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MIIM30003 - Medical & Applied Immunology > Lecture 34 - Immunodeficiencies > Flashcards

Lecture 34 - Immunodeficiencies Flashcards

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USMLE® Step 1 flashcards
1
Q

What factors are taken into account for diagnosis of immunodeficiencies?

A
  • Recurrent infection history
    • Also asthma, autoimmunity, cancer
  • Tests:
    • Serum Ab
    • B/T cell n°s in blood
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2
Q

What are the two broad categories of immune deficiency?

A
  • Primary
    • Inherited, genetic mutations
  • Secondary
    • Acquired
    • Varied aetiology:
      • ​Viral infection
      • Malnutrition
      • Leukaemia
      • Lymphoma
      • Chemotherapy
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3
Q

List some B cell deficiencies

A
  • X-linked agammaglobulinaemia
  • Hyper-IgM syndrome
  • Common variable immunodeficiency
  • Selective IgA immunodeficiency
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4
Q

Describe XLA

A
  • X-linked agammaglobulinaemia
  • Genetic mutation resulting in
    • No circulating B cells
    • ​No Ab production
  • Susceptible to pyogenic infections
    • ​Streptococci
    • Pneumococci
  • Treatment
    • (weekly, bimonthly) Intragam
    • Intravenous immunoglobulin
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5
Q

When is XLA usually diagnosed?

A

At 6-9 months, after maternal Ab wanes

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6
Q

Describe the aetiology of XLA

A
  • Mutation in Btk
    • ​Bruton’s Tyrosine Kinase
    • Needed for transduction of ‘success signal’ from pre-BCR at the pre-B cell stage
      • After heavy chain rearrangement
    • B cells can’t progress to Immate B cell stage
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7
Q

Describe HIGM syndrome

A
  • Primary immune deficiency
  • No isotype switching
    • ​No IgG, IgA
    • High levels of IgM
  • Susceptibility to recurrent bacterial infections
    • ​Streptococci
    • Pneumocystis carinii
  • Treatment
    • ​Recurrent IVIg
  • Aetiology
    • ​X-linked-HIGM: Genetic mutation in CD40L
    • AID mutation
    • CD40 mutation
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8
Q

Describe Selective IgA immunodeficiency

A
  • Unknown genetic mutation
  • Increased susceptibility to respiratory infections
  • Most common immunodeficiency
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9
Q

Describe CVID

A
  • Common variable immunodeficiency
  • ‘Umbrella’ term
  • Variable reductions in IgA and IgG
  • Varying degrees of disease
  • Presents later in life
    • 30-40 yrs
  • Aetiology
    • Mutations not known
    • Result in defects in B cell maturation events in the GC (like some types of HIGM)
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10
Q

List some T cell deficiencies

A
  • Wiskott-Aldrich syndrome (WAS)
  • Familial haemophagocytic lymphohistocytosis (FHL)
  • DiGeorges syndrome
  • Bare lymphocyte syndrome
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11
Q

Describe WAS

A
  • Wiskott-Aldrich syndrome
  • Features:
    • ​Thrombocytopaenia
      • ​⇒ Severe haemorrhage, bruising
    • Impaired T cell function
    • Low serum Ig levels
  • Aetiology
    • ​Genetic mutation in WAS protein
  • Pathogenesis
    • ​Normal T cell development, decreased peripheral T cell n°s
    • WAS plays a role in:
      • Immunological synapse
      • Secretion of granzymes & perforin
    • ​Through:
      • Actin polymerisation
      • Cytoskeleton reorganisation upon TCR ligation
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12
Q

Describe FHL

  • Aetiology
  • Features
A
  • Familial haemophagocytic lymphohistocytosis
  • Presents very early in children
  • ‘Cytokine storm syndrome’
  • Aetiology
    • ​Missense mutation in Perforin
  • Features
    • ​Polyclonal CD8 T cell accumulation in LNs
    • Uncontrolled T cell activation
    • Progressive inflammation
      • ​Lethal, unless immunosuppressants are used
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13
Q

Describe DiGeorges syndrome

A
  • Features
    • ​No T cell responses
    • No T cell dependent Ab responses
  • Aetiology
    • ​Mutation in T-box 1 (TBX1)
      • ​Transcription factor
    • Spontaneous mutation in chromosome 22 during embryogenesis
      • Not inherited
  • Pathogenesis
    • ​No development of thymic epithelium during development
    • No T cell maturation
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14
Q

Describe Bare Lymphocyte syndrome

A
  • Aetiology
    • Mutation in any of the genes that control MHC II gene function
    • (not in MHC genes proper)
    • Bare lymphocyte syndrome I
      • TAP-1/2
    • Bare lymphocyte syndrome II
      • RFX
      • Class II transactivator (CIITA)
  • Pathogenesis
    • Little to no expression of MHC II on APCs
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15
Q

Describe SCID

A
  • Severe combined immune deficiency
  • Features
    • Profound deficiencies in B, T and NK cell function
    • Death before age 1 if no treatment
    • Recurrent infections
      • Candida albicans
      • Pneumocystis carinii
      • Parainfluenza
      • Cytomegalovirus
      • EBV
      • Mycobacteria
  • Treatment
    • Only BM transplant
  • Aetiology
    • ​X-linked SCID: common γ chain
      • Most common mutation (50%)
      • ​Many cytokines signal through receptors that involved the γc chain
    • Autosomal recessive SCID:
      • ​JAK3
      • ADA
      • RAG
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16
Q

List some cytokines that signal through receptors that involved the γc chain

A
  • IL-2
  • IL-4
  • IL-7
  • IL-9
  • IL-15
  • IL-21
17
Q

Describe the role of JAK3

A
  • Needed for downstream signalling through receptors that use yc chain
  • Mutation results in X-linked SCID-like syndrome
18
Q

Describe the role of ADA

A
  • Adenosine deaminase
    • ​Found in all tissues, most prominent in lymphocytes
  • Defect
    • ​Accumulation of toxic purine intermediates
    • This is felt most profoundly in lymphocytes, as they proliferate much more rapidly than other cells in the body
19
Q

Describe the role of RAG

A
  • RAG-1/2 required for Ig and TCR gene rearrangement
  • Defect:
    • Lack of B cells and T cells
20
Q

List the various treatments for immune deficiencies

A
  • IVIg
    • ​HIGM
    • XLA
  • Antibiotics
  • Gene therapy
    • Viral vectors deliver functional copy of gene
    • Trialled for SCID (ADA and yc chain def.)
  • BM transplant
    • ​SCID
    • GvHD
  • Enzyme replacement
21
Q

In general, what is the most common cause of secondary immunodeficiencies?

A

Infection, leading to suppression of immune responses or depletion of immune cells:

  • Measles
  • HIV
22
Q

How does measles infection cause immune deficiency?

A
  • Characterised by lack of B and T cell responses
  • Precise mechanism is unclear
    • Evidence that measles virus infects DCs
      • ​Kills / inactivates the DC
    • Production of a suppressive factor?
      • ​→ anergy
23
Q

What is the implication of the fact that many of the mutations causing primary immunodeficiencies are on the X chromosome?

A

Boys are much more commonly affected

24
Q

Describe CD40L

A
  • Member of the tumour necrosis superfamily
  • Expressed on activated T cells
  • Essential for:
    • T cell help
    • T cell co-stimulation of APCs
      • DCs, Macrophages
25
Q

Compare the severity of HIGM syndrome with different mutations

A
  • CD40L mutation: most severe
    • X-linked
  • AID mutation: less severe
26
Q

What is the importance of AID?

A
  • Essential for:
    • Class switch recombination
    • Somatic hypermutation
  • Mutation results in HIGM syndrome
27
Q

What does a perforin mutation result in?

A

FHL: familial haemophagocytic lymphohistocytosis

28
Q

What syndrome does mutation in the common γ chain result in?

A

SCID: severe combined immune deficiency

29
Q

Which cytokine is vital for NK cell function?

A
  • IL-15
  • Signals through the γc chain
30
Q

Which was the first mutation to be treated with gene replacement therapy?

A

ADA mutation: SCID

31
Q

List mutations that lead to SCID

A
  • γc chain
  • JAK4
  • ADA
  • RAG1/2
32
Q

What are the considerations for repeated antibiotic therapy for immune deficiencies?

A
  • Selection of resistant mutants
  • Associated toxicity
33
Q

What is the best treatment for primary immune deficiencies?

A
  • Gene therapy
  • Adresses the underlying defect of the disease
  • Still very experimental
34
Q

Which bacteria produces superantigens?

A

Staph. aureus

MIIM30003 - Medical & Applied Immunology (30 decks)

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