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Immunogenetics: Changing the Face of Immunodeficiency 60 J Clin Pathol 2000;53:60–65 Immunogenetics: changing the face of immunodeficiency Alison M Jones, Hubert B Gaspar Primary immunodeficiency is increasingly rec- treatment in some cases, and for developing ognised in both children and adults. Although strategies for somatic gene therapy. clearly defined disorders are individually rare, collectively they form a significant group. The molecular basis of several disorders has been Specific disorders known for over a decade, but in the past 10 Those immunodeficiencies for which the un- years there has been a massive increase in the derlying molecular defects have been defined definition of defects underlying many immuno- are summarised in tables 1 and 2. In several of deficiencies. these disorders, knowledge of the molecular Management of immunodeficiency has his- basis has led to the improvements in manage- torically consisted of supportive treatment, ment outlined above. In other cases ongoing including antibiotics, immunoglobulin (Ig) research is continuing to add to our under- replacement, and in some cases, immuno- standing of the molecular mechanisms of modulation and immunosuppression. Bone immune function. It is not within the scope of marrow transplantation has been standard this review to go into detail for every disorder, treatment for the past 20 years, but only for so several illustrative diseases will be discussed. clearly defined cases of severe combined immunodeficiency (SCID) and a few other disorders known to have a very poor outlook X linked agammaglobulinaemia (XLA) without bone marrow transplantation. Accu- X linked agammaglobulinaemia is the arche- mulating worldwide experience is now provid- typal humoral immunodeficiency, presenting in ing evidence for poor long term prognoses in its classical form with susceptibility to bacterial many other situations, even with optimal medi- infection, absent or low circulating mature B cells, and absence of all immunoglobulin cal treatment. Bone marrow transplantation is isotypes.1 Standard treatment is with life long therefore being considered for increasing num- immunoglobulin replacement. The outlook is bers of children aVected by these disorders, good provided that adequate IgG levels are and, in parallel with this, there is a pressing maintained and infections are promptly treated. need to define individual disorders as accu- There is, however, a significant risk of entero- rately and as early as possible. viral infection, and chronic meningoencephalitis The recent increase in knowledge of the can develop despite immunoglobulin replace- molecular defects underlying many immuno- ment therapy.2 The diagnosis of XLA has been deficiencies has led to several improvements in made on lack of peripheral B lymphocytes, diagnosis and management. absence of immunoglobulin production, and in First, precise molecular diagnosis is now some cases an X linked pedigree. However, girls possible in many cases, allowing earlier deci- with congenital agammaglobulinaemia and ab- sions to be made about the most appropriate sent B cells3 and boys with a similar immuno- management. This is particularly applicable in logical profile but from an autosomal pedigree children who have evidence of combined have also been reported, suggesting that the (cellular and humoral) immunodeficiency, but same immunophenotype can arise from a with “milder” clinical phenotypes than infants number of molecular defects. with classical SCID. Some of these children are In 1993, two groups identified the gene found to have identical molecular defects to defective in XLA, one using a positional Department of those causing SCID, and in these cases the long Immunology, Great cloning strategy and another using a reverse 45 Ormond Street term outlook is now known to be poor enough genetic approach. Subsequently designated Hospital NHS Trust, to justify bone marrow transplantation at an Btk (Bruton’s tyrosine kinase), the gene is a Great Ormond Street, early stage. non-receptor tyrosine kinase expressed in the B London WC1N 3JH, Second, accurate carrier detection and first and myelomonocytic cell lineages but not in T UK trimester prenatal diagnosis are possible in any cells. Btk is activated following stimulation of A M Jones family where the precise mutation has been several cell surface receptors including most 6 Molecular defined. In some cases prenatal diagnosis of an importantly the B cell receptor. In addition, Immunology Unit, aVected fetus may not lead to termination of interaction of Btk with a variety of intracellular Institute of Child pregnancy, but can allow preparation for bone signalling molecules including PIP3 Health, University marrow transplantation early in the neonatal (phosphatidylinositol-3,4,5-trisphosphate) and College London, period, or even in utero in selected cases. Ear- PLCã1 (phospholipase Cã1) is crucial for London WC1N 1EH, UK lier bone marrow transplantation is associated regulation of the sustained calcium signal in 7 H B Gaspar with a greater chance of a successful outcome. response to BCR engagement (reviewed in ). Third, knowledge of the molecular basis of However, despite the large volume of experi- Correspondence to: immunodeficiencies allows further research mental data, it is still unclear precisely how Dr Jones email: Alison.Jones@ into the mechanisms of the immune defects, defects in Btk lead to the arrest in B cell matu- gosh-tr.nthames.nhs.uk with the possibility of designing more rational ration seen in XLA. Immunogenetics 61 The identification of the Btk gene defect mal lymphocyte subpopulations, and appar- allows unambiguous assignment of a molecular ently normal T cell function. The clinical phe- diagnosis to individuals with XLA and to notype is one of susceptibility to bacterial female carriers. This is particularly important infection, but for many years before the as defects in µ heavy chain and ë5/14.1 surro- responsible gene was identified it was known gate light chain (components of the pre-B cell thatboysaVected by XHM were susceptible to receptor) have also been shown to give rise to opportunistic infection with organisms such as congenital agammaglobulinaemia.89 Further- Pneumocystis carinii.14 More recently, particular more, screening of individuals with atypical or susceptibility to Cryptosporidium parvum has less severe XLA phenotypes, including those also been recognised. It was therefore not sur- previously labelled as common variable prising when the gene responsible for XHM immunodeficiency or immunoglobulin sub- was identified in 1993 as that coding for CD40 class deficiency, has shown that some of these ligand (CD40L), a surface molecule present on 10 individuals may also have Btk defects. activated T cells.15–17 CD40L is essential for Mutation detection in XLA has traditionally immunoglobulin isotype switching through its been carried out by initial screening of the 19 interaction with CD40 on the surface of B exons of the Btk gene by single stranded cells, but it also plays an as yet undefined role in conformation polymorphism (SSCP) analysis T cell function. T cell proliferative responses to and subsequent direct sequencing of the a range of antigens have been shown to be aVected exon. This is a time consuming defective in CD40L deficiency.18 CD40L is technique that may take months to complete, also expressed on the surface of biliary epithe- and has a sensitivity of only 90%. More lial cells, and CD40/CD40L interaction here is recently generation of specific anti-Btk anti- thought to be involved in control of intracellu- bodies has allowed development of more rapid lar pathogens such as C parvum. methods of diagnosis. Analysis of Btk protein A further problem in CD40L deficiency is expression in peripheral blood mononuclear that of susceptibility to liver disease and cells of XLA patients by intracellular fluores- liver/gastrointestinal malignancy, with a possi- cence activated cell sorter (FACS) or western ble link between chronic cryptosporidial infec- blot analysis shows that over 90% lack Btk tion and sclerosing cholangitis.19 The Euro- expression.11 12 These techniques have also pean Society for Immunodeficiency database been useful in determining carrier status. In for CD40L deficiency currently contains clini- obligate carriers of XLA, intracellular FACS cal and molecular data from 113 aVected staining of monocytes shows a dual population males. The actuarial survival at 25 years is only of Btk expressing and Btk non-expressing cells 25%, and the incidence of liver disease by the since monocytes are randomly X inactivated in age of 20 years is 80%.20 There is so far little these women.11 Similarly, if an XLA patient apparent genotype/phenotype correlation, and expresses a Btk protein of abnormal size, west- there is considerable intrafamilial variation in ern blot analysis of monocytes from carrier females shows expression of an abnormal and clinical phenotype, so predictions of severity or normal sized band, thereby confirming carrier likelihood of liver disease are not possible. status. Knowledge of the molecular basis of XHM allows accurate diagnosis not only in boys who have a typical phenotype or a positive family CD40 ligand deficiency history but also in some cases of previously X linked hyper IgM syndrome (XHM) has undefined hypogammaglobulinaemia. Several been recognised since 1966,13 its characteristic adult males diagnosed as aVected by common immunological phenotype including very low variable immunodeficiency (CVID) have re- IgG and IgA levels, normal or raised IgM, nor- cently been found to have CD40L deficiency.
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