W11L14 - Genetic Immune Deficiency Disorders

Question 1

Clinical History of Recurrent Infections

Answer 1

Clinical history of recurrent infections of the same or similar pathogens is suggestive of an immune deficiency disorder

1. Recurrent bacterial infection (pyogenic)
   - antibody, complement, phagocyte dysfunction
2. Recurrent/persistent fungal skin infection or virus infection
   - T cell dysfunction

Question 2

Primary and Secondary Immunodeficiency

Answer 2

Primary immunodeficiency
- present at birth
- genetic disorders - many X linked
- many infants die of infection before identified
- some have little effect on health due compensation mechanism
Secondary immunodeficiency
- acquired (drug or infection)

Question 3

Severe Combined Immune Deficiency (SCID) - Overview

Answer 3

Failure to develop B and T cells
Early and Thymus and lymphoid tissue reduced
Early in life the child has many recurrent infections
Death in 2 to 3 years without treatment
Numerous genetic mutations
X-linked and autosomal

Question 4

X-Linked SCID (XSCID)

Answer 4

Most common SCID
Mutation in IL2RG gene on X-chromosome
- 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
- mostly males
T cells and NK-cells fail to develop
B cells normal but can not function properly due to lack of T-cell help

Question 5

Not X-Linked but like XSCID

Answer 5

Mutation in autosomal kinase Jak3
Jak3 physically associated with common ϒc
Signal transduction is effected in the same way as XSCID
Exactly the same manifestations as XSCID
- T cell and NK cell development impaired
- B cells normal but not functioning
Other rare mutations exist for same effect
- e.g common beta chain (βc) for IL2 receptor

Question 6

SCID Causes

Answer 6

SCID can be caused by autosomal mutations
Defects in adenosine deaminase (ADA)
- 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 7

Treatment for SCID

Answer 7

Antibiotics for bacterial infection
Intravenous immunoglobulin (every 3-4 wks)
Enzyme therapy, PEG-ADA to replace ADA
- effective in 90% with ADA SCID
Bone marrow transplant
Gene therapy, replace defective gene

Question 8

X-Linked Agammaglobulinemia

Answer 8

Low numbers of B cells
Low immunoglobulin levels
- new born have a transient low immunoglobulin level
No humoural immunity
Mutation (300) in B cell tyrosine kinase (BTK) gene on X chromosome
- BKT essential for B-cell maturation
- males affected mostly (only one copy of X)
- treated with immunoglobulin replacement

Question 9

Primary IgA Deficiency

Answer 9

Reduced level of IgA production
Specific cause unknown
Usually asymptomatic
Some patients tend to have increased respiratory infections due to reduced sIgA

Question 10

DiGeorge Syndrome

Answer 10

22q11.2 deletion syndrome
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)
After age 5 most T-cells increase - thymus remanen

Question 11

Wiskott-Aldrich Syndrome

Answer 11

Effects platelets
- thrombocytopenia, eczema, bloody diarrhoea
Also reduced 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 haematopoietic cells
- regulator of lymphocyte and platelet development
- effects actin cytoskeleton in cells needed for immune synapses
- required for suppressive action in Treg (=> autoimmune diseases)
- T cells fail to respond normally to activation signals
Treat blood clotting, transfusion, BM Tx, gene therapy

Question 12

CCR5

Answer 12

Cysteine-cysteine chemokine receptor 5 (CCR5) is a receptor found on macrophages/monocytes/activated T cells
It is the receptor for pro inflammatory cytokines CCL3, 4 and 5
Epithelial cell release CCL3, 4, 5 in response to infection and attract macrophages to sight

Question 13

CCR5Δ32

Answer 13

A 32 bp deletion in CCR5 results in a truncated non-functional form called CCR5Δ32
Originated in northern Europe (Vikings)
Gene frequency:
- 10% in Northern Europe
- 8% in Southern Europe and Mid-east
- None in Asian, Southern/Western Africa
Other receptors can do the same job so no bad effects due to CCR5Δ32

Question 14

CCR5 and HIV

Answer 14

CCR5 is an essential co-receptor for HIV
- probably the main receptor
- CD4 probably required for conformational change in gp120/gp41 revealing binding site for CCR5
Homozygous CCR5Δ32 individuals resistant to HIV infection
Heterozygous have delayed disease
- immune to AIDS - not quite
CXCR4 can also act as receptor (usually late infection), expressed on T cells
- X4 strain of HIV does not require CCR5