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Pathology (Guide) > Immunology - Autoinflammatory + Autoimmune > Flashcards

Immunology - Autoinflammatory + Autoimmune Flashcards

1
Q

How are autoinflammatory and autoimmune diseases characterised?

A

Immunopathology in the absence of infection

Autoinflammatory = innate immune response
- Not characterised by auto-antibodies
- Weaker HLA associations

Autoimmune = Adaptive immune response
- Autoantibodies present
- HLA associations common

Mixed Disease = Mixed Innate/Adaptive
- Autoantibodies absent
- HLA associations possible

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2
Q

What are some rare monogenic autoinflammatory diseases?

A
  • Familial mediterranean fever
  • TRAPS
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3
Q

What are some polygenic autoinflammatory diseases?

A
  • Crohn’s disease
  • Ulcerative colitis
  • Osteoarthritis
  • Giant cell arteritis
  • Takayasu’s arteritis
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4
Q

What are some mixed pattern diseases?

A
  • Ankylosing spondylitis
  • Psoriatic arthritis
  • Behcet’s syndrome
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5
Q

What are some polygenic autoimmune diseases?

A
  • Rheumatoid arthritis
  • Myaesthenia Gravis
  • Pernicious anaemia
  • Graves disease
  • SLE
  • Primary biliary cirrhosis
  • ANCA associated vasculitis
  • Goodpasture disease
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6
Q

What are some rare monogenic autoimmune diseases?

A
  • APS-1, APECED
  • ALPS
  • IPEX
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7
Q

What is the cause and characteristics of monogenic autoinflammatory diseases?

A

Cause:
- Mutations in gene encoding protein involved in pathway associated with innate immune cell function

Characteristics:
- Abnormal signalling via key cytokine pathways involving TNF +/- IL-1 is common

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8
Q

What is the pathogenesis of Familial Mediterranean Fever?

A
  • Autosomal Recessive
  • Mutation in MEFV gene
  • Gene encodes pyrin-marenostrin
  • Pyrin-marenostrin expressed mainly in neutrophils
  • Failure to regulate cryopyrin driven activation of neutrophils
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9
Q

What is the clinical presentation of Familial Mediterranean Fever?

A
  • Periodic fevers lasting 48-96hrs
  • Abdo pain (peritonitis)
  • Chest pain (Pleurisy + Pericarditis)
  • Arthritis
  • Rash
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10
Q

How is Familial Mediterranean Fever a long term risk of AA Amyloidosis?

A
  • Liver produces serum amyloid A as acute phase protein
  • Serum amyloid A deposits in kidneys, liver spleen
  • Kidney deposition most clinically important
  • Proteinuria = nephrotic syndrome
  • Renal failure
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11
Q

What is the treatment for Familial Mediterranean Fever?

A
  • Colchicine 500ug BD
  • Anakinra (IL-1 receptor antagonist)
  • Etanercept (TNF α inhibitor)
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12
Q

What is the MoA of Colchicine?

A

Binds ot tubulin in neutrophils + disrupts neutrophil functions (inc. migration + chemokine secretion)

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13
Q

What is a monogenic autoimmune disease?

A

Mutation of a protein involved in a pathway associated with adaptive immune cell function

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14
Q

What is APS1/APECED?

A
  • Autoimmune Polyendocrine Syndrome Type 1
  • Autoimmune PolyEndocrinopathy Candidiasis Ectodermal Dystrophy Syndrome
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15
Q

What is the abnormality in APS1/APECED?

A

Abnormality in central tolerance

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16
Q

What is the inheritance pattern of APS1/APECED?

A

Autosomal recessive

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17
Q

What is pathogenesis of APS1/APECED?

A
  • Defect in autoimmune regulator AIRE
  • AIRE = transcription factor involved in development of T cell tolerance in thymus
  • Defect causes upregulation of expression of self-antigens by thymic cells + promotes T cell apoptosis
  • Defect leads to failure of central tolerance causing auto-reactive T + B cells
18
Q

What are the clinical features of APS1/APECED?

A

Multiple Auto-immune diseases:
- Hypoparathyroidism
- Addison’s
- Hypothyroidism
- Diabetes
- Vitiligo
- Enteropathy

Abs VS IL17 + IL22 leads to candidiasis

19
Q

What is IPEX?

A

Immune dysregulation, polyendocrinopathy, enteropathy

20
Q

What is the abnormality in IPEX?

A

Abnormality of regulatory T cells (failure of peripheral tolerance)

21
Q

What is the inheritance of IPEX?

A

X-linked

22
Q

What is the pathogenesis of IPEX?

A
  • Mutations in Foxp3 causes failure to negatively regulate T cell responses
  • Results in autoreactive B cells
  • Foxp3 is required for development of Treg cells
23
Q

What are some clinical features of IPEX?

A

Autoimmune diseases:
- Diabetes
- Hypothyroidism
- Enteropathy

  • Diarrhoea
  • Diabetes
  • Dermatitis
24
Q

What is ALPS?

A

Autoimmune lymphoproliferative syndrome

25
Q

What is the abnormality in ALPS?

A

Abnormality of lymphocyte apoptosis

26
Q

What is the inheritance pattern of ALPS?

A

Autosomal Dominant (incomplete penetrance)

27
Q

What is the pathogenesis of ALPS?

A

Mutations within FAS pathway
- e.g. TNFRSF6 - encodes FAS
- Disease is heterogenous depending on mutation

Defect in apoptosis of lymphocytes resilts in failure of tolerance + lymphocyte homeostasis

28
Q

What are some clinical features of ALPS?

A
  • High lymphocyte numbers (CD4 + CD8 T cells)
  • Splenomegaly
  • Lymphadenopathy
  • Autoimmune diseases (commonly autoimmune cytopenias)
  • High risk: Lymphoma
29
Q

What are polygenic auto-inflammatory diseases?

A
  • Mutations in genes encoding proetins involved in innate immune cell function
  • Local factors at sites predisposed to disease lead to activate of innate immune cells (e.g. macrophages + neutrophils) resulting in tissue damage
  • HLA associations less strong
  • Not characteristed by presence of auto-antibodies
30
Q

What is peripheral tolerance?

A
  1. T cells can’t be activated without co-stimulation
  2. Action of regulatory T cells
  3. Sites of immune privilege (e.g. eyes, testes, CNS)
31
Q

What is central tolerance?

A

The deletion of auto-reactive lymphocytes in sites of maturation

32
Q

What mutations are associated with Crohn’s disease in polygenic autoinflammatory disease?

A

IBD1 gene (Chr 16) identified as NOD2 (CARD-15)
- NOD2 expressed in cytoplasm of myeloid cells
- NOD2 is an intracellular receptor for bacterial products (it recognises muramyl dipeptide) + stimulates NFKb
- Activation of NFKb results in autophagy in dendritic cells

33
Q

What are mixed pattern diseases?

A
  • Mutations in genes encoding proteins involved in pathways associated with innate immune cell function + adaptive immune cell function
  • HLA associations may be present
  • Auto-antibodies not usually a feature
34
Q

What are polygenic autoimmune diseases?

A
  • Mutations in genes encoding proteins invoveld in adaptive immune cell function
  • HLA associations
  • Aberrant B cell + T cell responses in primary + secondary lymphoid organs lead to breaking of tolerance with developemnt of immune reactivity towards self antigens
  • Auto-antibodies found
35
Q

What are the genetic polymorphisms involved in polygenic autoimmune diseases and how do they operate?

A

PTPN22:
- Lymphocyte specific tyrosine phosphatase with suppresses T cell activation
- Associated with development of RA, SLE, T1DM

CTLA4:
- Receptor for CD80/CD86 expressed by T cells which transmits inhibitory signal to control T cell activation
- Associated with SLE, T1DM, autoimmune thyroid disease

36
Q

What HLA allele is associated with Ankylosing Spondylitis?

A

HLA B27

37
Q

What HLA allele is associated with Goodpasture’s syndrome?

A

HLA DR15/DR2

38
Q

What HLA allele is associated with Graves’ Disease?

A

HLA-DR3

39
Q

What HLA allele is associated with SLE?

A

HLA-DR3

40
Q

What HLA allele is associated with T1DM?

A

HLA DR3/DR4

41
Q

What HLA allele is associated with Rheumatoid arthritis?

A

HLA DR4
(There are 4 walls in a Rheum)

42
Q

What HLA alleles are associated with coeliacs disease?

A

DQ2/DQ8
( I 8 2 much gluten at Dairy Queen)

Pathology (Guide) (84 decks)

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