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MIIM30002 > Lecture 30: Immunodeficiencies > Flashcards

Lecture 30: Immunodeficiencies Flashcards

1
Q

When do immunodeficiencies occur?

A

when one or more components of the immune system are defective

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2
Q

What enables greater understanding of the molecular basis for immune function?

A

characterisation of where mutations occur

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3
Q

What are the two categories of immunodeficiency?

A

inherited immunodeficiency and acquired immunodeficiency

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4
Q

What is inherited immunodeficiency?

A

genetic mutations that result in immune system failure

often X-linked and autosomal recessive

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5
Q

What is acquired immunodeficiency?

A

suppression of immune responses, immune cell depletion
most commonly associated with infection
also malnutrition, leukemia, chemotherapy, autoimmunity

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6
Q

What is the proportion of those with inherited immunodeficiency who are male?

A

> 60%

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7
Q

What is the major consequence of immunodeficiency?

A

increased susceptibility to infection -> recurrent infections / allergy / autoimmunity / cancer

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8
Q

How are immunodeficiencies diagnosed?

A

by testing antibody in serum and lymphocyte counts in the blood

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9
Q

How are immunodeficiencies treated?

A

antibiotics, intravenous immunoglobulin, enzyme replacement and bone marrow transplant

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10
Q

What are the types of primary immunodeficiencies?

A

B cell and T cell deficiencies

also combined deficiencies (SCID)

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11
Q

What is X-linked agammaglobulinemia caused by? What does this result in?

A

caused by a mutation in the gene coding for Bruton’s tyrosine kinase (Btk)
results in an inability of pre-B cells to make a complete BCR, leading to pre-B cell apoptosis

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12
Q

Why does X-linked agammaglobulinemia result in immunodeficiency?

A

results in a block in B cell development which leads to a lack of antibody production

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13
Q

How is X-linked agammaglobulinemia treated?

A

routine intravenous Ig therapy (weekly / monthly)

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14
Q

What is hyper IgM syndrome?

A

family of genetic disorders associated with an absence of isotype switching (no IgG, IgA)
therefore there is a compensatory increase in IgM serum

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15
Q

How is hyper IgM syndrome treated?

A

routine intravenous Ig therapy

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16
Q

What is X-linked hyper IgM syndrome caused by?

A

mutations in CD40L -> defective CD40 signalling

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17
Q

Where is CD40L and CD40 expressed?

A

CD40L: expressed on activated T cells
CD40: expressed on B cells, macrophages, DC

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18
Q

What is the CD40-CD40L interaction essential for?

A

isotype switching, affinity maturation, memory B cell generation
macrophage activation

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19
Q

What is hyper IgM syndrome type 2 / AID deficiency caused by?

A

a mutation in activation-induced cytidine deaminase (AID) which results in a block in isotype switching and affinity maturation

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20
Q

What is the role of AID?

A

initiates a cascade that results in dsDNA breaks -> allows new constant region in the heavy chain to be introduced -> point mutations in variable regions (somatic hypermutation)

21
Q

What is selective IgA immunodeficiency caused by?

A

a block in B cell differentiation into IgA-plasma cells

genetic defect is unknown

22
Q

What does selective IgA immunodeficiency result in?

A

patients have increased susceptibility to respiratory infections (little to no IgA at mucosal surfaces)

23
Q

What is common variable immunodeficiency (CVID) caused by?

A

defect in 1 or more genes affecting B cell growth or stimulation

24
Q

What does common variable immunodeficiency result in?

A

present with variable reductions in IgG and IgA

varying degrees of disease (mild-recurrent infections)

25
Q

What is Wiskott-Aldrich syndrome caused by?

A

X-linked genetic defect in WAS protein

26
Q

What does Wiskott-Aldrich syndrome (T cell deficiency) result in?

A

induces actin polymerisation and redistribution in lymphoid cells, affecting cell movement and signalling

27
Q

What is Wiskott-Aldrich syndrome characterised by?

A

thrombocytopenia (low platelet count), susceptibility to bruising/haemorrhage and impaired T cell function, low serum Ig levels

28
Q

How does Wiskott-Aldrich syndrome affect T cell development?

A

there is normal T cell development (thymus), but there are decreased numbers of peripheral T cells

29
Q

What is the role of WAS expressed in T cells?

A

plays a role in actin polymerisation and cytoskeleton reorganisation upon TCR ligation
required for the formation of the immunological synapse

30
Q

What is familial hemophagocytic lymphohistiocytosis (T cell deficiency)?

A

autosomal recessive disorder (missense mutations)

31
Q

What does familial hemophagocytic lymphohistiocytosis result in?

A

lack of perforin in CD8+ T cells, polyclonal CD8+ T cell accumulation in lymph nodes and uncontrolled T cell activation, cytokine storm

32
Q

What does epidermodysplasia verruciformis (T cell deficiency) result in?

A

abnormal susceptibility to cutaneous HPV infection and defective T cell immunity

33
Q

What is epidermodysplasia verruciformis (T cell deficiency) caused by?

A

mutations in EVER1, EVER2 genes

involved in the regulation of zinc homeostasis in lymphocytes

34
Q

What is DiGeorges syndrome caused by?

A

deletion of genes from chromosome 22 which can occur randomly
rarely inherited and present from birth

35
Q

What are the symptoms of DiGeorges syndrome?

A

congenital heart disease, facial abnormalities, cleft palate, learning difficulties, frequent infections (defect in T cell maturation)

36
Q

What can a mutation in Tbx1 result in?

A

a failure of thymic epithelium development during embryogenesis

37
Q

What is bare lymphocyte syndrome II caused by?

A 
mutations in any one of four genes that control expression of MHC class II genes
-> class II transactivator (CIITA), RFXANK, RFX5, RFXAP
38
Q

What does bare lymphocyte syndrome II result in?

A

little or no MHC class II expression on surface of B cells, macrophages or dendritic cells

39
Q

What is the consequence of no MHC II expression?

A

failed positive selection in the thymus -> reduced helper T

cells, reduced antigen presentation

40
Q

What is severe combined immunodeficiency (SCID) caused by?

A

defect in >14 genes which results in profound deficiencies in B, T and NK cell function

41
Q

What is the only current treatment for severe combined immunodeficiency (SCID)?

A

bone marrow transplant

42
Q

What is X-linked SCID caused by?

A

mutation in common g-chain (CD132) which is present in several cytokine receptors

43
Q

What does X-linked SCID result in?

A

absence of functional B, T and NK cells

infants suffer increased susceptibility to array of opportunistic infections

44
Q

What genes are mutated on autosomal chromosomes in autosomal recessive SCID?

A

JAK3 (tyrosine kinase), adenosine deaminase (ADA) and recombinase activating genes (RAG)

45
Q

What is JAK3?

A

a tyrosine kinase that mediates downstream signalling after cytokines bind g-chain receptor

46
Q

What is autosomal recessive SCID (ADA) caused by?

A

defect in adenosine deaminase (ADA) enzyme

47
Q

What is ADA required for? What happens when there is a defect in this enzyme?

A

breakdown of purines
defect results in accumulation of toxic intermediates (deoxyadenosine) -> destruction of lymphocytes and progressive lymphopenia

48
Q

What is autosomal recessive SCID (RAG) caused by? What happens when there is a defect in this enzyme?

A

defect in RAG genes
result in a complete lack of mature B and T cells
NK cells are not affected

49
Q

What are recombinase activating genes required for?

A

VDJ recombination in developing lymphocytes

MIIM30002 (25 decks)

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