hydrolyze phospholipids in there cell membrane
What are the two types of antimicrobial peptides and how are they activated?
Membrane targeting peptides
- Amphipathic
- Disrupt plasma membrane by forming pores
Non-membrane targeting proteins
- Inhibit enzymes or other biomolecules
- Bind and sequester nutrients from pathogens
- Activated by proteolysis to release peptide
What are defensins? What are cathelicidins?
- Effective (broad spectrum) against bacteria, fungi, and enveloped viruses
- α-defensins - produced in neutrophils (primary granule) and Panth cells
- β-defensins - produced in epithelial cells
- Broad spectrum
- Produced by macrophages and neutrophils
- Propeptide is found in secondary granules of neutrophils
What are histatins? What is RegIIIα?
- Effective against yeast
- Promotes wound healing
- Produced in oral cavity
- C-type lectin (carb binding protein)
- Produced in intestines
- Effective against gram-positive bacteria
What are the nomenclature rules of complement proteins?
- Most designated with letter C
- When cleaved, a smaller fragment(a) and larger fragment(b) is formed C2 is exception
- ex C3a, C3b
- C1 is composed of proteins Q, R, S
- Other complement proteins include MBL, ficolins, B, Factor D, MASP
What are the outcomes of the complement system
- Inflammation
- Phagocytosis
- Membrane attack
What is the central and most important step in the complement system?
- All three pathways converge and make C3 convertase
- C3a is mediator of inflammation
- C3b is main effector molecule
- C3b can bind to C3 convertase to make C5 convertase which leads to MAC (membrane attack complex)formation to disrupt cell membrane
What happens to C3b if it does not attach to its target surface? Why?
- If it does not find its target surface it will be deactivated via hydrolysis
-It is deactivated because if it isn’t it may attack the wrong target and it is a highly reactive thioester bond
How is the lectin pathway triggered? What are mannose-binding lectins? What are ficolins?
- Pathway uses soluble receptors to recognize microbial surfaces. Begins with recognition of PAMPs by PRRs (MBL and ficolins)
MBL
- Made in the liver
- 3 monomers = 1 triomer, each MBL has 2-6 triomers
- Associated w/ MASP-1, -2, -3, MAp19, and MAp44
- Binds to mannose, fructose, Nacetylglucosamine (peptidoglycan) residues
Ficolins
- Produced by neutrophils, liver, lungs
- Similar structure to MBL
- Three types
- Ficolin-1, -2: bind to acetylated sugars (N-acetylglucosamine)
- Bind to D-fructose and D-galactose
- No binding to mannose
Outline the steps of the lectin pathway.
- PRR binds to pathogen surface enabling MASP-1 to cleave and activate MASP-2
- MASP-2 cleaves C2 and C4
a. C4b covalently binds to surface of pathogen
b. C2a + C4b = C3 convertase (C4b2a) - C3 convertase cleaves C3
a. C3a initiates inflammation
b. C3b binds to microbial surface as opsonin
c. C3b binds to C3 convertase to make C5 convertase and bind to C5 - MASP-3 is regulatory to control MASP-2 immune response
How is the classical pathway triggered? What is the main function?
- Begins when pathogen sensor,C1, binds to pathogen surface, C-reactive protein, or an antibody (main function)
Describe the structure of C1 complex.
- Composed of C1q, C1r, C1s
- Hexamer of trimers
- C1r, C1s are serine proteases (similar to MASP-2)
Outline the steps of the classical pathway.
- C1q binding activates C1r which cleaves C1s
- C1s cleaves C2 and C4
- C3 convertase (C4b2a) is assembled the same way as the lectin pathway
How does the complement system ensure it does not harm the wrong cell? (2 mechanisms)
- C4b and C3b are both inactivated by hydrolysis if covalent bond is not formed on pathogen surface
- C2 can only be cleaved if bound to C4
What is the purpose of the alternative pathway?
- It is an amplification loop for C3b formation that is accelerated by properdin when pathogens are present
- Can be activated by C3b produced by lectin or classical
- can be activated spontaneously
Outline the steps of the alternative pathway.
- C3b from previous pathway binds to factor B
- Factor D cleaves factor B into Ba and Bb
- Bb binds to C3b forming C3 convertase (C3bBb)
- C3b production is amplified
How does spontaneous activation of the alternative pathway occur?
- Hydrolysis of the thioester bond in C3 must occur to form C3(H2O)
- Factor B binds to C3(H2O) and factor D cleaves factor B = C3 convertase C3(H2O)Bb
What is Factor P? What is its purpose?
- Properdin - made of neutrophils and binds to pathogen surface
- Convertase of alternative pathway only last 90 seconds but properdin allows a x5-10 extension
What do complement regulator proteins do?
- Prevent convertase from forming or promote rapid dissociation
- DAF competes w/ factor B to bind to C3b
- Factor 1 cleaves C3b to iC3b(inactive)
- CR1 (compliment receptor 1) and factor H inhibit convertase formation
What happens when the compliment system is activated and C3b coats the pathogen?
- C5 convertase is generated
What are the two possible C5 convertases?
- C4b2a3b - Lectin and Classical
- C3b2Bb - Alternative
How do phagocytes recognize compliment proteins?
- Phagocytes recognize complement proteins by their compliment receptors
- C3b is main opsinin, CR1 main receptor
- C5a activates macrophage –> phagocytosis
- Minor opsinin is C4b and cleaved forms of C3b
What happens to the small fragments of compliment proteins when they’re cleaved?
- They initiate a local inflammatory response
What is a MAC? What are the steps in its formation?
- Membrane attack complex
- When compliment proteins assemble and insert themselves in a membrane creating a pore
- C5b binds C6,7
- Complex binds to surface
- C8 binds and inserts into surface
- C9 binds and polymerizes creating pore
