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YR5 Immunology > Autoimmune and Autoinflammatory Disease 1 > Flashcards

Autoimmune and Autoinflammatory Disease 1 Flashcards

1
Q

What triggers

a) fevers/malaise seen in primary EBV

b) abscess formation

what is the immune response?

A

Pathogens

a: Adaptive response: Cytokines

b: Innate response: Neutrophils

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2
Q

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?

A

No obvious pathogen

a) Innate response: Cytokines

b) Adaptive response: Antibodies

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3
Q

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

a) Auto-inflammatory: neutrophils + macrophages

b) Mixed

c) Auto-immune: B+T cells

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4
Q

What is the pathophysiology of auto-inflammatory diseases?

A

Local factors at sites predisposed to disease lead to activation of innate immune cells (macrophages + neutrophils)

Result in tissue damage.

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5
Q

What is the pathophysiology of auto-immune disease?

A

Aberrant T + B cell responses in primary + secondary lymphoid organs lead to breaking of tolerance with development of immune reactivity towards self-antigens.

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6
Q

How may auto-immune disease manifest clinically?

A

Organ-specific antibodies may predate presentation by years.

Adaptive immune response plays predominant role in presentation of disease.

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7
Q

Are the following polygenic or monogenic?

a) Innate immune response

b) Mixed Innate/Adaptive

c) Adaptive immune response

A

a) Polygenic + monogenic

b) Polygenic

c) Polygenic + monogenic

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8
Q

What is a germline mutation affecting DNA synthesis?

A

Alteration in DNA that occurs in germ cells (sperm + ova + progenitors)

Passed on to offspring.

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9
Q

What is a somatic mutation affecting DNA synthesis?

A

Alteration in DNA occurs in single body cell after conception

Does NOT affect germ cells, so is NOT inherited.

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10
Q

What are epigenetics?

A

(Heritable) Change in gene expression e.g. via DNA methylation.

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11
Q

What is microRNA (miRNA)?

A

Small, non-coding, single stranded RNA.

Targets mRNA + regulate protein production.

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12
Q

What are 2 rare monogenic auto-inflammatory diseases?

A

Familial mediterranean fever

TRAPS

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13
Q

What are 5 polygenic auto-inflammatory diseases?

A

Crohn’s disease

Ulcerative colitis

Osteoarthritis

Giant cell arteritis

Takayasu’s arteritis

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14
Q

What are 3 mixed pattern diseases?

A

Axial spondyloarthritis

Psoriatic arthritis

Behcet’s syndrome

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15
Q

What are 8 polygenic auto-immune diseases?

A

Rheumatoid arthritis

Systemic lupus erythematosus

Myaesthenia Gravis

Primary biliary cirrhosis

Pernicious anaemia

ANCA associated vasculitis

Graves disease

Goodpasture disease

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16
Q

What are 4 rare monogenic auto-immune diseases?

A

APS-1 aka. APECED

ALPS

IPEX

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17
Q

What is the pathophysiology of monogenic auto-inflammatory disease?

A

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.

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18
Q

Give 3 signs and symptoms of monogenic auto-inflammatory disease?

A

Periodic fevers

Skin/ joint/ serosal/ CNS inflammation

High CRP

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19
Q

What is Muckle-Wells Syndrome (MWS)? Name the gene mutated, protein encoded and pattern of inheritance

A

MONOgenic auto-INFLAMMATORY disease

Gene: NLRP3 GoF

Protein: NALP3, Cryopyrin

More ASC activation

Pattern of inheritence: AD

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20
Q

What is Familial-Mediterranean Fever (FMF)?

Name the gene mutated, protein encoded and pattern of inheritance

A

MONOgenic auto-INFLAMMATORY disease

Gene: MEFV LoF

Protein: Pyrin-Marenostrin

Pattern of inheritence: AR

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21
Q

What is TNF receptor associated periodic syndrome (TRAPS)? Name the gene, protein and pattern of inheritance

A

MONOgenic auto-INFLAMMATORY disease

Gene: TNFRSF1

Protein: TNF receptor

Pattern of inheritence: AD

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22
Q

What is Hyper-IgD with periodic fever syndrome (HIDS)?

A

MONOgenic auto-INFLAMMATORY disease

Gene: MK

Protein: Mevalonate kinase

Pattern of inheritence: AR

23
Q

What is the inflammasome complex?

A

Complex of proteins that work together to activate Caspase 1, which will then activate different cytokines + inflammatory processes resulting in inflammation

24
Q

What is the inflammasome complex composed of?

A

Apoptosis-associated speck like protein (ASC)
+
Procaspase 1

25
Q

What is ASC inhibited by?

A

Pyrin-Marenostrin:

Constantly made by body
Inhibits ASC, thus inhibits activity of inflammasome complex

26
Q

What is ASC activated by?

A

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

27
Q

What is the pathogenesis of Familial Mediterranean Fever?

A

LoF in MEFV

Less Pyrin-Marenostrin

Less inhibition of ASC

Unopposed activation of inflammasome complex

28
Q

Where is Pyrin-marenostrin mainly expressed?

A

Neutrophils

29
Q

Give 5 features of clinical presentation in Familial Mediterranean Fever?

A

Periodic fevers lasting 48-96h a/w:

Abdo pain due to peritonitis

Chest pain due to pleurisy + pericarditis

Arthritis

Rash

30
Q

What are the complications associated with Familial Mediterranean Fever?

A

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
31
Q

What are investigations for Familial Mediterranean Fever?

A

High CRP

High SAA

Blood sample to specialist genetics lab to identify MEFV mutation

32
Q

What is the treatment for Familial Mediterranean Fever?

A

Colchicine 500ug bd: Binds to tubulin in neutrophils + disrupts neutrophil functions inc. migration + chemokine secretion.

IL-1 blocker (Anakinra, Canukinumab).

TNF alpha blocker.

33
Q

What is the pathophysiology of monogenic auto-immune disease?

A

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

34
Q

What is the pathophysiology of Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX)?

A

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

35
Q

What is central and peripheral tolerance? What plays a major role in the mechanisms governing these phenomenons?

A

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

36
Q

What is the clinical presentation of IPEX?

A

AI diseases:

  • Diabetes Mellitus
  • Hypothyroidism
  • Enteropathy

‘Diarrhoea, diabetes + dermatitis’

37
Q

What is the role of the FAS pathway? Why is this important?

A

Encodes cell death in auto-reactive + defective lymphocytes

Causes apoptosis post-immune response- prevents accumulation of lymphocytes

38
Q

What is the pathophysiology of auto-immune lymphoproliferative syndrome
(ALPS)?

A

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’.

39
Q

What is the clinical presentation of ALPS?

A

High lymphocyte numbers with large spleen + LNs.

AI disease: Commonly AI cytopenias.

Lymphoma- due to unregulated proliferation

40
Q

What is the pathophysiology of polygenic auto-inflammatory diseases?

A

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.

41
Q

What is the pathophysiology of inflammatory bowel disease?

A

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.

42
Q

What is the pathophysiology of Crohn’s Disease?

A

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.

43
Q

Where is NOD2 expressed? What is the function of NOD2?

A

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

44
Q

What is NOD2 also known as?

A

CARD-15

=Caspase activating recruitment domain -15

45
Q

What are 5 clinical features of Crohn’s Disease?

A

Abdominal pain + tenderness

Diarrhoea (blood, pus, mucous)

Fevers

Malaise

Aphthous ulcers

46
Q

What is the treatment of Crohn’s Disease?

A

Corticosteroids (acutely)

Azathioprine

or

Anti-TNF alpha antibody

47
Q

What is the pathophysiology of mixed pattern diseases?

A

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.

48
Q

Which genes are associated ankylosing spondylitis (axial spondyloarthritis)?

A

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.

49
Q

Where does inflammation tend to occur in ankylosing spondylitis?

A

Enhanced inflammation occurs at specific sites where there are high tensile forces.

=Entheses: Sites of insertions of ligaments or tendons.

50
Q

What is the clinical presentation of ankylosing spondylitis?

A

Low back pain + stiffness

Enthesitis

Large joint arthritis

51
Q

What is the treatment of ankylosing spondylitis?

A

NSAIDs

Immunosuppression:

  • Anti-TNF alpha
  • Anti-IL17
52
Q

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
A

Familial Mediterranean fever

53
Q

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
A

IPEX syndrome due to FoxP3 mutation

54
Q

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
A

Crohn’s disease

YR5 Immunology (14 decks)

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