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
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 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
