Affecting T cells and B cells combined immunodeficiency disorders

Severe combined immunodeficiency—SCID

A mixed group of disorders that all have grossly impaired T- and B-cell function leading to death normally within the first years of life. They can be broadly classified into 5 groups depending on their clinical and pathological characteristics. Reticular dysgenesis (see above) is generally considered to be a SCID variant, accounting for 3% of the total. Other types are:

1. Adenosine deaminase deficiency (16%).

Adenosine deaminase deficiency

A recessively inherited enzyme deficiency. ADA is rate limiting in purine salvage metabolism and is essential for the synthesis of nucleotides in cells incapable of de novo purine synthesis—including lymphocytes. The gene for ADA is on chromosome 20q13.4, and many mutations have been defined. Gene deletion leads to very low ADA activity and a profound T and B lymphopenia with early onset of clinical symptoms. Other tissues are involved, and there may be bony defects and neurologic disturbances. A similar rare syndrome is seen with deficiency of the enzyme purine nucleoside phosphorylase. It is less severe and presents later.

Other forms of SCID

SCID with both T-cell and B-cell lymphopenia is a recessive disorder that also occurs without the enzyme deficiencies described above, but the commonest form of the disease is X-linked and shows a lack only of T cells. It appears to be due to a defect in the gene coding for the g chain of the interleukin (IL)-2 receptor. There are other rare SCID variants where T cells are present but dysfunctional, including MHC class II deficiency, where lymphocytes fail to express MHC class II molecules; and Omenn's syndrome which presents in early infancy with the clinical features of acute widespread graft versus host disease (skin rash, hepatosplenomegaly, diarrhoea, failure to thrive) coupled with persistent infections. It is thought to be due to a failure in T-cell development with inability to recognise self antigens.

Treatment of SCID

• Matched BMT is the treatment of choice for all varieties; a good outcome can be expected in >90%.

• No pre-conditioning needed for matched donors.

• Mis-matched BMT results improving but donor marrow needs careful mature T-cell depletion and patients may need conditioning.

• ADA deficiency can be treated with regular enzyme replacement using a polyethylene glycol-linked ADA preparation.

• ADA deficiency has also been treated with gene replacement therapy, with so far only a transient effect, but the technique shows promise.

Wiskott-Aldrich Syndrome

An X-linked disorder with a triad of (1) eczema, (2) thrombocytopenia with characteristically small platelets, and (3) T- and B-cell dysfunction with susceptibility to infections, particularly otitis media and pneumonia. Due to a mutation in the gene encoding the Wiskott-Aldrich syndrome protein (WASP), important inter alia in regulating the cytoskeleton of haemopoietic cells.

• Presents in childhood.

• Tendency to immune cytopenias—compounding pre-existing throm-bocytopenia and causing haemolytic anaemia.

• Herpes simplex, EBV, varicella and CMV may be severe and life threatening.

• Greatly increased risk of lymphoid malignancy in adulthood for survivors.

• Splenectomy greatly increases risk of fatal infection.

• Need prophylactic antibiotics and immunoglobulin replacement therapy.

• BMT now treatment of choice; early in childhood if possible.

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