Block B Part 2: Soluble Mediators, Complement and Cell Mediated Immunity Flashcards
What are 4 examples of soluble blood components?
Complement
Antimicrobial proteins (listed below)
Lactoferrin
Bactericidal (AKA permeability-increasing protein)
Defensins
(Lecture 4, Slide 3)
What does lactoferrin do?
Bind iron
(Lecture 4, Slide 3)
What form are complement and antimicrobial proteins often present in in the blood?
An inactive form
(Lecture 4, Slide 3)
What puts complement and antimicrobial proteins in the blood into their active form?
An immune response
(Lecture 4, Slide 3)
Are soluble mediators site specific?
They often are but not always
(Lecture 4, Slide 4)
What are defensins?
A family of antimicrobial proteins
(Lecture 4, Slide 5)
What 2 classes are defensins divided into?
α-defensins and ß-defensins
(Lecture 4, Slide 5)
What are 2 ways that α-defensins are produced?
They are secreted by Paneth cells in the small intestine and produced by neutrophils
(Lecture 4, Slide 5)
What are 2 ways that ß-defensins are produced?
They are continuously secreted at mucosal surfaces for protection and are produced by a broad range of epithelial cells
(Lecture 4, Slide 5)
What are cathelicidins?
Natural antimicrobial proteins
(Lecture 4, Slide 6)
What are 2 places cathelicidins are constantly produced?
Neutrophils and macrophages
(Lecture 4, Slide 6)
What are cathelicidins produced in response to?
Infection by keratinocytes (Outer layer skin cells) and epithelial cells in the lungs and intestine
(Lecture 4, Slide 6)
What are cathelicidins synthesised as?
Precursor proteins
(Lecture 4, Slide 6)
How are cathelicidins cleaved into 2 peptides?
Proteolytically
(Lecture 4, Slide 6)
What does proteolytically mean?
The process of breaking down or cleaving protein through the action of enzymes called “proteases” or “peptidases”
(Lecture 4, Slide 6)
What is the only cathelicidin gene identified in humans?
CAMP - cathelicidin antimicrobial peptide
(Lecture 4, Slide 6)
What is lysozyme?
A proteolytic enzyme contained inside of lysosomes (membrane-bond organelle)
(Lecture 4, Slide 7)
What layer of gram-positive bacteria does lysozyme degrade?
The peptidoglycan layer
(Lecture 4, Slide 7)
What does lysozyme degrading the peptidoglycan layer of gram-positive bacteria do to them?
It makes them burst open under their own internal pressure
(Lecture 4, Slide 7)
Why is lysozyme inactive against most gram-negative bacteria?
As it cannot penetrate the outer membrane to get to the peptidoglycan layer
(Lecture 4, Slide 7)
Who identified the complement system in 1895?
Jules Bordet
(Lecture 4, Slide 8)
What is the complement system?
A integrated system of approximately 30 soluble fluid phase and membrane proteins
(Lecture 4, Slide 8)
What are the plasma components of the complement system a part of?
Proteolytic cascades
(Lecture 4, Slide 8)
What are the 4 functions of the complement system?
Induces acute inflammation
Opsonises (marks) bacteria for phagocytosis
Bactericidal (kills bacteria) by inducing osmotic lysis (bursting of a cell due to osmotic pressure changes)
Facilitates removal of dead/apoptotic cells
(Lecture 4, Slide 9)
What does a “C” in front of proteins associated with the complement system mean?
Protein is associated with the classical and Mannan-Binding-Lectin (MBL) pathways
(Lecture 4, Slide 10)
What are complement proteins cleaved into?
1 large (usually “b”) and 1 small (usually “a”) peptide
(Lecture 4, Slide 10)
What letters are used in front of complement proteins of the alternative pathway?
B or D etc
(Lecture 4, Slide 10)
What 4 things does C1q recognise?
Gram-negative bacteria
Some viruses
Damaged cells
Altered Proteins or antibodies bound to antigens
(Lecture 4, Slide 14)
What does C1q induce after recognising a threat in the classical pathway of the complement system?
The formation of the classical pathway C3 convertase (C4b2b)
(Lecture 4, Slide 14)
What 2 proteases does C1q bind with in the classical pathway of the complement system?
C1r and C1s
(Lecture 4, Slide 14)
What does binding of C1q to C1r and C1s lead to in the classical pathway of the complement system?
C1r and C1s becoming activated
(Lecture 4, Slide 14)
What do C1r and C1s do after becoming activated in the classical pathway of the complement system?
It cleaves C2/4 producing C3 convertase
(Lecture 4, Slide 14)
What does the production of C3 convertase trigger in the classical and mannose-binding lectin pathway of the complement system?
The rest of the cascade
(Lecture 4, Slide 14)
What is the first step of the Mannose-binding lectin pathway of the complement system?
A soluble PRRs (pattern recognition receptor); Mannose-binding lectin (MBL) or Ficolins binds to specific sugars that can be found on many bacteria, fungi and some viruses
(Lecture 4, Slide 15)
What is Mannose-binding lectin (MBL) secreted by?
Hepatocytes
(Lecture 4, Slide 15)
What does Mannose-binding lectin (MBL) or Ficolins binding to specific sugars activate in the Mannose-binding lectin pathway of the complement system?
MBL-associated serine proteases (MASPs 1/2)
(Lecture 4, Slide 15)
What do MASPs 1 and 2 do after being activated in the Mannose-binding lectin pathway of the complement system?
They cleave C2/C4 to form C3 convertase
(Lecture 4, Slide 15)
How can the alternative pathway of the complement system be initiated?
When a spontaneously activated complement component binds to the surface of a pathogen
(Lecture 4, Slide 16)
What can the alternative pathway of the complement system act as?
An amplifier for all 3 pathways of the complement system
(Lecture 4, Slide 16)
What percentage of complement activation does the alternative pathway make up?
~ 80-90%
(Lecture 4, Slide 16)
What forms Membrane Attack Complex (MAC)?
Assembly of the terminal components of complement
(Lecture 4, Slide 17)
What is the first step of formation of Membrane Attack Complex?
Cleavage of C5 by a C5 convertase to release C5b
(Lecture 4, Slide 17)
What is the second step of formation of Membrane Attack Complex?
C5b binds C6, and then the C5b,6 complex binds C7
(Lecture 4, Slide 17)
What is the third step of formation of Membrane Attack Complex?
The C5b,6,7 complex (C5b-7 complex) undergoes a conformational change, leading to exposure of a hydrophobic site on C7, which inserts into the lipid bilayer
(Lecture 4, Slide 17)
What is the fourth step of formation of Membrane Attack Complex?
C8 and C9 bind to the C5b-7 complex and also insert into the lipid bilayer
(Lecture 4, Slide 17)
What is the 5th and final step of formation of Membrane Attack Complex?
Polymerization of between 10 and 16 molecules of C9 into a pore forming structure, known as the Membrane Attack Complex
(Lecture 4, Slide 17)
What are C3a and C5a?
Anaphylatoxins
(Lecture 4, Slide 18)
What are 3 functions of C3a?
Can produce inflammation and induce mast cell degranulation and stimulates extravasation of leukocytes from the blood stream to surrounding tissues
(Lecture 4, Slide 18)
What are 3 functions of C5a?
Can produce inflammation and can activate mast cells and neutrophils and can act as a potent chemoattractant
(Lecture 4, Slide 18)
What is the function of C5b?
It is a strong inducer of the Membrane Attack Complex
(Lecture 4, Slide 18)
What is C3b also known as?
Opsonin
(Lecture 4, Slide 18)
What are 3 ways in which cell-mediated immunity protects the body?
Activates Macrophages and NK cells
Stimulates cytokine secretion
Activates antigen-specific cytotoxic T cells (CD8+)
(Lecture 5, Slide 6)
What is cell-mediated immunity most effective in destroying?
Cells infected with viruses, intracellular bacteria or cancer
(Lecture 5, Slide 6)
What line of defence is cell-mediated immunity?
Third
(Lecture 5, Slide 6)
What are 4 types of T-cell?
T-helper cells (CD4+)
Cytotoxic T cells (T-killer)(CD8+)
T-suppressor cells
T-memory cells
(Lecture 5, Slide 8)
What is the function of T-suppressor cells?
Suppresses the actions of activated T cells once the threat has ended
(Lecture 5, Slide 8)
What do T-suppressor cells prevent?
Over reactivity of immune cells
(Lecture 5, Slide 8)
What is the function of T-memory cells?
They create larger and faster responses upon repeated exposure to the same antigen - acquired immunity
(Lecture 5, Slide 8)
What MHC Classes do helper and cytotoxic T cells have?
Helper T cells have both class I and II
Cytotoxic T cells only have class I
(Lecture 5, Slide 9)
What is the function of MHC class I receptors?
Aids in differentiation between self and foreign cells and pathogens
(Lecture 5, Slide 9)
What is the function of MHC class II receptors?
They are present on antigen-presenting cells alongside MHC-I. MHC-1 will present antigen whereas MHC-II will present phagocytosed pathogens
(Lecture 5, Slide 9)
How do cytotoxic T cells, kill the pathogen?
They lyse the body’s own cells to get rid of abnormal cells or pathogen infected cells
(Lecture 5, Slide 11)
What does lyse mean?
The breaking down or destruction of a cells membrane leading to a release of it’s contents
(Lecture 5, Slide 11)
What do cytotoxic T cells require in order to lyse a cell?
Close contact
(Lecture 5, Slide 11)
What can cytotoxic T-cells cause in addition to lysis?
Apoptosis of the target cell
(Lecture 5, Slide 11)
What occurs in CD4+ Th1-dependent cytotoxic T cell generation?
The naive CD4+ (helper) T cell recognises its antigen on a antigen presenting cell and becomes activated and sends signals to cytotoxic T cells to cause them to proliferate and differentiate
(Lecture 5, Slide 13)
What occurs in CD4+ Th1-independent Tc generation?
A naive CD8+ (cytotoxic) T cells recognises its antigen presenting on the MHC class I receptor of an antigen presenting cell and becomes activated leading to proliferation and differentiation
(Lecture 5, Slide 14)
What 2 chemicals do cytotoxic T cells release to trigger lysis / apoptosis?
Perforin (for lysis)
Granzymes (a protease to trigger apoptosis)
(Lecture 5, Slide 15)
Why may the delayed-type hypersensitivity response (Type 4 response) be required?
If cytotoxic T cell responses are not enough to eliminate all intercellular pathogens
(Lecture 5, Slide 16)
What can an inappropriate inflammatory response cause?
Significant tissue damage or even death under certain circumstances
(Lecture 5, Slide 17)
How is a delayed type hypersensitivity (type 4) response induced?
Certain antigens activate specific populations of helper T cells which secrete cytokines to induce a delayed type hypersensitivity response
(Lecture 5, Slide 17)
What is recruited to the site of inflammation instead of neutrophils in a delayed type hypersensitivity response?
Macrophages
(Lecture 5, Slide 17)
Why are macrophages recruited to the site of inflammation in a delayed type hypersensitivity response?
To kill phagocytosed microbes / pathogens
(Lecture 5, Slide 18)
How is the magnitude of the delayed type hypersensitivity response increased?
Macrophages and helper T cells stimulate each other forming an amplification loop
(Lecture 5, Slide 19)
What 2 cytokines contribute to macrophage activation in a delayed type hypersensitivity response in the presence of IFN-γ?
TNF-α (tumour necrosis factor) and IL-2 (interleukin-2)
(Lecture 5, Slide 19)
What retains macrophages at the delayed type hypersensitivity response and how is it produced?
Macrophage Inhibition Factor (MIF) secreted by Th cells
(Lecture 5, Slide 19)
What happens upon antigen elimination in delayed type hypersensitivity responses?
Macrophages no longer stimulate Th cytokine production
(Lectures 5, Slide 19)
