Severe combined immunodeficiencies (SCID)

SCID consists of a group of genetic disorders characterized by a block in T lymphocyte differentiation that is variably associated with abnormal development of other lymphocyte lineages, i.e. B or NK lymphocytes or more rarely of the myeloid lineage [1,2]. At least eight diseases can be distinguished according to phenotype and inheritance pattern (Table 1). The overall frequency is estimated to 1 in 75 000–100 000 births [3,4]. Only those SCIDs with severe T cell depletion will be discussed here, leaving those who usually have normal T cell numbers (e.g. MHC class II and Zap-70 deficiency) for a separate review. Severe combined immunodeficiencies (SCID) Severe combined immunodeficiencies (SCID) The clinical presentation is fairly uniform and is characterized by early onset of infections, mainly of the respiratory tract and gut. We reviewed the frequency of infections and the diagnosis in 117 patients with SCID who were referred to our centre [3]. Oral candidiasis, persistent diarrhoea with growth impairment and/or interstitial pneumonitis are the most frequent infectious manifestations leading to diagnosis. There are no differences between the various SCIDs, except for an earlier onset of infections in patients with ADA deficiency. The persistence and recurrence of infections in SCID patients rapidly lead to growth impairment and malnutrition. Our findings were similar to an American study of 100 infants [4]. Even common opportunistic organisms such as Pneumocystis carinii and Aspergillus species can cause infections. Intracellular organisms such as listeria and legionella can cause devastating disease, as can viruses, especially those of the herpes group. Infection by Epstein–Barr virus (EBV), although rare in this age group, can lead to uncontrolled B lymphocyte proliferative disorders (BLPD) in B(+) SCID patients, similar to that seen in immunosuppressed transplant recipients. Thirty-one such cases have been reported [5]. Some occurred following therapy of SCID (thymic transplant, fetal liver transplant or T-depleted marrow transplant), which was presumably the source of EBV. BLPD has also developed in untreated SCID patients [6]. Live vaccines can also cause life-threatening infections. We have observed BCG infection in 10/28 vaccinated patients (including two with local infection and eight with disseminated involvement of the liver, spleen and lungs), which was fatal in three cases [3]. Interestingly, three of six patients who received oral attenuated poliovirus had detectable virus in the stools, but none developed poliomyelitis; this was probably either because of slow viral replication in transplant recipients or because of protection by maternal immunoglobulins. It is clear that live vaccine must not be given to children at risk for SCID. Non-infectious clinical manifestations consist mainly of graft-versus-host disease (GVHD) caused by the patients' inability to reject allogeneic cells. The two possible sources of allogeneic cells are maternal lymphocytes and transfusion. Maternal T lymphocyte engraftment is frequently detected in SCID patients using molecular tools [7,8]. Circulating maternal T cells are detected in approximately 50% of cases. It is noteworthy that maternal T cells are not found in ADA-deficient patients, possibly because maternal T cells are killed by the raised levels of deoxyadenosine (see below). Maternal T lymphocyte numbers range from 10 to several thousand/μl of blood. They usually have a normal phenotype, with some degree of in vivo activation, as shown by the expression of MHC class II molecules and/or the IL-2 receptor [9]. In some cases, maternal T cells have been reported to be clonal [5,9], a finding suggestive of either transplacental passage of a very small number of T cells or secondary expansion of alloreactive clones in the host. The most intriguing observation regarding maternal T cell engraftment in SCID patients is the paucity of clinical manifestations. In the majority of cases, the presence of maternal T cells is entirely asymptomatic, while approximately 30–40% of patients have mild symptoms and signs such as erythema with skin T cell infiltration, eosinophilia, and elevated liver enzymes with periportal T cell infiltration [3]. In recent years there have been no reports of fatal GVHD caused by maternal T cell engraftment in SCID patients. Several explanations have been proposed: they include oligoclonality of maternal T cells with lack of alloreactivity toward the child's antigens, or tolerance of transfused maternal T cells because of associated mild haematopoietic stem cell engraftment (and T cell differentiation). The presence of a few maternal T cells in the periphery should not delay or confuse the diagnosis of SCID. It may be an obstacle to T cell engraftment following T-depleted haplo-identical bone marrow transplantation (BMT), especially if the donor is not the mother and if the patient is not treated with myeloablative and immunosuppressive drugs [10,11]. Following HLA-identical BMT, there is usually a dramatic expansion of donor T cells cytotoxic for maternal cells 10–12 days post-BMT, that results in their rapid elimination [12,13]. This ‘graft versus graft’ reaction can cause transient GVHD symptoms. In contrast, post-natal inoculation with allogeneic lymphocytes by plasma, erythrocyte, platelet or leusocyte transfusion usually causes a fatal acute GVHD syndrome marked by diffuse necrotizing erythroderma, gut mucosa abrasion and biliary epithelium destruction, sometimes associated with stroma cell lesions in the marrow. This GVHD syndrome can occur within 2–4 weeks and is usually resistant to the most powerful immunosuppressive drugs. In a small number of cases (two out of 11 in our experience) GVHD does not develop, although allogeneic anti-host T cells can be detected and cause resistance to BM engraftment [3]. About 20% of patients with SCID have a phenotype characterized by an absence of mature T and B lymphocytes, while functional NK cells are detectable [3,4]. Usually the thymus is hypoplastic. The condition can be cured by allogeneic bone marrow transplantation. This T(–) B(–) form of SCID has an autosomal recessive inheritance and will be covered in a separate review. X-linked SCID (SCID-X1) accounts for 50–60% of cases of SCID [14]. It is characterized by an absence of mature T and NK lymphocytes, whereas B cells have a normal phenotype and are present in increased numbers. Histologically, the thymus lacks a cortex/medullar differentiation. Lymphoid precursors are scarce, and Hassal's corpuscles are not detectable [15]. Peripheral lymphoid organs are also hypoplastic. These data indicate that there is an early block in the T cell differentiation pathway in this disease. SCID-X1 is curable by allogeneic BMT, indicating that the defect is intrinsic to the lymphoid lineage [14]. Studies of X-chromosome inactivation patterns in obligate carriers have shown a skewed pattern in T and NK cells as well as in B cells, whereas a random pattern was usually detected in the other haematopoietic lineages [16,17]. The SCID-X1 gene product is therefore expressed and involved in the maturation of the T, B, and NK cell lineages. Of note is the observation that the X chromosome inactivation pattern is more skewed in mature than immature B cells [18]. The SCID-X1 locus was mapped to Xq12-13.1 [19]. It was then recognized that the gene encoding the γ-chain of the IL-2 receptor (now renamed γc) was localized to the same region, and mutations of the γc gene were found in SCID-X1 patients [20]. That γc mutations cause SCID-X1 has now been proven in several ways: all patients with SCID-X1 have the γc gene mutation [21,22], in vitro gene transfer of γc into patient's EBV-transformed B cells and marrow cells corrects the high-affinity, IL-2 receptor deficiency and NK cell differentiation block, respectively [23–26]. Canine XL-SCID is also associated with a mutation in the γc gene [27]. Finally, γc(–) mice exhibit a similar, although not entirely identical, phenotype (see below) [28,29]. γc belongs to the haematopoietic cytokine receptor family, characterized by four conserved cysteines and the repeated WS motif [30]. The γc-chain is constitutively expressed by T cells, B and NK cells, as well as myeloid cells and erythroblasts (reviewed in [31]). γc expression together with the IL-2Rα and β subunits generates the high-affinity receptor for IL-2, and plays a major role in signal transduction through activation of its associated tyrosine kinase JAK-3 [31]. A number of mutations of the γc gene have now been reported in SCID-X1 patients [21,22]. Since the disease is lethal, a 30% rate for new mutations is expected for each generation, accounting for the variety of mutations found. It is remarkable that many single amino acid substitutions in the extracellular domain are sufficient to abrogate T and NK cell differentiation. Some affect conserved cysteines and the WS motif, the structure of which is likely to be required for the overall configuration of the molecule [21]. Others, like an ala→val substitution in position 156, create a molecule that is expressed but fails to bind IL-2 or to transduce signals [32]. γc is a member not only of the IL-2 receptor but also of the IL-4, IL-7, IL-9, and IL-15 receptors [33], augmenting in each case the affinity for the cytokine and participating in signal transduction. The SCID-X1 phenotype appears therefore to be the complex association of defects in these five cytokine/receptor systems. Recent studies in mutant mice generated by homologous recombination have brought significant insight into the role of IL-7 in T cell differentiation. γc(–) mice have a profound immunodeficiency [28,29]. The T cell phenotype of γc mice is virtually identical to the IL-7(–) and IL-7Rα(–) mice [34,35]. These data strongly argue for a major role of IL-7 in inducing survival and proliferation of early T cell progenitors in the thymus [36–38]. This is confirmed by the block in T cell development observed in two patients with IL-7Rα deficiencies [39] (see below). Furthermore, γδ T cells are completely lacking in γc(–) mice. The NK cell deficiency observed in SCID-X1 is likely to be the main consequence of defective IL-15-induced signalling. Indeed, IL-15 (with SCF) can trigger CD56+ NK cell generation from CD34+ marrow progenitors [40]. We found that following γc gene transfer into SCID-X1 patients' marrow, functional NK cells (CD56+) can differentiate in the presence of SCF and IL-15 [26]. SCID-X1 B cells make IgE in the presence of IL-4 and a CD40-mediated signal [15]. However, SCID-X1 EBV-B cells do not activate JAK-3 and STAT6 in the presence of IL-4 [18]. These results can be explained by the presence of a γc-independent IL-4 receptor able to transduce at least some signals after IL-4 binding. As expected, IL-2 and IL-15 do not induce an immunoglobulin switch in SCID-X1 B cells, in contrast to their effects on control B cells [15]. V(D)J elements of immunoglobulin normally rearrange in SCID-X1 B cells, while most of the JH are in germ-line configuration, probably reflecting a lack of T cell help [41]. In rare instances, γc gene mutations have been found in patients lacking not only T and NK cells but also B cells. No obvious explanation appears for this ‘atypical’ phenotype [3]. This fact further stresses the lack of demonstrable correlation between genotype and phenotype observed so far. It may very well be that modifier gene(s) could play a role. A non-X-linked form of SCID characterized by a phenotype identical to SCID-X1 has been shown to be the consequence of mutations of the JAK-3 encoding gene [42,43]. JAK-3 is a tyrosine kinase that is bound to the intracellular tail of γc and is activated upon cytokine binding to the multichain receptor. JAK-3 phosphorylates STAT-5 protein. Phosphorylated STAT proteins dimerize and are translocated to the nucleus where they act as transcription inducing factors for several genes involved in progression of cell division [44]. The identical phenotype of γc and JAK-3 deficiencies demonstrate the essential role of JAK-3 in transducing signals triggered by cytokine binding. A number of distinct mutations, most leading to premature stop codons, lead to a similar T(–), NK(–), B(+) phenotype. In two patients with a T(–) B(+) NK(+) SCID phenotype, mutations impairing the expression of the α subunit of the IL-7 receptor have been described [39]. The IL-7 receptor is composed of IL-7Rα and γc. This observation confirms the essential role of IL-7 in the early steps of T cell differentiation, while it can be dispensable, at least in humans, for B cell differentiation. Some other patients with a same SCID phenotype do not exhibit mutations in the IL-7Rα encoding gene. The mechanism underlying the T cell deficiency remains unknown. A potential IL-7 deficiency should lead to the same phenotype, but this would not be corrected by classical BMT since IL-7 is produced by stromal cells. A combined X-linked immunodeficiency characterized by progressive loss of T and B cell function leading to has been described in several In two patients' T cells were found to be In family, the X-chromosome inactivation pattern in obligate carriers together with gene was with a form of X-linked SCID. of the γc gene in the two and of normal which for and 20% of γc A single substitution in the position of 1 was found that probably of 1 in the abnormal while a normal generated the normal encoding a with a substitution in position The γc-chain could be detected in EBV-B cells from the A number of high-affinity IL-2 binding was This case that expression of the γc may T cell differentiation, with only a small number of clones the T cell differentiation As a identical phenotype has been reported with γc mutations that JAK-3 binding and T cell activation In case with normal numbers of T and B lymphocytes, T cells were shown to in the presence of However, IL-2 binding was It was that this was the mechanism of the defective T cell it was shown that in this a mutation of γc caused the binding to This case be the consequence of defective while of the γc receptor with other is This with the observation of a SCID-X1 phenotype caused by a γc mutation (and but so with and described a profound in SCID-X1 phenotype following an at bone marrow transplantation a γc gene most of the intracellular domain of the developed functional T cells that were of T cells were detected a following BMT, in numbers. The mechanism by in the absence of possible JAK-3 activation, these T cells have and been functional is not Finally, an SCID-X1 patient had T cells which were able to to and γc expression could not be detected on the patient's B cells, and while NK cells were not T cells γc. In the B cells, the γc gene was found to be substitution at position In T cells the mutation could not be found. The mother is a of the These results could be for by a mutation that in a T This observation two of a rare at least for a a T cell The to this cell lineage appears very to the of gene transfer as a for SCID-X1 using A similar has been described in a patient with deficiency These indicate that it is very likely that more ‘atypical’ of SCID do and are all T cell immunodeficiencies should be for the SCID molecular About 20% of SCIDs are caused by ADA deficiency. ADA is a that to and to It belongs to the pathway of The mechanism by which ADA deficiency to severe T, NK and B other is now The immunodeficiency is the consequence of of and that are to lymphocytes, especially to immature lymphocytes which can is into lymphocytes to a mature lymphocytes are able to into in contrast to other cell lineages. cell division by an required for generation of the other In their can also be by inactivation of which a group to There is also for cells that may of in to a of Furthermore, In most cases at ADA deficiency results in a SCID with very T and B cell manifestations occur earlier than in other of SCID [3]. In to severe infections and to approximately 50% of patients with and of the and mild Some patients have and It is to a diagnosis of viral but of following of ADA deficiency a consequence of the deficiency and abnormal function have been in some patients, as well as It is not proven that the lesions are to ADA deficiency. The early onset of ADA deficiency is associated with detectable in and lymphocytes, levels 100 ADA gene mutations affect the of the or there is a within the ADA gene. In some other patients, clinical onset is by several T cell may not be and there is eosinophilia, with ADA in ADA deficiency has also been with the clinical manifestations after or years or as described in several patients In those patients with a T cell manifestations are not as in other T cell at the age of years has been described as the of ADA deficiency In patients with ADA levels are usually elevated than in the early onset of the ADA gene may consist of mutations or mutations not the of the However, is further increased by the fact that most patients are The ADA gene has been mapped to and It consists of into mutations and mutations of the ADA gene that induce SCID have been characterized and study of mutations inducing ADA function will the This is a very rare SCID condition characterized not only by defective lymphoid differentiation but also by a block of myeloid differentiation. recessive inheritance is but not to the of the syndrome It is not clear some of SCID with a syndrome or could be secondary to persistent viral infection in some cases. is the mechanism of the syndrome but its haematopoietic is since it is curable by BMT Of SCID has been described in an with that following SCID has been associated with in two with absence of T cells and very B cell The inheritance is to be autosomal The consist of It is not this is a syndrome or a is involved in the development of the of the tract and lymphocyte differentiation. a tyrosine deficiency was reported in a with a profound T cell mild NK cell and B cell This phenotype appears similar to the of mice and confirms the of this in T lymphocyte Interestingly, T cell development was The of SCID is and most of the patients have by the age of 1 and of infections with substitution and for carinii are required but can at include of in to fatal GVHD and of live vaccines such as The is allogeneic BMT as described years The BMT is in that no or is required to usually in a as only T cells NK are of donor identical BMT is characterized by rapid T cell following expansion of the donor T lymphocyte with generated T cells detected after This appears to be the for development of T cells in thymus of the absence of the of is in recent Since the early SCID patients lacking an identical donor have been treated with stem cell transplantation. GVHD by T cell elimination of the marrow was the to A recent in the absence of survival can is not a at least for SCID Studies on the of marrow transplantation in SCID patients some to the of in the of haematopoietic cell but they also it is not in the absence of T lymphocyte engraftment whereas B cell and myeloid cell engraftment are it is not haematopoietic stem cells from the donor and differentiate into T cells, or common lymphoid progenitors in the marrow to the where they the loss of T cells can be since common lymphoid progenitors do not have the for of BMT in SCID is the frequent deficiency of B cells. patients in donor B cells a of functional B cells contrast, the majority of patients with B cells after transplantation are to normal of and have to be treated with immunoglobulins. the genetic defect of the B cells with to a deficiency of γc or this However, in a number of cases B cells, those γc-chain expression or can make and after marrow transplantation. It may be that in SCID patients who have persistent after the of lymphocytes, is to the required for normal B cell this is transplantation early in should the of normally B cells. The SCID condition can also affect in patients with T(–) B(–) the of engraftment and survival after transplantation of marrow are It is that NK cells for the rate of in the absence of It has also been that defective in a of patients with deficiencies in T and B cells, but normal NK cells, accounts for severe caused by GVHD or this of patients should be treated with a that the of NK cells. there for further in the of rapid of T cells and B cell function are two that could early from viral infections to T cell deficiency) and to B cell The of donor T cell that the risk of GVHD can be and the of involved in cell proliferation (e.g. are ADA deficiency can also be treated by substitution with ADA to usually results in of levels in cells. The T cell within weeks with of T cell is in most patients of cases The to to the most severe phenotype associated with of the The of has to be increased in some patients, in those who to while of T cell may with It is to of versus stem cell transplantation. of SCIDs, of BMT, and the of SCID genes to an in the potential of gene therapy in this The expected to be to cells, because SCID gene growth or differentiation signals to lymphocyte were for The of mutations in γc and ADA deficiency and of a to T cells in mice further of T cells from ADA-deficient patients after vivo infection with a the ADA gene to persistent of functional T cells an However, was not ADA gene transfer into marrow or cells at in the of numbers of cells gene transfer and which the potential growth of cells, are possible explanations for these of the T and NK cell immunodeficiency in three patients with γc deficiency following γc gene transfer into CD34+ cells using a These results demonstrate a can be to cells leading to clinical However, is required to the potential of this therapy for this and other SCID for most of the SCID diagnosis by molecular in cases at risk by at of In the other cases, can be to fetal lymphocyte in the at of two with SCID were treated by in of CD34+ cells this as there is the same risk of to the at and it may not in NK(+) SCID.