Auto - Inflammtory Diseases Flashcards
What is the difference between innate and adaptive immune system?
- innate immunity - body immediate, general defence against pathogens 🦠
- adaptive immunity - specialised, targeted response that developed over time
What is the difference between ** auto inflammation 🔥 ** and ** auto - immunity **?
✅ auto inflammation -> where the body will mistakenly trigger inflammation without an external threat.
✅ Autoimmunity —> when the body attacks its own tissues and cells
What sets the boundaries for auto immunity?
- mutations associated with cells and molecules invoved in the adaptive immune system (ie specific + targeted).
What sets the boundaries for auto - inflammation?
- mutations in cells associated with innate immunity at disease prone sites (rmb innate immunity associated with inflammation)
What are familial monogenic diseases?
🧬 genetic disorders, that are caused by a single gene.
The disease is often inherited within a predictable pattern within families, and can result in specific health problems or conditions.
What are familial monogenic diseases caused by?
- mutations in a single gene (ie in CF, disease is caused due to mutations in the CFTR gene and thus non functional CFTR)
What are the general characteristics of monogenic auto - inflammatory diseases?
✅ unprovoked attacks of inflammation (ie may not be due to infection etc there is no stimulus)
✅ absence of high tier autoantibodies or antigenic specific T cells , ie the adaptive immune response - ie the inflammation seen is largely mediated by the cells and molecules of the innate system.
✅ pre - existing errors of the innate immune system — ie significant boost predisposition.
Give a few examples of familial monogenic auto inflammatory disorders?
- 🥵 familial Mediterranean fever
- 🥶 CAPS (cyropyrin associated periodic syndromes).
- Blau syndrome
Which gene is mutated in Familial Mediterranean Fever and what are the clincal features / symptoms of FMF?
Gene : 🧬 MEFV protein
Clinical Features : periodic fevers lasting 3 0 7hrs), inflammation of serous tissue (ie lining the heart and inner abdomen) , arthritis.
Which gene is mutated in Cryopyrin - associated period syndromes (ie FCAS, MWS, and NOMID) and what are the clincal features / symptoms of CAPS?
- 🧬 NLRP3 gene
Clinical features : - 🥶 cold induced autoinflammation
- 👂 cochlear inflammation
- 🥵 fevers
- 🤧 sterile menigitis
- 🦴 Bone lesions.
Which gene is mutated Blau Syndrome and what are the clincal features / symptoms of Blau Syndrome ?
🧬 mutated gene : NOD2
Clinical features :
- 🍬 granulomatous dermatitis
- uveitis (inflammation of the inner eye) n
- arthritis 👵
Are these diseases, FMF, CAPS and Blau syndrome, autosomal dominant or recessive?
FMF - AR
BS - AD
CAPS - AD
Give 3 examples of the cryopyrin associated periodic syndrome (CAPS) diseases?
- ✅ familial cold autoinflammatory syndrome (FCAS)
- ✅ Muckle - Wells syndrome (MWS)
- ✅ NOMID/ CINCA
What is CAPS?
A spectrum of disease ranging from mildFCAS to severe NOMID/CINCA. They are rare and hereditary inflammatory diseases that each encompass their own 3 phenotypes.
CAPS
What is FCAS and and what are the symptoms?
Familial cold autoinflammatory syndrome.
- inflammation that occurs when weather is cold 🥶and temperatures are low ❄️
- symptoms : rash on the skin, arthralgia (joint pain), conjunctivitis (red eye)
Mild caps
CAPS :
What is MWS and what are the symptoms?
Muckle - Wells Syndrome
CAPS characterised by skin / urticaria rash ** and ** sensorineural deafness 👂 🧏🏽♀️
Between mild and severe CAPS
CAPS
What is NOMID/CINCA and what are the symptoms?
A more sporadic (ie occurs randomly) and severe CAPS disease.
Symptoms include : progressive chronic meningitis, visual 👁️ and intellectual 🧠 damage, and destructive arthritis 🦴
Auto - immune diseases tend to have flares what are these?
✅ periodic fever syndromes where the disease will amplify and worsen and then go back to normal state periodically and sporadically.
💊 there isn’t necessarily a particular target for most of these types of conditions
What is caspase 1?
A converting enzyme that cleaves other proteins such as ** precursors for inflammatory cytokines IL - 1B and IL - 18 **
What are NLR proteins?
Other wise known as “Nucleotide - binding Oligomerization Domain - like receptors (NOD)” are a type of protein/ receptor that detect harmful pathogens 🦠 in our cells.
When they recognise these threats, they triger a series of signals that will ➕ activate our immune system to defend against the invading cells.
Give two examples of inflammatory cytokines?
- IL - 1B
- IL - 18.
What are inflammasomes
- 🥵 receptors of the **innate immune system* (obvs, they are inflammatory) —> they are large protein receptor structures made out of NLR proteins.
- ✅ they regulate the activation of capsase 1 and they can induce inflammation in response to infectious microbes and molecules deceived from host proteins.
Describe the structure of the NLRP3 inflammasomes?
They are composed of a N - terminal effector domain that comprise capsase recruitment domains (CARD) and pyrin domains.
What does activation fo the NLR lead to ?
Triggering of severe important immune processes such as inflammasomes formation (lots of NLR proteins conjugating to form multi protein complexes, that activate the release of pro - inflammatory cytokines IL -1 beta and IL -18).
Induction of antimicrobial responses and initiation of cell death (pyroptosis to avoid spread of pathogens by removing infected cells).
How does activation of the NLRP3 inflammasomes lead to the release of pro - inflammatory cytokines?
NLR proteins - in response to threat will form a complex , ie the NLRP3 inflammasomes.
This inflammasomes will activate procapsase 1 by cleaving it into its active form capsase 1.
Capsase 1 will then act enzymatically and will cleave IL- 1Beta and IL - 18 into their active form so we get an increase int he cytokines IL- beta and IL - 18.
What is caspase 1 and what is its function?
- enzyme
- function : cleave other proteins to ** activate apoptosis** and pryoptosis. Will also activate pro - inflammatory cytokines (ie IL - 1 beta)
What is IL - 1 beta and its function?
- interleukin involved in the promotion of inflammation 🥵, induction of fever 🤒, and activation of immune cells 👺 - thus is * pro - inflammatory*.
🤢 it also has a role in inflammatory disease and also contributes to response against infection.
What is IL - 18?
- interleukin involved in enhancing the production of IFN - Y, as well as contributing to the immune response, and defence against certain infections.
It also has a role in auto - immune and inflammatory response.
What are PAMPS and DAMPS?
PAMPS - pathogen - associated molecular patterns that are recognised by immune cells indicating the presence of pathogens. They are released from the pathogen.
DAMPS - damage associated molecular patterns - released by injured or damaged cells into the extracelluar space that will signal danger to the immune system.
How do PAMPS and DAMPS also lead to the activation of a pro - inflammatory response?
- They are detected by the immune receptors ie PRR and TLR
- detection leads to changes in the formation of NLRP inflammasomes which will multimerize.
- CARD domain of the inflammasomes picks up the pro capsase enzyme and activates it to capsase 1 (active form ✅).
- Active Capsase 1 will then convert pro - IL to active forms (ie IL - 1Beta and IL - 18) which are then released from teh cell leasing to inflammation and release of inflammatory cytokines.
What is the function of the CARD (capsase recruitment domains) of the inflammasomes?
Activate pro capsases into active form , ie ** capsase 1 **
Describe in very basic steps what the NLRP inflammasomes is and how it initiates the inflammatory response via a cascade?
NLRP inflammasomes - multi protein complex involved in initiation of an inflammatory response.
- Activation of inflammasomes from NLR proteins.
- Oligomerization
- Caspase 1 activation from pro caspsase by CARD domain of the inflammasomes.
- Cleavage of the pro interleukins by activated caspase 1
- Release of pro - inflammatory cytokines — lead to initiation and amplification of the inflammatory response.
The activation of NLRP Inflammasomes and the subsequent release of pro - inflammatory cytokines are essential for effective immune responses, but dysregulation can contribute to what?
- various inflammatory diseases.
There are lots of different ways we can cleave and thus activate pro capsase into capsase 1. Give two examples?
- flagellin
- sensor cleavage
Different auto - inflammatory diseases can be mediated by activated inflammasomes and IL - Beta production - how?
Mutations to the genes that are involved in inflammation pathway described
- ie CAPS involves mutations to functional NLRP and thus the whole inflammasomes is disrupted
- FMF - pyrin is the gene that is altered.
All of these gene mutations increase the ACTIVATION OF THE INFLAMMASOMES (DUUHHH ITS AN INFLAMMATORY RESPONSE) —> INCREASE IL - BETA WHICH CAN LEAD TO IT BEING RELEASED.
What is IL - 1?
Interleukin 1 - a family of pro inflammatory cytokines ➕ 🥵
- eg IL - 1 Beta or IL - 18
What does mutations in the genes involved in inflammasome formation and expression lead to?
Constant reactivation and increase in IL - 1.
Explain why we would want to target the IL - 1 receptor when treating auto - inflammatory diseases?
Targeting the IL - 1 receptor will prevent the excess IL -1 binding and eliciting a deleterious inflammatory response , ie inflammatory disease.
Describe how IL - 1RA antagonists work?
They bind to IL 1 receptors and prevent binding from IL1 molecules themselves -> thus blocks the effects of IL -1.
What do we mean when we say the clinical features of auto - inflammatory diseases are shared among other inflammatory disorders?
They have similar symptms and presentations. They may be driven either by IL -1 or conditions associated with IL -1 .
How can DAMPS generate inflammasomes?
Via sterile attack where breakdown fo damaged cells results in the release of DAMPS. These will activate inflammasomes via the toll - like receptors.
How do PAMPS activate the inflammasome?
Via microbial attack - ie they are released from the microbe 🦠 that infected the body, the host.
Activation of the inflammasomes can lead to chronic or acute inflammation. Is chronic low grade inflammation associated with ageing also mediated through the inflammasomes?
NO - it is not driven by inflammasomes, however it may be involved. .
How can a person with an auto - inflammatory conditions flares lead to them having tissue damage and thus multiple co - morbidities?
- in a flare up ie of patients with CAPS, they will have elevated levels of inflammatory cytokines and thus >er release of interleukins release.
If this was to happen in a regular basis - damage of tissues essp neural tissue as there is an inability to repair the damage tissue). - may lead to deafness, trouble with eyesight etc.
Give an example of an acute phase protein?
CRP - an enzyme produced in the liver during inflammation.
How are indications different between healthy and ppl with a flare up of an inflammatory chronic diseases?
In a flare up patients tend to produce these APPs at high levels and their CROp at high level for no obvious reason —> high levels may lead to damage in the tissues.
Name 3 anti - IL -1 beta biological drugs that we can use to to treat autoinflammatory conditions? i
- 💊 Anakinra
- 💊 Rilanocept
- 💊 Canakinumab.
What is the mechanism of action of Anakinra?
It is a recombinant competitive Human IL - 1 receptor antagonist.
Competes with IL-1α and IL-1β for the IL-1 receptor.
●Blocks binding of IL-1 to the IL-1 receptor.
What is the targeted cytokine for Anakinra?
IL - 1alpha
IL - 1Beta
Some side effects of Anakinra?
- 💉 injection site reactions
- 😷 ** URTI**
- 🤒 ** cases of localised herpes** 🦠
Describe the structure of Anakinra?
- ✅ recombinant interleukins (IL) - receptor antagonist.
- ✅ its a slightly modified version of the Human - IL -1 receptor antagonist protein, differing by addition of a single methionine residue at the amino terminus.
What is Anakinra commonly used to treat and how does it lead to benefit?
- Rheumatoid arthritis.
✅ it blocks the activity of IL - 1 in synovial joints
✅ It reduces the inflammatory and joint destructive processes associated with RA
What is the structure of Canakinumab?
- a human IgG MCAB
What is the mechanism of action of Canakinumab?
- It binds with high affinity and selectivity to human interleukins 1 - beta (I1 - 1Beta)
- It neutralises IL - 1Beta activity by blocking interaction with the IL - 1Beta receptor.
✅ It can thus be used for the treatment of gouty arthritis.
What is Canakinumab used to treat?
Gouty Arthritis
What is the structure of Rilonacept?
A fusion protein consisting of IL -1 receptor extracellular Domains AND the Fc portion of human IgG1 (ie the single long bit on the bottom).
It is a genetically engineered IL - 1 “trap”.
What is the mechanism of Rilanocept?
It binds and neutralises IL-1Beta to prevent its interaction with surface IL -1 receptors.
Ie it acts as a “decoy receptor” and thus prevents interaction of IL - 1 with the cell surface receptor.
What is a NOD sensor?
Type of protein found inside our cells that helps to detect and respond to potential threats (ie harmful bacteria).
How NOD sensors respond to the presence of harmful threats, ie bacteria in cells?
- ✅ trigger cellular responses that lead to an immune response to defend the cell and body against pathogens.
- ✅ stimulates anti - microbial peptide (AMP) and type 1 interferon protein (IFNbeta) which are both means of clearing the harmful substance to treat or avoid the disease
Give two examples of an auto - inflammatory disease that is associated with the NOD 2 gene?
Blau syndrome - mutation in the NOD gene will lead to chronic inflammation affecting skin (granulomatous) ,joints and eyes.
Crohn’s disease - variations int he NOD2 gene are associated with increased risk of Crohn’s disease.
Mutations of the NOD gene can lead to exaggerated stimulation of the immune system and thus the exaggerated production of type 1 interferon - What will this lead to regarding the immune system?
⭐️ Type 1 interferons elicit antiviral 🦠, anti proliferative, and anti microbial states by binding to the type 1 interferon receptor.
Exaggerated production of type 1 interferon will lead to dysregulation of the immune system.
- ❌ now, instead of removal of pathogens, the immune system will also attack the body’s OWN tissues - can lead to the development of conditions like Blaus Syndrome.
What is TNF alpha?
An inflammatory cytokines, produced by macrophages and monocyte during ACUTE inflammation; responsible for a diverse range of signalling effects within cells that lead to necrosis or apoptosis. \
✅ It also has a role in driving 🛞inflammatory responses by directly inducing inflammatory gene expression and also inducing cell death 💀
Which cells produce and release TNF - alpha?
Monocytes and macrophages.
Whats the rationale for TNF- alpha having a role in necrosis and apoptosis?
We dont need or want to be in a state of inflammation ALL the time - as we saw chronic inflammation can lead to tissue damage over time!
What usually happens to misfolded proteins in the cell?
They are degraded in the endoplasmic reticulum. ** (They can accumulate int he ER however leasing to ER stress) **
What is the unfolded protein response and what proteins does it involve?
A homeostatic response to the accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER).
- ✅ It keeps the cells folding capacity within balance so that there is enough protein present for function, however those that are unfolded or misfolded are properly removed.
- it involves signalling pathways mediated by IRE1, PERK and ATF6
What will an imbalance to the UPR (unfolded protein response) lead to?
- ER (endoreticulum) stress and increased accumulation/ conc of unfolded proteins —> if this persists this may lead to cell dysfunction and may contribute to various diseases.
What are the complications of sustained ER stress? (Ie accumulation fo unfolded or misfolded proteins)?
🤒 Accumulation of misfolded protiens - cell dysfunction - various diseases.
What may lead to the presence of misfolded proteins that will need to be cleared in the cell to avoid ER stress?
- gain in function mutations, associated with auto inflammatory diseases —> leads to production of abnormal proteins.
What is the problem if a cell, ie in inflammatory disease, acquires a gaon a of function mutation?
- misfolded protiens may accumulate - ER stress - overwhelm fo the cell machinery
- in cells that turnover very slowly or not at all (ie neurones) —-> this may inhibit translation and may lead to cell death.
How does the UPR work out avoid ER stress caused by accumulation of misfolded proteins?
🦥 it slowssss down protein synthesis to restore balance and alleviate the burden on the ER which is responsible for protien folding and also clearance of the misfolded protiens.
What is the link between the UPR and auto - inflammatory disease?
🌟mis folded proteins that accumulate can extracellularly, can drive IL - 1Beta production (PRO INFLAMM) → the lack of ability to get rid of the misfolded protein can implicate autoinflammatory diseases.
Give two examples of how UPR may lead to neurological disease?
ERAD - endoplasmic reticulum associated protein ** degradation ** 🛻 🏗️
In normal cells as described we have a balance between ERAD and protein folding.
In ALS we have UPR dysfunction —-> breakdown of protien folding and more destruction of proteins via ERAD pathway —> lack of proteins for the brain - overtime, loss of function to the brain + Px develope a neurological condition.
Give one example of a metabolic disease, neurodegenerative disease and neoplasticism disease and immune disorder that are associated with ER protein folding defects and the UPR?
Metabolic disease - Insulin resistance
Neuro- degenerative - Alzheimer’s and ALS
Neoplasticism - Glioblastoma
Immune disorder - Viral infection
What triggers the UPR response?
ER stress where there is an imbalance between the proteins being made and the ability of the cells endoplasmic reticulum to properly fold and process the proteins.
What are 5 differences between autoinflammation and auto immunity?
Auto inflammation —> innate immune response uses macrophages signals via the NLR proteins), few autoantibodies, early onset (ie in childhood).
Auto immunity —> adaptive immune system, response uses T and B cells, signalling is through the TLR, autoantibodies are invovled and its late onset (except for monogenic dispense).
