Chronic Inflammation Flashcards
What is the innate immune system?
Refers to nonspecific defence mechanisms that come into play
What are the 3 possible outcomes of acute inflammation?
- Resolution (ideal)
- Repair
- Chronic inflammation
What is involved in ‘resolution’?
Phagocytosis of insulting agent, fibrinolysis, phagocytosis of debris
Tissue returns to normal state
What is involved in ‘repair’?
Organisation (replacement by granulation tissue) –> fibrous scar (collagen deposition).
Often happens where there is extensive amount of tissue destruction or tissue is not able to regenerate.
What is involved in ‘chronic inflammation’?
Acute inflammation (AI) progresses and turns into chronic.
Organisation (granulation tissue) + macrophages/lymphocytes/plasma cells.
Does AI involve innate or adaptive immunity?
Innate
Does CI involve innate or adaptive immunity?
Innate and adaptive
Timescale of AI compared to CI?
AI - hours/days
CI - weeks/months/years
What is angiogenesis?
New blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis.
What tends to happen to blood vessels in CI?
Angiogenesis and fibrosis (deposition of collagen)
I.e. concomitant tissue destruction and repair
What tends to happen to blood vessels in AI? What does this lead to?
Blood vessel dilatation and increased permeability
This leads to fluid exudation, rich in proteins eg Ig, fibrinogen.
What cells are primarily involved in AI?
Neutrophils, mast cells, macrophages
What cells are primarily involved in CI?
Macrophages, lymphocytes (T and B cells), plasma cells.
Physical features of AI?
Rubor, calor, tumor, dolor.
Physical features of CI?
Amyloidosis. Cachexia. Anaemia of chronic disease.
What is cachexia? What is this thought to be due to?
A “wasting” disorder that causes extreme weight loss and muscle wasting, and can include loss of body fat.
Thought to be due to release of cytokines.
What is amyloidosis? What is it due to?
Deposition of protein fibrils in various organs which can cause dysfunction.
Due to increase in serum amyloid A (produced by liver during infection/inflammation)
What is anaemia of chronic disease / anaemia of inflammation?
Cytokine release can affect bone marrow production of RBCs, leading to anaemia
What does helicobacter pylori cause?
Acute gastritis
What can happen if infection from helicobacter pylori is not cured?
Progresses to chronic inflammation
What are the circumstances under which CI can arise?
- Progression from acute e.g. helicobacter pylori.
- Recurrent episodes of acute e.g. chronic cholecystitis.
- Persistent infection by certain microorganisms (difficult to remove) e.g. TB, leprosy
- Prolonged exposure to potentially toxic agents (endogenous e.g. bone, exogenous e.g. asbestos fibres, sutures).
- Autoimmunity e.g. Hashimoto’s thyroiditis.
- Unknown e.g. Crohn’s disease, ulcerative colitis, sarcoidosis.
How can bone be an endogenous cause of CI?
If bone has splintered off and sits in tissue –> macrophages and cells of CI response will try to phagocytose and remove it (difficult to remove)
What is Hashimoto’s thyroiditis?
CI of thyroid gland
What is chronic pyelonephritis?
Chronic inflammation and infection of the kidney
Can occur due to obstruction of ureter which can lead to stagnant urine in kidney –> infection and inflammation
Inflammation leads to tissue destruction
What is cirrhosis?
Prolonged exposure to toxic agent (hepatitis, alcohol) leads to late stage of scarring (fibrosis) of the liver
CI response leads to tissue destruction, attempts for tissue repair (forms nodules), collagen deposition
Why can prolonged exposure to toxic agents lead to CI?
Toxic agents are difficult to phagocytose –> prolonged immune response
What key components are found in connective tissue cells during CI?
- Mast cells
- Fibroblasts
- Macrophages
Where are mast cells located?
Located in areas below the epithelium in connective tissue surrounding blood cells
What is the function of mast cells during CI?
Produce granules (contain important chemical mediators e.g histamine)
What is the effect of histamine?
Histamine increases the permeability of the capillaries to white blood cells and some proteins, to allow them to engage pathogens in the infected tissues.
Shape of fibroblasts?
Elongated/oval/spindle shaped
Function of fibroblasts in CI?
Synthesises ECM and collagen –> gives rise to fibrous scars
Where are macrophages found?
Essentially all tissues
Function of macrophages?
- Phagocytosis (dead/dying cells and cellular debris)
- Innate immunity (nonspecific defence)
- Adaptive immunity (specific defence)
How does phagocytosis by macrophages play a key role in CI?
Important in chronic inflammation as the early stages of inflammation are dominated by neutrophils, which are then ingested by macrophages.
Will ingest foreign materials such as pathogens and recruit additional macrophages if needed
What happens when a macrophage ingests a pathogen?
The pathogen becomes trapped in a phagosome, which then fuses with a lysosome. Within the phagolysosome, enzymes etc digest the pathogen.
What is a polymorphonuclear leukocyte?
Another name for a neutrophil
Where are neutrophils found?
In the blood - most abundant type of granulocyte
How are neutrophils formed?
From stem cells in the bone marrow
Role of neutrophils in inflammation?
- Part of innate immune system (nonspecific)
- A type of phagocyte
- During inflammation, neutrophils are one of the first responders to migrate toward the site of inflammation.
- They migrate through the blood vessels and then through interstitial tissue in a process called chemotaxis.
- They are the predominant cells in pus
Hallmark of acute inflammation
What key components are found in the blood during CI?
How can these cells respond to injury?
- Neutrophils
- Lymphocytes
- Platelets
- Monocytes
- Clotting factors
- Eosinophils
- Basophils
Respond by adhering to wall of vessel and migrating through endothelium into the tissue.
What are the 3 major types of lymphocytes?
Include NK cells, T cells, B cells
Make up 18-42% of leukocytes
Role of platelets in inflammation?
- Platelets contain a number of inflammatory mediators
- Release of these cytokines and chemokines enables platelets to recruit leukocytes to the site of inflammation
What are monocytes?
Is the circulating form of a macrophage
What is found in the connective tissue matrix?
- Elastic fibres
- Collagen fibres
- Proteoglycans
Describe development of a macrophage
Originate in bone marrow: Pluripotent stem cell –> myeloid stem cell
Then travel into blood: circulate as monocytes
Emigrate out into tissues: become macrophages
What are the macrophages of the CNS called?
Microglia
What are the macrophages of the liver called?
Kupffer cells
What are the macrophages of the lung called?
Alveolar macrophages
What are the macrophages of the bone called?
Osteoclasts
What happens when macrophages are activated?
Activated macrophages exhibit enhanced killing of intracellular microorganisms, increased secretion of cytokines and mediators, and higher expression of co-stimulatory molecules..
What can macrophages be activated by?
Can be activated by cytokines such as interferon-gamma (IFN-gamma) and bacterial endotoxins, such as lipopolysaccharide (LPS).
How are eosinophils important in CI?
Recruited from blood into tissues during inflammation.
- Can release inflammatory mediators
- Important in parasitic infections
- Implicated in allergic reactions
How are mast cells involved in CI?
- Release mediators (e.g. histamine)
- High affinity for IgE
Basic pathway after tissue injury?
Tissue injury, cells that are circulating in blood are attracted by chemical mediators, they adhere to endothelium and emigrate through to tissue
Once macrophages pass into tissues, what do they do?
Phagocytose debris and injurious agents
Then present the material (antigens) to the T cells
Also produce various cytokines
What is effect of macrophages presenting antigen to T cell?
T cells become activated
What is role of activated T cells?
- T cell proliferation
- Secrete cytokines (e.g. TNF)
- Activate B cells
What do B cells in turn form?
Plasma cells
What do plasma cells produce?
Immunoglobulins
What are the effects of the chemical mediators released by activated T cells?
- Activate macrophages
- Can lead to chronic inflammation
What are the consequences of the release of chemical mediators?
- Activate fibroblasts - lay down collagen, causing fibrosis
- Some are able to cause tissue injury and destruction
What is granulation tissue?
Granulation tissue is comprised of:
- New blood vessels (angiogenesis)
- Collagen deposition by fibroblasts –> scar
Acute inflammation can become ‘organised’. What does this mean
Organisation of tissues is their replacement by
granulation tissue.
When does ‘organisation’ occur?
Occurs as a progression to CI
What is the process of ‘organisation’?
– new capillaries grow into the inert material (inflammatory exudate) – macrophages migrate into the zone – fibroblasts proliferate – fibrosis
What is a granulomatous inflammation?
Inflammation in which there are granuloma
What is a granuloma?
A granuloma is a small area of inflammation; a collection of activated epithelioid macrophages
What does ‘epithelioid’ mean in regards to macrophages?
Resembling the epithelium (start to look like epithelial cells)
Have pink cytoplasm, indistinct cell membranes, oval nucleus
What does a granuloma tend to be surrounded by?
Mononuclear leucocytes (T cells, B cells)
May also contain multinucleate giant cells
What is caseation?
Transformation of tissue into a soft cheese-like mass, as in tuberculosis.
What is a caseating granuloma?
Has a core of necrosis in the middle of it
What is a non-caseating granuloma?
No core of necrosis
Describe an early granuloma
Core of macrophages, rim of lymphocytes around the outside
Describe a caseous epithelioid granuloma
From inner layer outwards:
- Caseous necrosis in the middle (cells have died)
- Centre surrounded by macrophages and giant cells
- Then layer of lymphocytes and plasma cells
- Then layer of fibroblasts producing collagen
What are Langhans-type giant cells?
Large cells found in granulomatous conditions, formed by the fusion of epithelioid cells (macrophages) to form one huge cell with multiple nuclei
What are the 2 types of giant cells?
- Multinucleated
2. Langhans-type
Describe nuclei of multinucleated giant cells
Nuclei are scattered
Describe nuclei of Langhans-type giant cells
Nuclei are structured around the perimeter of the cell in the shape of a horseshoe
Describe a non-caseating epithelioid granuloma
Exactly the same as a caseous granuloma BUT no core of necrosis
What is granulomatous inflammation caused by?
Limited causes. Often caused by things that macrophages struggle to phagocytose.
- Bacterial (TB, leprosy, syphilis, cat-scratch)
- Parasitic (schistosomiasis)
- Fungal (histoplasma, cryptococcus)
- Inorganic metals or dust (silicosis, berylliosis)
- Foreign body (suture, vascular graft)
- Unknown (sarcoidosis, ulcerative colitis)
What is serum protein A? Where is it released from? What is it released in response to?
A highly conserved acute-phase protein produced by liver.
Released in response to inflammation or infection - stimulated by proinflammatory cytokines, such as IL-6, Il-1,TNF
