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Some problems concerning the diseases due to deficiencies of the T immune system in infancy and childhood are reviewed. The relationships between SCID and Nezelof syndrome and the pathogenesis of this group of diseases are particularly discussed.
In common with other organ systems in the body the immune system demonstrates functional disturbances which may lead to numerous immunological disorders with grave consequences for the health of the patient. Whenever the complex network of regulation and counter-regulation mechanisms within the defence system is impaired, by hereditary or acquired defects, immunological defect syndromes occur. One of the disorders that has been the object of intensive discussion in this context over the past few years is the acquired immune deficiency syndrome AIDS, a dangerous viral infection that mostly affects the T4 cells, whose helper and inductor function is absolutely essential for successful immunological defence. Furthermore, functional impairment of the antibody-producing plasma cells leads to the heterogeneous group of gammopathies which are characterized by an uncontrolled and excessive proliferation of structurally uniform antibody molecules in the blood. Overreactions of the immune system which wrongly attack endogenous tissue are accredited with causing the so-called auto-immune diseases. The clinical pictures within this group are exceptionally varied, and depend both on the self-antigen that the attack is aimed at as well as the erroneously triggered effector function that is affected. Whenever the immune system reacts disproportionately strongly against otherwise harmless foreign antigens, allergic clinical picture emerge.
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The heuristic concept of "inborn errors of metabolism" was introduced more then 70 years ago and by analogy has prompted the more recent introduction of the term "inborn errors of immunity". It is now well recognized that many inborn errors of immunity can be considered inborn errors of metabolism. Typically, many forms of severe combined immunodeficiency result from adenosine deaminase deficiency, i.e., an inborn error of purine metabolism. On the other hand, errors of immunity are often associated with "errors of morphogenesis", resulting from an intrinsically abnormal developmental process (malformation), a secondary or extrinsic interference with originally normal development (disruption), or an abnormal organization of cells into tissues (dysplasia). Twenty years after the original description, the DiGeorge anomaly should be considered an inborn error of morphogenesis and immunity due either to disruption or less frequently to malformation. In other immunodeficiencies, such as ataxia telangiectasia, the morphologic and immunologic errors result from a dyshistogenesis, i.e., dysplasia. Also, true malformation syndromes, such as Down's syndrome, are consistently associated with immunodeficiency.
The indications for immunoglobulin therapy in childhood have been well established for many years: prophylaxis is effective with single small doses, a full substitution needs multiple large applications. All other recommendations are ill-defined and result from wishful thinking rather than from solid clinical data. New is the possibility of safe i. v. Ig-application which could be realized through appropriate modification of gammaglobulin preparations. Some properties of the commercially available products are summarized. Our own experience with one of them is encouraging: as a matter of fact, fully effective gammaglobulin substitution is now possible in patients with antibody deficiency syndrome.
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The reproducibility of a simplified, sensitive and rapid agarose-cell droplet assay for leucocyte migration inhibition factor (LIF) activity was studied. Removal of T cells with anti-T-cell serum eliminated LIF activity, indicating that in humans it is probably the T cell that produces LIF. Cord blood lymphocytes produce LIF, although spontaneous migration of leucocytes is less than in older children. The cause of this apparently does not reside in the PMN leucocytes. Studies of children with immunodeficiency suggest that the T-cell population in humans is heterogenous. B-cell deficiencies such as hypogammaglobulinaemia, have normal PPD and PHA induced LIF production, whilst some patients with ataxia-telangiectasia have defective PPD LIF activity, their PHA LIF activity being only minimally depressed. On the other hand, Down's syndrome patients with reduced blood T cells have remarkably deficient LIF activity to PHA and relatively good activity to PPD. Children receiving steroid therapy lose much of their ability to produce LIF to the specific antigen PPD, but not to the non-specific mitogen PHA.
Genetic defects in T-cell function lead to susceptibility to infections or to other clinical problems that are more grave than those seen in disorders resulting in antibody deficiency alone. Those affected usually present during infancy with either common or opportunistic infections and rarely survive beyond infancy or childhood. The spectrum of T-cell defects ranges from the syndrome of severe combined immunodeficiency, in which T-cell function is absent, to combined immunodeficiency disorders in which there is some, but not adequate, T-cell function for a normal life span. Recent discoveries of the molecular causes of many of these defects have led to a new understanding of the flawed biology underlying the ever-growing number of defects. Most of these conditions could be diagnosed by means of screening for lymphopenia or for T-cell deficiency in cord blood at birth. Early recognition of those so afflicted is essential to the application of the most appropriate treatments for these conditions at a very early age. The latter treatments include both transplantation and gene therapy in addition to immunoglobulin replacement. Fully defining the molecular defects of such patients is also essential for genetic counseling of family members and prenatal diagnosis.
The epithelial cells of the thymus synthesize at least 30 different polypeptides: the thymic hormones. The structure of 4 of them is well known. They are named thymosin alpha 1, thymopoietin, thymulin and thymic humoral factor. Biological functions and secretion regulation of thymic hormones are described as well as the interactions between brain, thymus and endocrine glands. Blood levels and clinical usefulness of thymic hormones are reviewed in different congenital or acquired immunodeficient states and in autoimmune diseases.
Variation in clinical practice and its effect on outcome is little known for rare diseases such as primary antibody deficiency. As part of a national audit a survey of all 30 consultant immunologists in the United Kingdom dealing with primary antibody deficiency syndromes in adults and children was carried out in 1993 to ascertain their practices in diagnosis and management. Consensus guidelines were published after the survey was completed. Comparison of the survey results of clinical practice at the time the guidelines were published with the standards identified highlighted that the practice of a minority of specialists was at variance with their peers and with the consensus document, particularly in the use of intramuscular immunoglobulin, the dose and frequency of intravenous immunoglobulin, and target trough immunoglobulin G concentration, which has implications for the quality of patient care. However, much closer agreement existed in the key areas of management, such as diagnosis and selection of intravenous immunoglobulin. The approach and the problems identified are relevant to the management of other rare diseases, in which diagnosis and management is complex and there are few specialists with the necessary knowledge to undertake such care. This survey, the first attempted audit of practice, shows that within a motivated group of specialists highly significant differences in practice may exist and the authors emphasise the importance of setting clear guidelines against which care can be assessed.
BACKGROUND: Intravenous immunoglobulin (IVIG) is the mainstay therapy in human immune deficiency states characterized by qualitative and quantitative reductions in B cells. In addition, however, there is widespread use of IVIG in a number of other areas, including neuroimmunologic, infectious, dermatologic, hematologic, autoimmune, inflammatory and idiopathic disorders. In many of these cases, there are little objective data to support the use. METHODS: We performed a review of more than 400 publications in PubMed using the key words 'intravenous immunoglobulin' and excluded publications that focused on immune deficiency, for which the indication for IVIG is already clear. RESULTS: For a number of off-label indications, there is significant evidence of efficacy and IVIG has become the standard of care for many clinical syndromes other than immune deficiency. In some conditions, however, the data have not been well controlled or randomized and are often limited to case reports that are difficult to interpret. Although the critical shortage of IVIG of the last decade is no longer an issue, IVIG is expensive and not without risk. The use of IVIG should be based not only on clinical data, but also, and especially, on the biological rationale for its use. CONCLUSIONS: The appropriate use of IVIG is an important issue that is difficult to resolve, and will continue to challenge clinicians based on expense and potentially limited supply, including the intrinsic limitations of donor plasma. The establishment of national and international voluntary registries to report use of IVIG in disorders for which evidence is lacking would be a first step toward facilitating randomized, controlled clinical trials.