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MedEd + PathSoc + Laz's Qs + Romesh Path > Immuno 5: Autoinflammatory + AI diseases > Flashcards

Immuno 5: Autoinflammatory + AI diseases Flashcards

1
Q

Difference between autoinflammatory and autoimune diseases?

A

AutoINflammatory – driven by components of the INnate immune system

Autoimmune – driven by components of the adaptive immune system

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2
Q

Which cells are mainly responsible for:
Autoinflammatory Diseases
Autoimmune Diseases

A

Autoinflammatory Diseases:
Macrophages and neutrophils (disease is usually localised)

Autoimmune Diseases:
T and B cells

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3
Q

Mutations in which pathways are implicated in monogenic autoinflammatory disease?

A

Innate immune cell function – abnormal signalling via key cytokine pathways involving TNF-alpha or IL-1

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4
Q

Which protein is upregulated in autoinflammatory diseases caused by a gain-of-function mutation in NLRP3?

A

Cryopyrin (NALP3)

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5
Q

Name 3 diseases that are caused by this mutation (GoF of NLRP3 gene)

Inheritance of these conditions?

A

This leads to upregulated cryopyrin as seen in:

  • Muckle Wells syndrome
  • Familial cold autoinflammatory syndrome
  • Chronic infantile neurological cutaneous articular syndrome

All of these are autosomal dominant

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6
Q

What are some other examples of monogenic autoinflammatory conditions?

A

TNF receptor associated periodic syndrome (TNF receptor mutation)

Hyper IgD with periodic fever syndrome (mevalonate kinase mutation)

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7
Q

Describe how the inflammasome complex functions

A

Inflammasome complex pathway:
+ The pathway is activated by toxins, pathogens and urate crystals
+ These act via cryopyrin and ASC (apoptosis-associated speck-like protein) to activate procaspin 1
+ Activation of procaspin 1 results in the production of NFκB, IL1 and apoptosis

  • Pyrin-maronestrin is a negative regulator of this pathway
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8
Q

Pathophysiology of Familial mediterranean fever?

A

This is an AR autoinflammatory disease

LoF mutation in MEFV -> decreased pyrin-marenostrin (normally inhibits inflam pathway) -> upregulated inflammasome complex

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9
Q

Which cells contain pyrin-maronestrin?

A

Neutrophils

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10
Q

Clinical features of familial mediterranean fever? increased risk?

A

Fever and serositis periodically (48-96 hrs) decreases after serositis

Serositis symptoms:
Abdominal pain (peritonitis)
Chest pain (pleurisy, pericarditis)
Arthritis 
Rash

Increased risk of AA amyloidosis - due to reguar and chronic inflam

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11
Q

Mx of familial mediterranean fever?

A

Colchicine (inhibits neutrophil function)

Anakinra (anti-IL-1R)

Etanercept (TNFa inhibitor)

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12
Q

Most common cause of fever that comes and goes w/ unknown origin?

A

Subacute endocarditis - FMF is alot rarer

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13
Q

What are the three main mechanisms of monogenic autoimmune diseases + what conditions involved?

A

Defect of central tolerance – APS-1/APECED

Defect of peripheral tolerance – IPEX

Defect of lymphocyte apoptosis – ALPS

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14
Q

What is the difference between central and peripheral tolerance

A

CENTRAL TOLERANCE – deletion of auto-reactive lymphocytes in sites of maturation (BM + Thymus)

PERIPHERAL TOLERANCE (outside BM + thymus)

  1. T cells cannot be activated without co-stimulation
  2. Action of regulatory T cells
  3. Sites of immune privilege – e.g. eyes, testes, CNS
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15
Q

What is APS-1 / APECED?

A

This is a Monogenic Autoimune disease

Autoimmune polyendocrine syndrome type I (APS-1) or

Autoimmune polyendocrinopathy ectodermal dystrophy syndrome (APECED) - OLD NAME

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16
Q

What pathophysiology of APS-1 / APECED ? what gene?

A

AIRE = Transcription factor responsible for expression of self-antigens in the thymus and promotes apoptosis of self-reactive T cells

Defects in AIRE leads to a failure of central tolerance and the release of auto-reactive T cells

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17
Q

Which autoimmune conditions tend to occur in APS-1 / APECED? which are main ones?

A 
Hypoparathyroidism (COMMON) 
Addison’s disease (COMMON)
Hypothyroidism 
Diabetes mellitus 
Vitiligo
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18
Q

what infection most likely to occur + why in APS-1 / APECED

A

Candidiasis – anti-IL17 and anti-IL22 antibody formation leads to chronic yeast infections

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19
Q

What is IPEX?

A

This is a Monogenic Autoimune disease

Immune dysregulation, poylendocrinopathy, enteropathy, X-linked syndrome (IPEX)

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20
Q

What is the pathophysiology of IPEX?

A

FoxP3 – required for the development of Treg cells

A lack of Tregs leads to autoantibody formation (failure of peripheral tolerance)

Tregs = important for down regulating immune response

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21
Q

What signs are seen in a person w/ IPEX?

A

Foxp3 hence 3 Ds (+H)

Diarrhoea - enteropathy
Diabetes - T1DM
Dermatitis
Hypothyroidism

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22
Q

What is ALPS?

A

This is a Monogenic Autoimune disease

Autoimmune lymphoproliferative syndrome (ALPS) - most heterogenous

23
Q

Which mutations cause ALPS?

A

Various mutations in the FAS pathway -> defects in apoptosis of lymphocytes

This leads to:

  • Failure of lymphocyte tolerance (as autoreactive lymphocytes don’t die by apoptosis)
  • Failure of lymphocyte homeostasis (you keep producing lymphocytes)
24
Q

Clinical presentation of ALPS? high risk of?

A

Very high lymphocyte count – double-negative (CD4- CD8-) T cells

Splenomegaly and lymphadenopathy

Autoimmune diseases, especially cytopaenias (thrombo, haemolytic anaemia)

High risk of lymphoma

25
Q

A mutation in which of the following diseases is most likely to be associated with the development of of autoimmune haemolytic anaemia?

Familial Mediterranean fever
APS-1
IPEX
ALPS

A

ALPS – most commonly causes cytopaenias

APS-1 and IPEX are more likely to cause endocrinopathies

26
Q

Are polygenic or monogenic Autoinflammatory / autoimmune conditions more common?

A

Monogenic are a lot rarer

27
Q

Describe familial inheritance of Crohns?

A

15% have a family history

50% vs <10% disease concordance in monozygotic versus dizygotic twins

28
Q

What genes are involved in Crohns and where is this found?

A

NOD2 (aka CARD15) gene found on IBD1 on chromosome 16

29
Q

Where is NOD2 found and what is its role?

A

Cytoplasm of myeloid cells

Acts as a microbial sensor (recognises muramyl dipeptide)

30
Q

Mx of Crohns?

A

Steroids (remission inducing)

Azathioprine/6-MP

Anti-TNFalpha

Anti-IL12/23

31
Q

Exam Qs common difference between UC and Crohns?

A

Diarrhoea:
Bloody -> UC (in reality can be seen in both)
Watery -> Crohns

32
Q

What is the genetic pattern behind Crohns?

A

Polygenic autoinflammatory disease

33
Q

What is an example of polygenic mixed pattern disease?

A

Ankolysing spondylitis

34
Q

What is the strongest genetic association of ankylosing spondylitis?

A

HLA-B27 - 50% of cases

Affects both adaptive (CD8 T cells) and innate (NK cells) immune system

35
Q

What else is HLA-B27 linked w/?

A

Particularly important in spondyloarthropathy:

  • JIA
  • Reactive Arthritis
  • Psoriatic arthritis
  • undifferentiated spondyloarthritis

Anterior uvetis
IBD

36
Q

How does ankylosing spondylitis present?

A

At sites with high shear forces (i.e. entheses)

Sacroiliac joint
Achilles tendon

General picture involves inflammatory lower back pain (worse in morning and with rest)

37
Q

Mx of ankylosing spondylitis?

A

NSAIDs + physio
Anti-TNFalpha
Anti-IL17

38
Q

What are the 2 genetic requriements of polygenic autoimmune diseases?

A

Sensitisation to antigens

Overcoming peripheral tolerance

39
Q 
List the autoimmune diseases associated with the following HLA polymorphisms:
HLA-DR3
HLA-DR3/4
HLA-DR4
HLA-DR15
A

DR3
Graves’ disease
SLE

DR3/4
Type 1 diabetes mellitus

DR4
Rheumatoid arthritis

DR15
Goodpasture’s syndrome

40
Q

Name and state the function of 2 genes that are involved in T cell activation and are often mutated in polygenic autoimmune disease

A

PTPN22 – suppresses T cell activation

CTLA4 – regulates T cell function (expressed by T cells)

41
Q

Outline the Gel and Coombs effector mechanisms of immunopathology.

A

Type I: IgE-mediated immediate hypersensitivity
Type II: antibody reacts with cellular antigen
Type III: antibody reacts with soluble antigen to form an immune complex
Type IV: delayed-type hypersensitivity, T cell-mediated response

NOTE: autoimmunity is most common with type II hypersensitivity

42
Q

List some inflammatory mediators involved in type I responses that are:
Pre-formed
Synthesised

A

Pre-formed
Histamine, serotonin, proteases

Synthesised
Leukotrienes, prostaglandins, bradykinin, cytokines

43
Q

Outline the pathophysiology of IgE-mediated type I responses.

A

IgE binds to a foreign antigen (e.g. pollen)

The Fc portion binds to mast cells and basophils leading to degranulation

44
Q

What are the consequences of immune complex formation in type III hypersensitivity reactions?

A

Complexes deposit in vessels and activate complement and immune cells using thier Fc portion

Can cause small vessel bleeding -> purpuric rash

45
Q

Give some examples of type IV hypersensitivity mediated diseases and state the autoantigen involved

A

Insulin-dependent diabetes mellitus – pancreatic beta-cell antigen

Multiple sclerosis – myelin basic protein, proteolipid protein, myelin oligodendrocyte glycoprotein

46
Q

How can type IV reactions cause autoimmune disease?

A

HLA I – CD8 –> damage cells via perforin or fas

HLA II – CD4 –> damage cells via TNF and cytokine production, lymphotoxin, HLA upregulation

47
Q

What Gell and Coombs classification is myasthenia gravis?

Type I
Type II
Type III
Type IV

A

Type II – anti-nAChR antibodies

48
Q

Young male patient with intractable diarrhoea, type 1 diabetes and severe eczema. Diagnosis?

A

IPEX

49
Q

15 year old with recurrent candidiasis, nail pitting and hypoparathyroidism. Name the causative mutation

A

Mutation in TF AIRE

50
Q
  1. 10 year old with abdominal fullness and splenomegaly. FBC reveals high lymphocytes. History of autoimmune thrombocytopenia. Diagnosis?
A

ALPS

51
Q

Man develops swollen lips/tongue when blowing up balloons at daughter’s birthday party

Which type of reaction?

A

Type 1

52
Q

Healthcare worker notices itchy skin rash after wearing latex gloves at work for a few months

Which type of reaction?

A

Type 4

53
Q

Patient develops skin rash, joint aches and fever after being given penicillin for a chest infection

Which type of reaction?

A

Type 3

MedEd + PathSoc + Laz's Qs + Romesh Path (99 decks)

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