A A

Figure 1 Ontogeny of T lymphocytes. The blocks in differentiation/maturation in the primary immunodeficiencies are as follows: A, reticular dysgenesis; B, thymic aplasia/X-linked SCID/PNP deficiency/RAG and JAK3 kinase defects; C, ADA/class II deficiency; D, leaky types of JAK3 and ZAP-70 kinase deficiency; E. some CVID patients, CD3 -y chain defects, and leaky types of CD3 e chain defects.

of one isotype with hyperimmunoglobulinemia. However, functional antibodies are rarely detected. Most affected children die within 1 year of diagnosis unless they receive a successful bone marrow transplant.

X-linked SCID

Affected infants have inherited defects in the common y chain for interleukin 2 (IL-2), IL-4, IL-7, IL-9 and IL-15 receptors; the defect accounts for about one-third of all SClDs. Involvement of multiple cytokine receptors explains the severity of this condition.

Adenosine deaminase (ADA) deficiency

The disease was discovered by chance during the routine analysis of erythrocyte isoenzymes in a SCID infant. ADA has a central role in the interconversion pathways of purine metabolism, a defect in the enzyme leading to the accumulation of deoxyadenos-ine. This accumulates in the plasma and its appearance in the urine is a useful diagnostic marker. Deox-yadenosine is toxic to both T and B lymphocytes, as well as macrophages, which accounts for the very poor prognosis when compared to PNP deficiency (see below). There is a spectrum of clinical severity, probably reflecting different mutations in the ADA gene. Regular subcutaneous injection of calf ADA linked to polyethylene glycol (PEG-ADA) can restore immunocompetence. However bone marrow transplantation provides the only definitive cure. The ADA gene on chromosome 20 has been cloned, and transfection of the gene into bone marrow stem cells or peripheral lymphocytes of patients has been achieved, but so far not enough ADA has been produced to restore immunocompetence.

Purine nucleoside phosphorylase (PNP) deficiency

In 1975, Giblett and colleagues discovered PNP deficiency when screening for purine metabolic defects in patients with T cell deficiencies. The enzyme is important for the interconversion of purines in cells, although its absence only compromises the function of T cells, and in some patients the central nervous system (CNS) and/or neutrophil and erythrocyte development. The substrates for PNP are guanosine and deoxyguanosine, which accumulate in the serum and appear in the urine, the latter being a useful diagnostic marker for the disease. The clinical features are heterogeneous, probably reflecting different mutations in the PNP gene on chromosome 14; some patients present with predominantly CNS features of hypotonia or spasticity, and some have neutropenia or megaloblastic anemia. The numbers of circulating T cells are profoundly depressed (<10%) in severe cases who suffer from the same complications as patients with thymic aplasia. The thymus gland is sometimes atrophic at birth or may gradually atrophy in the first few years of life in those with a delayed onset of the immunodeficiency.

Attempts to block the accumulation of guanosine or deoxyguanosine with purine analogs have been unsuccessful. Bone marrow transplantation remains the treatment of choice in severe cases, although this will not reverse the CNS disease.

JAK3 kinase deficiency

Mutation in this important kinase in the T cell signal transduction pathway is a rare cause of SCID.

Reticular dysgenesis

This is the most severe type of SCID, due to an inherited defect in a pluripotential bone marrow stem cell from which lymphocytes, neutrophils and monocytes are derived. In one reported case there was normal monocyte development. Affected infants only survive a few weeks after birth unless they receive a successful bone marrow transplant.

RAG defects

Mutations in the recombination-activating genes (RAG-I and -2) account for about a third of T~B SCID, preventing VDJ rearrangement of immunoglobulin and T cell receptor genes.

Defects in NF-AT transcription factor

This rare defect was initially thought to be due to a specific deficiency of IL-2 and was then found to involve NF-AT which controls the transcription of many cytokines.

MHC class II deficiency

This rare autosomal recessive disorder is caused by genetic defects in transcription factors which regulate the MHC class II gene, resulting in failure to express class II on lymphocytes and macrophages; many patients are of North African descent. There is usually a moderate CD4+ T cell lymphopenia; lymphocytes proliferate normally in vitro with mitogens, but not with specific antigens, and fail to stimulate or respond in a mixed lymphocyte reaction. Molecular defects have been found in three different transcription factors (RFX5, RFXAP and CI 1TA), and there is a fourth type to be identified.

Omenn's syndrome (familial reticuloendotheliosis)

This unusual form of SCID is characterized by thickened eczematous skin, massive lymphadenopathy, and hepatosplenomegaly due to infiltration of polyclonal lymphocytes, histiocytes, and eosinophils. Circulating B cells may be present at birth, then gradually disappear as the patient becomes severely hypogammaglobulinemic. Until recently many thought that this condition represented a chronic GVH (graft-versus-host) disease due to maternal engraftment of an SCID fetus, but there is now good evidence that it is a distinct disorder.

ZAP-70 defects

A rare genetic cause of SCID involves a tyrosine kinase which interacts with the £ chains of the CD3 complex, causing a severe functional T cell defect with absence of CD8+ cells.

Cellular immune defects and dwarfism

There is a distinct disorder characterized by short limb dwarfism, thin hair and variable T cell deficiency, sometimes with severe hypoplastic anemia. Relatively common in the Old Order Amesh, over a hundred cases have now been reported in Finland and sporadically elsewhere. SCID occurs in only-rare cases. The relevant gene has been localized to chromosome 9pl2. There is another, much rare condition characterized by redundant skinfolds and hair loss due to ectodermal dysplasia, dwarfism and SCID.

Antibody deficiency syndromes (Figure 2)

Following Bruton's first description of agammaglobulinemia in 1952, a large number of patients have been described with various patterns of antibody deficiency, ranging from an almost total absence of all isotypes to selective isotype and subclass deficiencies. Now that test immunization is becoming a routine diagnostic procedure, patients arc being recognized with depressed antibody responses despite normal serum immunoglobulin levels. Some of the rare conditions are due to genetic defects on the X chromosome, while others are either single-gene or multigene autosomal defects.

The treatment is regular intramuscular, subcutaneous or intravenous immunoglobulin replacement therapy and antibiotics for infections.

X-linked agammaglobulinemia (XLA)

This disease is caused by mutations in a cytoplasmic-tyrosine kinase (Bruton's tyrosine kinase - Btk) which is critical for the differentiation/proliferation of pre-B cells in the bone marrow. There are virtually no circulating surface positive IgM B lymphocytes and there is no antibody production, although cellular immunity remains intact. Autosomal recessive inheritance of mutations in the immunoglobulin p-chain can cause a similar phenotype in females. The patients present with upper and lower respiratory tract infection, usually due to nontypable Haemophilus influenzae, in the first 2 years of life. Pneumococcal septicemia and meningitis may occur, and in the gut Campylobacter and Giardia infections are common; mycoplasma arthritis is an important but less common complication. There is usually an uneventful recovery from common viral infections, although enteroviruses, particularly echoviruses, may cause an ultimately fatal chronic meningitis. A few patients with X-linked agammaglobulinemia and growth hormone deficiency have been reported, but

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