Inflammasome Diseases Flashcards
Effects of IL-1 in various tissues
IL-1α vs IL-1β
IL-1α: Constitutively present in many cell types
IL-1β: Stimulated by activation of TLRs, TNF-α, and IL-1 itself
Basic diagram of IL-1β production and action
Transcription of pro-IL-1β is induced by. . .
IL-1, TNF, TLR stimulation
Levels of IL-1β regulation
- Transcription (needs pro-inflammatory signal)
- Activation of pro-caspase-1 via inflammasome formation
- Activation of pro-IL-1β to IL-1β
- Secretion of IL-1β (Gasdermin D)
- Binding to target receptor (IL-1RA as competitive inhibitor)
NLRP3 inflammasome diagram
Supersaturation point for monosodium urate
6.8mg/dL
Gout typically presents as. . .
A disease of episodic symptomatic periods, termed “gout attacks.”
Gout attacks are characterized by rapid onset of exquisite pain associated with warmth, swelling, and erythema of the affected joint. The pain escalates from the faintest twinges to its most intense level over an 8- to 12-hour period. Initial attacks usually affect only one joint
The acute attack may be accompanied by fever (typically only if multiple joints are involved), chills, and malaise. Desquamation of the skin may occur as the attack resolves. Treatment quickly relieves pain, and even untreated attacks go away after 1-2 weeks.
In half of all gout patients, the first gout attack involves the ___.
In half of all gout patients, the first gout attack involves the first metatarsophalangeal joint.
Podagra
Gout of the first metatarsophalangeal joint.
3 Stages of Gout
- Asymptomatic hyperuricemia
- Intermittent acute attacks with symptom-free interims
- Chronic gouty arthritis with constant symptoms and superimposed acute gout attacks
A diagnosis of gout is confirmed by. . .
synovial fluid analysis demonstrating MSU crystals or by the presence of tophi.
Podagra X-ray
Hyperuricemia most commonly results from . . .
. . . underexcretion of uric acid due to renal insufficiency or competition for excretion with organic acids, like low-dose aspirin or lactic acid in individuals with poor liver function (usually due to alcohol).
Uric acid production
Hyperuricemia caused by uric acid overproduction
Rare, but occasionally seen in diseases which caused increased nucleic acid turnover:
- psoriasis
- myeloproliferative diseases
- hemoltyic anemia
In addition to decreasing uric acid excretion, ___ is a source of purines.
In addition to decreasing uric acid excretion, alcoholic beer is a source of purines.
Epidemiology of gout
- Usually men
- Usually over 30 years of age
- Incidence increases significantly with rising uric acid levels
Hyperuricemia in the absence of gout
NOT an indication for treatment. It is unclear as to why, but some people with high uric acid just don’t get gout.
How gout initiates NLRP3 activation
- MΦ is activated by some stimulus (TNF, IL-1, TLR, etc etc)
- MΦ upregulates NLRP3
- NLRP3 senses monosodium urate crystals and activates
- Inflammasome asembles and activates caspase-1
- Caspase-1 cleaves IL-1β and Gasdermin D, enabling IL-1β secretion
- IL-1β brings in a surge of PMNs
- PMNs attack tissue with ROS and proteases and produce more pro-inflammatory mediators
- Joint damage and acute pain
The appearance of acute gout can be confused with ____.
The appearance of acute gout can be confused with cellulitis
Treatment of a gout flare
- NSAIDs (inhibit COX2)
- prednisone (inhibit PLA2)
- colchine (thought to act by inhibiting inflammasome)
Prevention of gout flares
- Aimed at lowering uric acid serum levels
- Probenecid increases uric acid excretion via kidney, if kidney function is not impaired
- Allopurinol or febuxostat, xanthine oxidase inhibitors
- Recombinant uricase (lyses uric acid to allantoin, a highly soluble breakdown product), but many patients will have an immune response against uricase
Treatments that inhibit uric acid formation may ___.
Treatments that inhibit uric acid formation may precipitate an acute gout attack by rapidly changing serum uric acid.
This may be inhibited by treating simultaneously with an anti-inflammatory
On polarized light microscopy, monosodium urate crystals are ___ while calcium pyrophosphate crystals are ___.
On polarized light microscopy, monosodium urate crystals are negatively birefringent while calcium pyrophosphate crystals are positively birefringent.
Like MSUC, CPPC may ___. Unlike MSUC, CPPC may ___.
Like MSUC, CPPC may activate NLRP3. Unlike MSUC, CPPC may deposit in cartilage.
Radiographic findings of ____ are diagnostic for pseudogout.
Radiographic findings of punctate and linear densities in hyaline articular cartilage or fibrocartilage are diagnostic for pseudogout.
Pseudogout of the wrist
Not every patient with CPPD crystal deposition develops ___.
Not every patient with CPPD crystal deposition develops an acute inflammatory arthritis.
Actually, the number is 25%, only a minority.
In half of all pseudogout patients, the first gout attack involves the ___.
In half of all pseudogout patients, the first gout attack involves the knees.
Most important risk factor for pseudogout
age
Epidemiology of pseudogout
- Age
- Trauma (including surgery)
- Genetic factors (neonatal cases are described in literature)
- Metabolic and endocrine conditions (namely hypothyroidisum, hyperparathyroidism, and hemochromatosis
Treatment of a pseudogout flare
- NSAIDs (inhibit COX2)
- prednisone (inhibit PLA2)
- colchine (thought to act by inhibiting inflammasome)
The same as for gout, except there are no equivalents for preventative therapies.
Periodic fever syndromes
Group of monogenic disorders characterized by episodes of fever, elevated CRP and ESR. Locations of inflammation vary with disease. A subset of these diseases are associated with mutations resulting in aberrant IL-1β processing.
Cryopyrin-associated periodic syndromes
Result of mutations in NLRP3. Associated with elevated IL-1β during attacks. Fever, rash, arthralgias or arthritis, hearing loss and conjunctivitis. CAPS is treated by inhibition of IL-1.
Familial Mediterranean Fever
Most common periodic fever syndrome. Genetic mutation in MEVF gene, encoding pyrin, the central component of the pyrin inflammasome, which also activates caspase-1 and thereby IL-1β.
Episodic fevers lasting 1-3 days, monoarthritis, rash and severe abdominal pain
Rilonacept
Soluble IL-1R. Binds IL-1β > IL-1α > IL-1Ra
Anakinra
Recombinant IL-1Ra
Canakinumab
IgG1 anti-IL-1β mAb
minimal erythema dose
Minimum amount of a particular wavelength of light capable of inducing erythema on an individual’s skin
Acne vulgaris
Chronic inflammatory disease of the pilosebaceous follicles. Comedo and comedone make up the primary lesions, but are usually accompanied by erythematous papules and pustules as a result of inflammation.
Comedo
A comedo is the primary lesion of acne. It may be seen as a flat or slightly elevated papule with a dilated central opening filled with blackened keratin. (blackheads)
Comedone
Yellowish, pus-filled papules. (whiteheads)
Propionibacterium acnes
Major microorganism which contributes to the etiology of acne. Activates the NLRP3 inflammasome in skin macrophages and TLR-2 dependent IL-1 production in keratinocytes.
“Primary” phenomena
X is the primary presentation and we don’t know what causes underly it.
Etiology of primary gout?
Who the fuck knows
Lesch-Nyhan
Loss-of-function mutation in HPRT, the enzyme which recycles guanine and hypoxanthine for use in nucleotide syntesis. May cause gout and also has strange behavioral symptoms which involve self-mutilation.
Khan Academy gout overview image
CPPD and pseudogout
Not necessarily synonymous. CPPD may be asymptomatic, but pseudogout is symptomatic by definition. Think of pseudogout as a subset of CPPD.
