Lecture 10 - Genetic Immune Deficiency Disorders

Question 1

A mutation in what gene causes Burton’s agammaglobulinaemia?

Answer 1

– Mutation (300) in B-cell tyrosine kinase (BTK) gene on X chromosome (BKT essential for B-cell maturation, males mostly affected as they only have one X copy, treated with immunoglobulin replacement)

– Low numbers of B cells
– Low Immunoglobulin levels
– No humoural immunity

Question 2

What is the most common mutation in XSCID?

Answer 2

• Mutation in IL2RG gene on X-chromosome

Question 3

How does the mutation in XSCID affect the cells?

Answer 3

– Mutation encodes the IL2 receptor (IL2R) common Gamma chain (ϒc)

– Required for other receptors as well (IL-2, 4, 7, 9, 15, 21)

– IL-7 required for T-cells, IL-15 for NK cell
development

Question 4

The defect in XSCID effects T cells and NK cells. Why is it call “combined” immune deficiency?

Answer 4

– Numerous genetic mutations
– X-linked and autosomal
– Failure to develop B and T cells
– Thymus and lymphoid tissue reduced

Question 5

What are the cellular effects of mutations in adenosine deaminase (ADA) and
what disease does it cause?

Answer 5

– leads to reduced purine synthesis by salvage pathway defect

– Accumulation of S-adenosylhomocysteine which is toxic to T and B cells

– Lymphopenia develops after birth

– Effects other cells and so SCID is part of broader clinical defects

Question 6

What is DiGeorge syndrome and what causes it?

Answer 6

– Failure to form T-cells due to hypoplasia of thymus (partial or complete)

– Infants have cleft palate, facial cleft, low set ears, absence of parathyroid gland, heart malformed

– Deletion in a single gene, TBX1 (codes
for a transcription factor), chromosome 22

– Both cell mediated immunity and antibody
production effected (since no T cell help)

Question 7

What is Wiskott-Aldrich syndrome? How can autoimmune disease result from
the syndrome?

Answer 7

• Affects platelets and so was first described as a clotting disorder
• Reduces T-cells, defective NK-cell cytolysis and antibody responses (recurrent infections)
• Defective gene on X chromosome coding for WAS protein (WASP)

• WASP expressed on all haemopoietic cells
– Regulator of lymphocyte and platelet development
– Effects actin cytoskeleton in cells needed for immune synapses
– Required for suppressive action in Treg

• Get autoimmune diseases (T-cells fail to respond normally to activation signals)

Question 8

What is the benefit of having the mutation CCR5Δ32?

Answer 8

• CCR5 is an essential co-receptor for HIV
• Homozygous CCR5Δ32 individuals resistant to HIV infection, Heterozygous have delayed disease (not necessarily immune to AIDS)

Question 9

What are the drawbacks to having the mutation CCR5Δ32?

Answer 9

• Heterozygous CCR5Δ32 has been associated with greater infection rate of West Nile Virus
• Homozygous CCR5Δ32 associated with fatal West Nile Virus encephalitis

Question 10

What is CCR5Δ32?

Answer 10

• A 32 bp deletion in CCR5 results in a truncated non-functional form called CCR5Δ32
• Originated in northern Europe (Vikings)
• Other receptors can do the same job so no bad effects due to CCR5Δ32