Flashcards in IMI8: Autoimmunity and autoimmune inflammation Deck (80)
Define autoinflammatory diseases?
A group of rare disease characterised by seemingly unprovoked episodes of fever and inflammation. Because the inflammatory episodes occur regularly, the diseases are also known as periodic fever syndromes. Autoinflammatory diseases thus involve abnormal activation of the innate immune system.
Give a few examples of autoinflammatory diseases
Familial Mediterranean fever (FMF)
Cryopyrin-associated periodic syndromes (CAPS), which include a variety of syndromes such as FCAS, MWS, NOMID
Deficiency of IL-1-Receptor Antagonist (DIRA)
Hyper IgD Syndrome (HIDS)
What is the body's first line of defence?
The innate immune system: When microbes, such as bacteria or viruses, invade the body the innate immune system quickly responds by triggering fever and inflammation, which help the body fight infection
What happens to the innate immune system in autoinflammatory diseases?
the innate immune system is activated without an apparent cause and it remains so for some time.
Name the main difference between autoimmune diseases and autoinflammatory diseases
Patients with autoinflammatory diseases do not produce autoantibodies. It is the lack of autoantibodies in autoinflammatory diseases that makes them different from autoimmune diseases.
What are autoantibodies?
Antibodies produced by the immune system that are directed against a given individual’s one or more own proteins.
What is the most common symptom of autoinflammatory disease?
What are the symptoms of an autoinflammatory disease?
sores, inflammation of eyes, muscles, joints, skin, the gastrointestinal tract and internal organs. If not properly controlled, repeated inflammation can lead to amyloidosis.
What is amyloidosis?
A serious condition caused by a build-up of amyloid protein in organs and tissues throughout the body. Amyloid protein deposits can make it difficult for the organs and tissues to work properly. Without treatment, this can lead to organ (such as kidney and heart) failure.
What is the most common autoinflammatory disease?
Familial Mediterranean fever (FMF)
Discuss the details of FMF
- most often seen in people of Middle Eastern ancestry. - both sexes equally
- symptoms usually start in childhood
- 1 in 250 to 1 in 500 in non-Ashkenazi Jews
- 1 in 1,000 in the Turkish population
The cause of FMF has been ascribed to abnormalities in a gene called MEFV which encodes for a protein called Pyrin. FMF is a recessive disease, meaning that about 85% of patients with FMF have changes (a mutation) in both copies of their MEFV gene. Interestingly, most individuals with a single mutation are completely healthy. Up to 1 in 4 healthy people in some eastern Mediterranean populations carry an MEFV mutation. This has led to the suggestion that FMF carriers may have had an evolutionary advantage in the past, such as possibly a diminished vulnerability to infections prevalent in their environment.
What is Pyrin?
An intracellular pattern recognition receptor (PRR) found in macrophages. Unlike other PRRs, Pyrin does not directly recognise pathogens
Where is Pyrin produced?
What is Pyrin believed to do?
Keep inflammation under control, this may have something to do with its ability to interact with the cytoskeleton, where it is located. There is evidence to suggest that pyrin carries out its functions by, at least in part, behaving as a monitor of certain cell processes such as the function of the Rho GTPases.
What are Rho GTPases?
Small G proteins and they represent a sub-family of the Ras family. They are small messengers that enable cells to communicate with each other and are involved in cytoskeletal rearrangements, cell shape and cellular transport pathways, as well as in the regulation of a number of transcription factors.
Why is Pyrin activated when Rho GTPase function is shut down?
Members of this family of GTPases are common targets of bacterial exotoxins and blocking Rho activity can interfere with macrophage migration and phagocytosis, therefore Pyrin can counter this.
After activation, what does Pyrin do?
It plays an important role in assembling the molecular complex called the inflammasome. Inflammasomes form in response to infection although, as you will recall, various other stimuli can also trigger inflammasome assembly.
What is the inflammasome?
An intracellular multiprotein oligomer that promotes the maturation and secretion of pro-inflammatory cytokines.
What is the mutated pyrin protein thought to do to the inflammasome?
The mutated pyrin protein is thought to cause inappropriate activation of the inflammasome, leading to release of the pro-inflammatory cytokine IL-1β.
The inflammasome is thought to be responsible for the activation of which caspases? What does this lead to?
caspase 1 and 5: leading to the processing and secretion of the pro-inflammatory cytokines IL-1β
Which proteins of the inflammasome come together on activation to form active caspase 1 and 5?
Protein called NALP1 and a adaptor protein ASC
What are caspases 1 and 5 and what do they do?
Enzyme proteases that cleave inactive proIL-1β to the active pro-inflammatory cytokine IL-1β.
What is the long term treatment of FMF? How does this drug work?
Colchicine: it is thought to inhibit multiple proinflammatory mechanisms and thereby relieve symptoms.
What are newer therapeutic targets focusing on?
Given that IL-1β is often overexpressed in autoinflammatory diseases (see figure in the section on the mechanism of IL-1β production during inflammasome activation), it is hardly a surprise that newer therapeutic approaches tend to target IL-1β.
Name some monoclonal antibodies that target IL-1β
anakinra, rilonacept and canakinumab
Describe the breach in self-tolerance, which allowed autoimmune diseases to arise
A simple hypothesis is that polymorphisms in various genes result in the defective regulation or reduced threshold for lymphocyte activation, and environmental factors initiate or augment activation of self-reactive lymphocytes that have escaped control and are, therefore, poised to react against self-antigens.
The ability of the immune system to recognise self-antigens as safe while remaining able to recognise and mount an appropriate immune response to foreign substances, which are perceived as a threat. Self-tolerance is thus absolutely critical to maintaining normal physiological function.
What are the two types of self-tolerance and what do they depend on?
- Central tolerance
- Peripheral tolerance
What does the mechanism of self-tolerance involve?
the removal of self-reactive lymphocytes that have receptors that bind strongly to self-antigens. These autoreactive cells are removed by apoptosis (programmed cell death), termed clonal deletion, or by the induction of anergy, which is a state when cells can no longer respond to the antigen.