Autoimmune and Autoinflammatory Disease 1 Flashcards
What triggers
a) fevers/malaise seen in primary EBV
b) abscess formation
what is the immune response?
Pathogens
a: Adaptive response: Cytokines
b: Innate response: Neutrophils
What triggers
a) sacroiliac joint inflammation in an individual with axial spondyloarthritis
b) anaemia due to red cell haemolysis secondary to anti-red cell antibodies?
No obvious pathogen
a) Innate response: Cytokines
b) Adaptive response: Antibodies
In the absence of a pathogen, what immunopathology do the following cause?
a) Innate immune response
b) Mixed Innate/ Adaptive
c) Adaptive immune response
a) Auto-inflammatory: neutrophils + macrophages
b) Mixed
c) Auto-immune: B+T cells
What is the pathophysiology of auto-inflammatory diseases?
Local factors at sites predisposed to disease lead to activation of innate immune cells (macrophages + neutrophils)
Result in tissue damage.
What is the pathophysiology of auto-immune disease?
Aberrant T + B cell responses in primary + secondary lymphoid organs lead to breaking of tolerance with development of immune reactivity towards self-antigens.
How may auto-immune disease manifest clinically?
Organ-specific antibodies may predate presentation by years.
Adaptive immune response plays predominant role in presentation of disease.
Are the following polygenic or monogenic?
a) Innate immune response
b) Mixed Innate/Adaptive
c) Adaptive immune response
a) Polygenic + monogenic
b) Polygenic
c) Polygenic + monogenic
What is a germline mutation affecting DNA synthesis?
Alteration in DNA that occurs in germ cells (sperm + ova + progenitors)
Passed on to offspring.
What is a somatic mutation affecting DNA synthesis?
Alteration in DNA occurs in single body cell after conception
Does NOT affect germ cells, so is NOT inherited.
What are epigenetics?
(Heritable) Change in gene expression e.g. via DNA methylation.
What is microRNA (miRNA)?
Small, non-coding, single stranded RNA.
Targets mRNA + regulate protein production.
What are 2 rare monogenic auto-inflammatory diseases?
Familial mediterranean fever
TRAPS
What are 5 polygenic auto-inflammatory diseases?
Crohn’s disease
Ulcerative colitis
Osteoarthritis
Giant cell arteritis
Takayasu’s arteritis
What are 3 mixed pattern diseases?
Axial spondyloarthritis
Psoriatic arthritis
Behcet’s syndrome
What are 8 polygenic auto-immune diseases?
Rheumatoid arthritis
Systemic lupus erythematosus
Myaesthenia Gravis
Primary biliary cirrhosis
Pernicious anaemia
ANCA associated vasculitis
Graves disease
Goodpasture disease
What are 4 rare monogenic auto-immune diseases?
APS-1 aka. APECED
ALPS
IPEX
What is the pathophysiology of monogenic auto-inflammatory disease?
Mutations in a gene encoding a protein involved in a pathway a/w innate immune cell function.
Abnormal signalling via key cytokine pathways involving TNF-alpha +/- IL-1 is common.
Give 3 signs and symptoms of monogenic auto-inflammatory disease?
Periodic fevers
Skin/ joint/ serosal/ CNS inflammation
High CRP
What is Muckle-Wells Syndrome (MWS)? Name the gene mutated, protein encoded and pattern of inheritance
MONOgenic auto-INFLAMMATORY disease
Gene: NLRP3 GoF
Protein: NALP3, Cryopyrin
More ASC activation
Pattern of inheritence: AD
What is Familial-Mediterranean Fever (FMF)?
Name the gene mutated, protein encoded and pattern of inheritance
MONOgenic auto-INFLAMMATORY disease
Gene: MEFV LoF
Protein: Pyrin-Marenostrin
Pattern of inheritence: AR
What is TNF receptor associated periodic syndrome (TRAPS)? Name the gene, protein and pattern of inheritance
MONOgenic auto-INFLAMMATORY disease
Gene: TNFRSF1
Protein: TNF receptor
Pattern of inheritence: AD
What is Hyper-IgD with periodic fever syndrome (HIDS)?
MONOgenic auto-INFLAMMATORY disease
Gene: MK
Protein: Mevalonate kinase
Pattern of inheritence: AR
What is the inflammasome complex?
Complex of proteins that work together to activate Caspase 1, which will then activate different cytokines + inflammatory processes resulting in inflammation
What is the inflammasome complex composed of?
Apoptosis-associated speck like protein (ASC)
+
Procaspase 1
What is ASC inhibited by?
Pyrin-Marenostrin:
Constantly made by body
Inhibits ASC, thus inhibits activity of inflammasome complex
What is ASC activated by?
Cryopyrin
produced in response to anything irritating: Toxins, Microbes, Urate
Results in activation of inflammasome complex
Leads to inflammation through release of cytokines (IL1, NF-KB)
Induces apoptosis
What is the pathogenesis of Familial Mediterranean Fever?
LoF in MEFV
Less Pyrin-Marenostrin
Less inhibition of ASC
Unopposed activation of inflammasome complex
Where is Pyrin-marenostrin mainly expressed?
Neutrophils
Give 5 features of clinical presentation in Familial Mediterranean Fever?
Periodic fevers lasting 48-96h a/w:
Abdo pain due to peritonitis
Chest pain due to pleurisy + pericarditis
Arthritis
Rash
What are the complications associated with Familial Mediterranean Fever?
AA amyloidosis
- Liver produces serum amyloid A as acute phase protein.
- SAA deposits in kidneys, liver, spleen.
- Deposition in kidney often most clinically important
- Proteinuria: Nephrotic syndrome
- Renal failure
What are investigations for Familial Mediterranean Fever?
High CRP
High SAA
Blood sample to specialist genetics lab to identify MEFV mutation
What is the treatment for Familial Mediterranean Fever?
Colchicine 500ug bd: Binds to tubulin in neutrophils + disrupts neutrophil functions inc. migration + chemokine secretion.
IL-1 blocker (Anakinra, Canukinumab).
TNF alpha blocker.
What is the pathophysiology of monogenic auto-immune disease?
Mutation in gene encoding a protein involved in a pathway a/w adaptive immune cell function.
Abnormality of regulatory T cells: IPEX
Abnormality of lymphocyte apoptosis: ALPS
What is the pathophysiology of Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX)?
Mutations in Foxp3 (Forkhead box p3) which is required for development of Treg cells.
Failure to downregulate T cell responses.
Failure in suppress autoreactive B cells.
Failure of peripheral tolerance
What is central and peripheral tolerance? What plays a major role in the mechanisms governing these phenomenons?
Central: eliminate self-reactive lymphocytes during their initial development in BM + Thymus
Peripheral: eliminate self-reactive lymphocytes that escape the radar of central mechanisms; in the peripheral tissues + secondary lymphoid organs
T regs
What is the clinical presentation of IPEX?
AI diseases:
- Diabetes Mellitus
- Hypothyroidism
- Enteropathy
‘Diarrhoea, diabetes + dermatitis’
What is the role of the FAS pathway? Why is this important?
Encodes cell death in auto-reactive + defective lymphocytes
Causes apoptosis post-immune response- prevents accumulation of lymphocytes
What is the pathophysiology of auto-immune lymphoproliferative syndrome
(ALPS)?
Mutations within FAS pathway e.g. Mutations in TNFRSF6 which encodes FAS.
Disease is heterogeneous depending on mutation.
Defect in apoptosis of lymphocytes.
Failure of tolerance + lymphocyte ‘homeostasis’.
What is the clinical presentation of ALPS?
High lymphocyte numbers with large spleen + LNs.
AI disease: Commonly AI cytopenias.
Lymphoma- due to unregulated proliferation
What is the pathophysiology of polygenic auto-inflammatory diseases?
MutationS in genes encoding proteins involved in pathwayS a/w innate immune cell function.
Local factors at sites predisposed to disease lead to activation of innate immune cells e.g. macrophages + neutrophils, with resulting tissue damage.
HLA associations LESS strong.
Generally NOT characterised by auto-antibodies.
What is the pathophysiology of inflammatory bowel disease?
Genetic polymorphisms.
Familial association + twin studies suggest genetic predisposition
15% have affected family member.
50% vs <10% disease concordance in monozygotic vs dizygotic twins.
>200 disease susceptibility loci found.
What is the pathophysiology of Crohn’s Disease?
IBD1 gene on chr 16 = NOD2
3 different mutations of this gene a/w Crohn’s.
NOD2 mutations present in 30% (i.e. not necessary).
Abnormal allele of NOD2 increases risk by 1.5-3x if 1 copy + 14-44x if 2 copies (ie not sufficient).
+ environmental factors e.g. smoking
Mutations also found in patients with Blau syndrome + some forms of sarcoidosis.
Where is NOD2 expressed? What is the function of NOD2?
In cytoplasm of myeloid cells: macrophages, neutrophils, DCs.
Intracellular receptor for muramyl dipeptide on bacterial products + promotes their clearance.
Induces NF-KB + autophagy in myeloid cells
Mutations= more active receptor - more NK-KB- more inflammation
What is NOD2 also known as?
CARD-15
=Caspase activating recruitment domain -15
What are 5 clinical features of Crohn’s Disease?
Abdominal pain + tenderness
Diarrhoea (blood, pus, mucous)
Fevers
Malaise
Aphthous ulcers
What is the treatment of Crohn’s Disease?
Corticosteroids (acutely)
Azathioprine
or
Anti-TNF alpha antibody
What is the pathophysiology of mixed pattern diseases?
MutationS in genes encoding proteinS involved in pathwayS a/w innate immune cell function.
+
MutationS in genes encoding proteinS involved in pathways a/w adaptive immune cell function.
HLA associations may be present.
Auto-antibodies are NOT usually a feature.
Which genes are associated ankylosing spondylitis (axial spondyloarthritis)?
Highly heritable: genetics account for 90% of the risk
HLA B27
Accounts for <50% overall genetic risk. Presents antigen to CD8 T cells. Ligand for killer immunoglobulin receptor.
IL23R
Receptor for IL23 which promotes differentiation of Th17 cells.
ILR2
Interleukin receptor type II. Decoy receptor that inhibits activity of IL1.
Where does inflammation tend to occur in ankylosing spondylitis?
Enhanced inflammation occurs at specific sites where there are high tensile forces.
=Entheses: Sites of insertions of ligaments or tendons.
What is the clinical presentation of ankylosing spondylitis?
Low back pain + stiffness
Enthesitis
Large joint arthritis
What is the treatment of ankylosing spondylitis?
NSAIDs
Immunosuppression:
- Anti-TNF alpha
- Anti-IL17
Which of the following is an example of a monogenic auto-inflammatory disease?
- Familial Mediterranean fever
- Graves’ disease
- Crohn’s disease
- Axial spondyloarthritis
- IPEX syndrome due to FoxP3 mutation
Familial Mediterranean fever
Which of the following is an example of a monogenic auto-immune disease?
- Familial Mediterranean fever
- Graves’ disease
- Crohn’s disease
- Axial spondyloarthritis
- IPEX syndrome due to FoxP3 mutation
IPEX syndrome due to FoxP3 mutation
Which of the following is an example of a polygenic auto-inflammatory disease?
- Familial Mediterranean fever
- Graves’ disease
- Crohn’s disease
- Axial spondyloarthritis
- IPEX syndrome due to FoxP3 mutation
Crohn’s disease
