Immunodeficiency Primary

A David B Webster, Department of Clinical Immunology, MRC Immunodeficiency Research Group, Royal Free Hospital School of Medicine, London, UK

The first patient with hypogammaglobulinemia was diagnosed by Bruton in 1952 soon after the introduction of serum protein electrophoresis. At about the same time, severe combined immunodeficiency (SCID) was described in Switzerland and has subsequently been subclassified into a number of different disorders. In 1965, DiGeorge showed that the thymus was important in humans by describing an athymic infant with recurrent infections.

The term 'primary' is taken to mean that the immunodeficiency is not secondary to any known infection, lymphoreticular malignancy, or drugs. Whilst most 'primary' disorders are due to single gene defects, 'common variable' immunodeficiency and selective immunoglobulin A (IgA) deficiency, which represent the most common disorders, are probably based on a polygenic mechanism. There are also some metabolic disorders where a variety of cell types, including lymphocytes, are affected. In such cases, the distinction between 'primary' and 'secondary' is somewhat arbitrary.

Selective T cell deficiencies

Thymic aplasia

In 1965, DiGeorge described a child without a thymus or parathyroid glands due to congenital malformation of the third and fourth pharyngeal pouch. Most patients have microdeletions at chromosome 22qll, or less frequently at 10pl3, where there are probably genes which control the development of the neural crest, from which cells migrate to the pharan-gea) pouches. The disorder is familial in a few cases and the prevalence is about 5 per 100 000 children. A spectrum of severity has been recognized, with some children lacking all thymic and parathyroid tissue, sometimes with additional abnormalities in midline structures such as the lips, palate, heart and major thoracic vessels, while others retain some thymic tissue and have mild symptoms. In the severe type, there is a virtual absence of circulating T lymphocytes, sometimes with a relative expansion of B cells. These patients are capable of making antibodies after immunization, although it is unclear whether the quality or quantity of antibodies produced is normal. In general, there is a raised incidence of chronic cytomegalovirus and varicella infection, and some affected children have developed systemic vaccinia infections after immunization. Recurrent bacterial infections are unusual. Autoimmune phenomena, such as hemolytic anemia and vitiligo, may occur.

Early attempts at therapy focused on repleting thymic hormone with fetal thymic grafts, and more recently purified thymic hormone; there is no good evidence that either of these strategies work. Fortunately, most patients have a remnant of thymic tissue left, and the numbers of circulating T cells gradually rise to normal during the first few years of life. There is a possibility that the majority of these lymphocytes are derived from the gut-associated lymphoid tissue.

CD3 defects

Two siblings with autosomal recessive inherited mutations in the CD3 7 chain gene have been reported, one dying from severe autoimmune disease in infancy, while the other remains healthy at 10 years; this was associated with about 50% of normal expression of the CD3/TCR complex. One child with recurrent lung infections is reported with inherited defects in the CD3 e gene. Since the CD3 e chain is crucial for normal T cell development, the residual 10% of normal expression of the CD3/TCR complex in this patient was presumably enough to provide partial T cell immunity.

Peptide transporter (TAP) defects

A few patients, some apparently not prone to infection, have been reported with very low expression of HLA class I on lymphocytes. This disorder was originally called the 'bare lymphocyte syndrome', but this term should be abandoned because it is sometimes confused with major histocompatibility complex (MHC) class II deficiency (see below). Two siblings with bronchiectasis were recently found to have mutations in the TAP2 gene, causing inefficient transportation of class I to the trans-Golgi compartment. Both had deficient natural killer (NK) cell activity, but no obvious predisposition to viral infection.

Severe combined immunodeficiency (SCID) (Figure 1)

The first cases of SCID were described in Switzerland in the 1950s, hence the original term 'Swiss type agammaglobulinemia', although later it became apparent that cellular immunity was severely compromised. A better understanding of the condition had to await the discovery of T and B lymphocyte markers in the 1970s. Since then the condition has been subclassified, and in most cases the disorder is understood at a molecular level. SCID occurs in about 1:50 000 live births. The syndrome is characterized by severe opportunistic fungal, viral, protozoal and bacterial infections. Affected infants fail to thrive, have chronic diarrhea due to enteric viruses and parasites, have extensive mucosal candidiasis, and develop Pneumocystis carinii pneumonia. These clinical features, together with the finding of very low numbers of circulating T cells, negative delayed hypersensitivity skin reactions, poor or absent T lymphocyte transformation in vitro with mitogens and thymic dysplasia (without Hassal's corpuscles), is virtually diagnostic. The exceptions are MHC class II deficiency, ZAP-70 defects and Omenn's syndrome, where there are often normal numbers of circulating lymphocytes. Circulating B cell numbers in SCID are variable and sometimes there is polyclonal expansion



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