31. Cell Death and Repair, Inflammation, Anti-Inflammatories (HT) Flashcards
What defines chronic inflammation?
The duration of the inflammation (i.e. it is persistent).
Compare acute and chronic inflammation.
- Chronic inflammation lasts for much longer than acute inflammation.
- Many of the same mediators are involved in both types of inflammation (e.g. prostaglandins and cytokines)
- Just as in acute inflammation, chronic inflammation is accompanied by repair -> This is an important problem in many conditions of chronic inflammation
The key to chronic inflammation is a continued driver of inflammation, such as the continued presence of an antigen that triggers an auto-immune reaction.
What are some histological features of chronic inflammation?
[IMPORTANT]
- Hard (indurated), red (erythematous) swelling (like in the Mantoux test)
- Mononuclear cell infiltrate -> Macrophages, lymphocytes, plasma cells
- Little oedema
- Angiogenesis (neovascularisation)
- Collagen deposition (with time)
Draw a diagram to summarise the massive breadth of disorders that can involved chronic inflammation.
[EXTRA]
What immune cells are and are not involved in chronic inflammation?
[IMPORTANT]
Involved:
- Mononuclear cells -> Macrophages (may include giant cells and epithelioid cells) and lymphocytes
Not involved:
- Polymorphonuclear cells (PMNs) -> Neutrophils, eosinophils, basophils, and mast cells (UNLESS it is repeated acute inflammation)
This is different from acute inflammation, where neutrophils are present.
Is pus involved in chronic inflammation?
No
Are these features seen in chronic inflammation:
- Vascularisation
- Collagen deposition
- Oedema
[IMPORTANT]
- Vascularisation -> Yes
- Collagen deposition -> Yes
- Oedema -> Not much
What are the different types of chronic inflammation you need to know about?
- Prolonged acute inflammation
- Repeated acute inflammation
- Innate immune triggered (non-immunologically specific)
- Adaptive immune triggered (immunologically specific):
- Infective
- Auto-immune
Using a disease example, describe the pathogenesis of chronic inflammation resulting from prolonged acute inflammation.
- Stimuli are the same as in acute inflammation -> So caused by presence of a foreign body (e.g. bacteria)
- Macrophages predominate but PMNs are still present
- Example: Chronic osteomyelitis
Using a disease example, describe the pathogenesis of chronic inflammation resulting from repeated acute inflammation.
- Pathogenesis the same as in acute inflammation -> May be caused be repeat exposure to a damaging stimulus, such as alcohol
- Repeat exposure leads to scarring and fibrosis
- Examples: Cholecystitis, Alcoholic cirrhosis
Using a disease example, describe the pathogenesis of innate immune triggered (non-immunologically specific) chronic inflammation.
[IMPORTANT]
- Triggered by long-term exposure to a toxic, NON-ANTIGENIC particle (e.g. silica dust)
- This stimulates recruitment of macrophages that phagocytose the particles but die due to the toxicity
- When they die, they release cytokines that lead to continued recruitment of macrophages and proliferation of fibroblasts
- The fibroblasts lead to collagen deposition and thus scarring
- Example: Silicosis
Using a disease example, describe the pathogenesis of adaptive immune triggered (immunologically specific) chronic inflammation. What are the two main types?
[IMPORTANT]
- Triggered by the long-term presence of a persistent ANTIGEN
- Leads to recruitment of CD4+ helper T cells, which co-ordinate an immune response
- Granulomas form, which are a group of epithelioid macrophages surrounded by a lymphocyte cuff -> Serve to isolate the antigens
- Macrophages are the secretory cells that are responsible for the tissue damage
- Example: Tuberculosis, Rheumatoid arthritis, Cirrhosis
- The two types are infective (e.g. TB) and auto-immune (e.g. rheumatoid arthritis)
Desribe the structure and evolution of a granuloma. When does it form?
[IMPORTANT]
- Features a group of epithelioid macrophages surrounded by a lymphocyte cuff
- It forms commonly in tuberculosis, which is an example of adaptive immune-triggered (immunologically specific)
What cells can granulomas contain?
Macrophage giant cells (MGCs) which are the result of macrophage fusion.
e.g Langhans cells in Tb granulomata
What is the Mantoux test and how does it work?
[IMPORTANT]
- A test for previous infection with tuberculosis, which involves injection of tuberculin intracutaneously skin
- Changes in skin visible at 12-24h. Maximum 24-48h. Indurated (hard), erythematous (red) swelling.
- The test works because T-cells sensitized by a prior infection are recruited to the skin site where they release cytokines, leading to vasodilation, oedema and recruitment of other inflammatory cells to the area.
- It is a classic example of Type IV hypersensitivity, also called delayed-type hypersensitivity
What is another test for past tuberculosis infection, apart from the Mantoux test?
[EXTRA]
ELISPOT
What is chronic osteomyelitis and what type of inflammation does it involve? Describe the pathogenesis.
- It is inflammation of the bone secondary to infection with pyogenic organisms
- It is a form of prolonged acute inflammation
- Pathogenesis:
- Stimuli the same as acute inflammation
- Macrophages predominate but PMN still present
What is alcoholic cirrhosis and what type of inflammation does it involve? Describe the pathogenesis.
[EXTRA]
- It is scarring of the liver and loss of function
- It involves repeated acute inflammation
- Pathogenesis:
- Alcohol toxicity leads to death of hepatocytes
- There is infiltration of neutrophils
- Continued alcohol intake leads to scarring
What is silicosis and what type of inflammation does it involved? Describe the pathogenesis.
- Simple chronic silicosis results from long-term exposure to low amounts of silica dust. Nodules of chronic inflammation and scarring provoked by the silica dust form in the lungs and chest lymph nodes.
- Involves innate immune triggered (non-immunologically specific) chronic inflammation
- Pathogenesis shown in diagram
What type of inflammation does tuberculosis involve?
Adaptive immune triggered (immunologically specific) chronic inflammation
(See lectures for pathogenesis)
What two cytokines are important in chronic inflammation?
IFN-γ and TNF-α
What are the roles of IFN-γ and TNF-α in chronic inflammation?
- IFN-γ -> Activates macrophages and other cells
- TNF-α -> Produced by macrophages and drives the immune response, including fever, apoptotic cell death and inflammation
What are the 3 ways in which the complement pathway allows response to an infection?
- Opsonisation (marking) of particles for phagocytosis
- C5a as a chemoattractant
- Membrane attack Complex (MAC).
What do complement system defects lead to?
They predispose to bacterial infections (e.g. C3 deficiency).
What does inappropriate complement activation lead to?
Lupus
What is the key component on the complement system and how is it generated? [IMPORTANT]
- C3b, which is generated by the cleavage of C3.
- The enzymes that do this are called C3 convertases.
What are the 3 steps to complement activation?
- Generation of C3 splitting enzymes (‘convertases’)
- Cleavage of complement protein C3
- Terminal lytic events (‘MAC attack’)
What are the three pathways that can activate the complement system?
- Classical pathway
- MBP lectin pathway
- Alternative pathway
Draw a summary of the activation and outcomes of the complement system.
What is the classical pathway of complement activation and how does it work?
It is the pathway that links the antibody response to innate immunity (i.e. antibodies bind to antigens triggers the complement system):
- C1q binds to antibody-antigen complexes
- Six molecules of C1q associated with C1r and C1s
- C1q binding causes C1r to cleave C1s to an active form
- C1s cleaves C4 and C2 to generate C4b and C2b*
- C4b2b is an active C3 Convertase
The C3 convertase can cleave C3 to C3b, which is the key component of the complement pathway.
What is the alternative pathway of complement activation and how does it work?
It is the pathway that activates the complement system when there is no antibody to trigger it (like in the classical pathway):
- Complement component C3 is an abundant plasma protein
- Initiated by spontaneous hydrolysis of C3 (‘tickover’)
- C3b molecule binds factor B and then this complex binds factor D
- This cleaves factor B to give Ba and Bb
- The C3b-Bb complex is the alternative pathway C3 convertase which can then produce many C3b molecules from C3 molecules
What is the MBP lectin pathway of complement activation and how does it work?
It is the pathway that activates the complement system after MBP binds to bacteria:
- MBP (aka MBL) is a plasma protein that binds to bacteria
- Serine proteinases MASP-1 and MASP-2 bind to the MBP
- These convert C4 into C4a and C4b, as well as C2 into C2a and 2b
- The end result of this is generation of C4b2b, which is the C3 convertase that can cleave many C3 molecules into C3b molecules
What makes C3b the most important component of the complement system?
C3b has a thioester bond which once activated can bind covalently to surface proteins & carbohydrates.
What is MAC and how does it work?
- Membrane Attack Complex
- It is one of the 3 main ways in which the complement pathway kills pathogens
What is the main chemoattractant in the complement system and what type of molecule is it?
C5a (as well as C3a and C4a) -> Anaphylotoxins
Describe how C5a is formed and how it acts as a chemoattractant.
- C3b + C3 convertase form C5 convertase, which makes C5a and C5b
- C5a acts through a G protein coupled receptor (GPCR) on:
- Endothelial cells
- Mast cells smooth muscle cells (SMCs)
- Phagocytes
- It causes activation, contraction and chemotaxis.
What are the main opsonins (involved in opsonisation) of the complement system?
C3b and C4b
Summarise the roles of C3, C3a and C5a in complement.
- C3 -> Activation of C3 is required in complement
- C3a + C5a -> Potent mediators of inflammation
How does the complement system interact with the coagulation cascade?
- Complement amplifies coagulation through the C5a-mediated induction of expression of tissue factor and plasminogen-activator inhibitor 1 (PAI1) by leukocytes.
- Activated clotting Factor XII (FXIIa) can activate the classical complement pathway through cleavage of the complement component C1.
What are kinins?
- A kinin is any of various structurally related polypeptides, such as bradykinin and kallidin.
- They act locally to induce vasodilation and contraction of smooth muscle.
What other pathways does complement interact with?
- Coagulation
- Kinin
- Fibrinolytic
Aside from complement, what are some other mediators of inflammation?
- Products of coagulation cascade
- Products of fibrinolytic cascade
- Kinins, prostaglandins and leukotrienes
What are leukotrienes?
Leukotrienes are inflammatory chemicals the body releases after coming in contact with an allergen or allergy trigger.
What are some acute phase proteins you need to know?
- C-reactive protein
- Alpha 1-antitrypsin
- Serum amyloid A
- Haptoglobulin
What causes production of C-reactive protein and what is its function?
- It is an acute-phase protein of hepatic origin that increases following interleukin-6 secretion by macrophages and T cells.
- It binds to lysophosphatidylcholine expressed on the surface of dead or dying cells (and some types of bacteria) in order to activate the complement system via C1q
What is the function of alpha-1 antitrypsin?
Protease inhibitor
What is the function of serum amyloid A?
Transport of cholesterol to the liver for secretion into the bile, the recruitment of immune cells to inflammatory sites, and the induction of enzymes that degrade extracellular matrix.
What is the function of haptoglobulin?
Haptoglobin binds to free hemoglobin released from erythrocytes with high affinity, and thereby inhibits its deleterious oxidative activity.
