(Section B: Immunology) Lecture 12: Innate Immunity III Flashcards
What does the immune system respond to?
- Invading organisms (bacteria, viruses, fungi, parasites)
- Transplanted blood cells or organs (unless “matched”)
What is immunological tolerance?
The immune system has the ability to discriminate self from nonself
What is immunological tolerance mediated by?
Innate and Adaptive Immune Mechanisms
What 2 examples of innate immune pathways for immunological tolerance do we discuss?
- Natural Killer Cell recognition of “missing self”
- The alternative pathway of complement activation
What cell-surface molecule allows the immune system to distinguish between self and nonself?
Major Histocompatibility Complex (MHC) proteins
What do MHC molecules do?
Inhibit killing activity of Natural Killer cells, a type of innate-like lymphoid cell (ILC)
Describe:
NK Cells
Natural Killer Cells
* Always in “on” position
* Type of Innate Lymphoid Cell
* Inhibitor receptors recognize MHC molecules
* “Self” signal turns NK cells off
What happens when there is a loss of MHC molecule expression?
Activates NK cells, promotes killing of altered self-cell
* Up-regulation of stress-induced ligands promotes killing of altered self-cell
Describe:
Mechanism of Killing by NK Cells
- Fas Ligand (FasL) attaches to Fas surface receptor to activate signal
- Perforin punches holes in the vesicles
- Granzyme B triggers apoptosis
How does perforin work?
- Can insert across lipid bilayer (transmembrane protein)
- Forms rings and holes
- Allows Granzyme B into the cell to trigger apoptosis
Do the 3 mechanisms of NK cells occur stepwise or simultaneously?
Stepwise
Define:
Complement System
Component(s) of plasma that complement antibody action to kill target cells
What does The Complement System comprise of?
Complex network of ~50 proteins with roles in innate immunity, adaptive immunity and inflammation
What are functions of the complement system?
- Directly kill cells (Alternative pathway)
- Interact with antibodies to kill cells (Classical pathway)
- Interact with lectins to kill cells (Lectin pathway)
- Opsonize pathogens to flag them for phagocytosis
- Function as a chemoattractant to recruit leukocytes and induce inflammation
Why is it called the Alternative Pathway?
It was discovered after the classical pathway
Alternative Pathway:
Step 1
- Spontaneous cleavage of protein C3, in blood plasma
- Spontaneously associates with protein Factor B
- In presence of Factor D, cleaves Factor B to Factor Bb and Factor Ba
- Factor Bb and C3 remain together
Results in protein with enzymatic activity known as Fluid-phase C3 Convertase (C3+Bb)
* “Fluid”, as it is floating around in blood plasma
Alternative Pathway:
Step 2
Fluid-phase C3 Convertase
* Recognizes protein C3
* Cleaves to C3 to form C3b and C3a
Results in protein with enzymatic activity (C3b)
* Covalently binds to cells, attaches to anything it comes in contact with
What does the C3a do?
Functions like a cytokine
* Chemoattractant properties
* Attracts neutrophils etc. to move towards the site where this is happening
Alternative Pathway:
Step 3
- C3b attached to the cell will recruit a Factor B
- In presence of TWO enzymes (Factor D and Properdin), Factor B is cleaved into Factor Ba (leaves) and Factor Bb (attached)
- A second molecule of C3b (formed by cleaving C3), attaches
Results in protein with enzymatic activity known as C5 Convertase
* Has ability to cleave protein C5 to C5a and C5b
* Happens constantly and very rapidly (very active)
What does C5a do?
Acts like a cytokine
* Powerful chemoattractant
* Attracts neutrophils etc.
What does C5b on a cell cause?
Membrane Attack Complex (MAC)
Describe:
Formation of Membrane Attack Complex
Cascade process
* C5b recruits C6
* They recruit C7
* They recruit C8
* They recruit C9
* Repeatedly recruits C9 to form a ring (comprises of 10-20+ C9)
C9 is similar to perforin, forms a ring and punches hole in the cell membrane
What is MAC important for?
Important for fighting invading organisms
* Immunodeficient patients may have deficiency in C proteins
Is the alternative pathway constantly happening?
Yes
What stops the alternative pathway?
- Decay-accelerating factor (DAF, CD55)
- Complement receptor 1 (CR1, CD35)
Promotes dissociation of C3 convertases from cells thus stopping the alternative pathway
What does the CD nomenclature mean?
Cluster of Differentiation
What was the history of inflammation?
First described by the Roman Celsus in the 1st century A.D.
* “Rubor et tumor cum calore et dolore”
* Means redness and swelling with heat and pain
In the 2nd century, Galen added “functio laesa”
* Loss of function (can be a consequence or a cause of inflammation)
Is inflammation good or bad?
Both good and bad:
* Inflammation coordinates immune responses, wound healing, and metabolism
* Unresolved inflammation can cause disease
Explain:
Inflammatory circuit
- Inflammatory stimulus detected by sensors
- Sensors send inflammatory signals to effectors and non effectors
- Effectors cause negative feedback
- Noneffectors cause feedforward (adaptation)
What are effectors and noneffectors?
Effectors: Eliminate cause of inflammation (ex. immune response)
Non-effectors: Tissues and organs that change their functional state to adapt to the perturbation and to support the effector response (fever, sleep etc.)
What are the 4 main purposes of inflammation?
- Coordinates delivery of blood components (plasma and leukocytes) to site of infection/injury
- Controls our metabolism, thermogenesis and aspects of behavior
- Containment of infection/injury by neutrophils, macrophages, and endothelial cells
- Tissue repair, wound healing, and return to homeostasis
What is the redness in inflammation caused by?
Vascular permeability, allowing movement of immune cells into inflamed site
Thermogenesis
Body temperature
What counts as “controlling metabolism, thermogenesis and aspects of behavior” in inflammation?
Fever, activity level etc.
What is swelling caused by in inflammation?
Correlated with neutrophils moving into infected or wounded area and containing it
* Neutrophil extracellular traps, granulomas
What does fever do in inflammation?
Slows replication of bacteria and viruses
What is the purpose of pain and loss of function in inflammation?
Alerts the host of the problem and prevent further damage
How are inflammatory stimuli classified?
- Exogenous - From outside the cell
- Endogenous - From inside the cell
List:
Exogenous inducers of inflammation and give examples
- PAMPs (lipopolysaccharide, dsRNA, ssRNA, flagellin)
- Chemicals (alum/asbestos) interacting with cellular receptors (TLRs, NLRs)
- Toxins and venom components (phytochemicals, bee sting)
- Complement proteins (C3a, C5a acting through C3aR, C5aR)
List:
Endogenous inducers of inflammation and give examples
- DAMPs (burn, frostbite, impact, puncture) induce inflammation
See DAMP signals for comprehensive list of signals
What are the 3 cytokines that play most important role as mediators of inflammation?
- Interleukin-1 (IL-1)
- Interleukin-6 (IL-6)
- Tumor Necrosis Factor (TNF)
