Bare Lymphocyte Syndrome, Type Ii

A number sign (#) is used with this entry because of evidence that this severe primary immunodeficiency, characterized by the absence of major histocompatibility complex (MHC) class II gene expression, results from defects in at least 4 different transacting regulatory genes required for transcription of MHC class II genes. There are at least 4 complementation groups: group A with a defect in the MHC2TA gene (600005); group C with a defect in the RFX5 gene (601863); group D with a defect in the RFXAP gene (601861); and group B with a defect in the RFXANK gene (603200). A fifth complementation group, group E, also results from a mutation in the RFX5 gene. The disorder is inherited as an autosomal recessive.

The bare lymphocyte syndrome type II is a member of the relatively heterogeneous class of SCID, or severe combined immunodeficiency. It is associated with, and probably results from, the lack of expression of HLA antigens on some cells of hematopoietic origin (Touraine et al., 1978). In addition to being of interest in its own right as a 'cause' of SCID, BLS provides insight into the role of MHC determinants in lymphocyte differentiation. In France, Touraine et al. (1980) reported 2 affected brothers, and a family in the Netherlands was reported by Schuurman et al. (1979, 1980). In the French family, 4 other sibs had died in infancy. BLS lymphocytes lacked HLA-A, -B, and -C antigens; they also lacked beta-2-microglobulin (109700) to a degree approaching that of the Daudi cell line which has a deletion of chromosome 15. Schuurman et al. (1980) reported studies of 2 unrelated families, 1 Turkish, the other Algerian. Consanguinity was likely in the former and certain in the latter. The affected children were of both sexes. First symptoms presented after the age of 3 or 4 months. All children had severe and persistent diarrhea, mucocutaneous candidiasis, interstitial pneumonia and various bacterial infections but no proved systemic viral infections. The findings of special studies supported the important role of class I HLA antigens in antigen recognition by T lymphocytes. It seemed that the abnormality in this syndrome might lie in the HLA genes or the B2M gene.

Marcadet et al. (1985) reported BLS in a 5-year-old girl born of first-cousin parents who had had repeated infections of the upper and lower respiratory tract, protracted diarrhea, and malabsorption for several years. The organisms included Hemophilus influenzae, Candida albicans, herpes simplex, cytomegalovirus, and adenovirus. Despite normal numbers of T and B lymphocytes, there were no delayed hypersensitivity reactions in vivo; panhypogammaglobulinemia was present, and antigen-induced lymphocyte proliferation and cell-mediated lymphocytotoxicity were absent in vitro. They also reported the disorder in a 4-year-old girl born of presumably unrelated parents of Algerian descent; 2 sisters and 1 brother had died of severe infections before age 4 years. In these 2 patients, Marcadet et al. (1985) showed by molecular genetic techniques that the HLA genes, although poorly expressed, were in fact present. Furthermore, therapeutic decisions concerning bone marrow transplantation were possible. In a family with 2 affected sibs, Sullivan et al. (1985) investigated the molecular basis of this syndrome by means of cDNA probes for both beta-2-microglobulin and class I MHC genes. Southern blots showed no gross internal defect in either. Northern blot analysis also showed no qualitative difference between affected and unaffected family members. In contrast, quantitation of transcripts demonstrated that both B2M and class I MHC were decreased and decreased in a coordinate fashion. The authors interpreted this to mean that BLS represents a pretranslational regulatory defect of expression of 2 genes. Baxter-Lowe et al. (1989) used in vitro amplification of the HLA genes and sequence-specific oligonucleotide probe hybridization (SSOPH) to investigate the HLA status of an infant with HLA-deficient severe combined immunodeficiency. The technology used permitted detection of HLA polymorphism at the level of single amino acid differences and eliminated the requirement for HLA expression. After determining the patient's haplotypes by this method, they selected a donor for bone marrow transplantation with a successful result.

As of 1985, 2 types of BLS had been identified: in type I (604571), the defect concerns only HLA class I molecules (Touraine et al., 1978; Schuurman et al., 1979), whereas in type II, both HLA class I and class II molecules are affected (Griscelli et al., 1980). In the latter disease, also called HLA class II-negative SCID, the abnormal expression of HLA molecules has been shown to be secondary to defective synthesis (Lisowska-Grospierre et al., 1985) due in turn to an abnormal transacting regulatory gene located outside the major histocompatibility complex (Marcadet et al., 1985; de Preval et al., 1985). The transacting regulatory factor, known as RF-X, binds to class II promoters and is defective in hereditary HLA deficiency type II, otherwise known as the 'bare lymphocyte syndrome.' The failure of HLA expression leads to immunodeficiency affecting both cellular and humoral responses to antigens. Death due to chronic diarrhea and repeated bacterial and viral infections frequently occurs in childhood. Lisowska-Grospierre et al. (1985) studied patients with an autosomal recessive combined immunodeficiency and an HLA-negative phenotype of activated T and B lymphocytes. The synthesis of the HLA-A, -B, and -C heavy chain was markedly decreased, whereas beta-2-microglobulin was made in normal amounts. No mRNA for either alpha or beta chains of HLA-DR was found. The Ii-chain, the invariant polypeptide associated intracellularly with HLA-DR, and its mRNA were made in normal amounts. Since the structural genes coding for class II polypeptides seemed to be unaffected, the genetic defect in these patients must have concerned the regulation of the expression of the HLA-DR genes. There appeared to be a transactive pleiotropic MHC-regulating gene located perhaps outside the MHC region. Will et al. (1990) described an offspring of healthy consanguineous Tunisian parents who had type II bare lymphocyte syndrome with the additional feature of neutropenia and neutrophil dysfunction (defective spontaneous migration and chemotaxis). Prenatal diagnosis was performed by Durandy et al. (1987) in 6 fetuses at risk for the disease, using membrane immunofluorescence on blood lymphocytes and monocytes. Two pregnancies were found to be affected.

Not only do the BLS trait and the MHC locus segregate independently (de Preval et al., 1985), but class II gene expression can be restored by fusion to a class II MHC-positive cell (Accolla et al., 1985). Several complementation groups have been defined by fusion studies (Hume and Lee, 1989). By studies of a panel of class II MHC-negative regulatory mutants, Kara and Glimcher (1991) demonstrated at least 2 distinct defects that affected gene expression by mechanisms other than direct promoter mutations. Some BLS cells had protein-promoter interactions, both in vitro and in vivo, suggesting a defect in gene activation. A mutation in an activation domain of a transcription factor or in a coactivator protein that does not directly contact DNA could be responsible. In other cases of BLS, Kara and Glimcher (1991) found no promoter interactions in vivo, despite the observation that such interactions occur in vitro. This finding suggested that the defect in these instances may involve promoter accessibility and, thus, chromatin structure. A mutation affecting a factor that interacts with a common locus activation region could prevent the organization of closed chromatin into an open domain. Alternatively, the defect might reside in a common transcription factor that serves not only to activate transcription but also to displace or reorganize nucleosomes locally. By the fusion complementation assay, using a relatively large number of class II-defective patient cell lines and mutant B-lymphoblastoid cell lines, Benichou and Strominger (1991) showed that genetic defects in at least 3, and probably 4, transactivating factors can lead to this phenotype, a failure to transcribe and express class II genes. Several specific DNA binding factors that bind to various class II gene promoters had been cloned. Lisowska-Grospierre et al. (1994) performed fusion experiments with B-cell and fibroblast cell lines from 22 HLA class II-deficient patients, representing two-thirds of all known cases. They found that 2 complementation groups accounted for 20 of the 22 cases. These 2 complementation groups corresponded closely to 2 ethnic groups: most patients of north African origin were classified into one group, while all patients originating from Spain were classified into a second main group.

In a comprehensive review, Mach et al. (1994) pointed to 2 general types of defects in BLS, which is a disease of gene regulation: in complementation group A, the defect resides in the C2TA gene, RFX binding is normal in vitro, and HLA class II promoter occupancy is normal in vivo. All patients in complementation groups B and C are defective in RFX binding in vitro and exhibit unoccupied class II promoters in vivo. Mach et al. (1994) noted that only a small number of patients had been assigned to complementation group A.

Wolf et al. (1995) reported the cases of identical twin brothers with a defect in constitutive and inducible surface expression of MHC class II molecules on B cells, monocytes, and activated T cells. Unlike previously reported patients, the 2 infants did not have a regulatory defect in the coordinated control of MHC class II gene transcription. Low levels of HLA-DR alpha-chain and beta-chain protein (142860) were detected and, most surprisingly, cellular and humoral immune responses were induced in both infants after tetanus vaccination. For 18 months after birth up until the time of report, the 2 boys had had a benign clinical course.

Douhan et al. (1996) concluded that the twin brothers in the study by Wolf et al. (1995) belonged to a previously unrecognized complementation group of MHC class II deficiency. In contrast to patients belonging to complementation groups A through D, the twin brothers showed a relatively benign clinical symptomatology and were able to mount MHC class II dependent T-cell responses and T-dependent antibody responses after vaccination, e.g., with tetanus toxoid (Wolf et al., 1995). However, similar to all other patients, MHC class II expression was undetectable on the surface of peripheral blood B cells, monocytes, and activated T cells, so that the cell type responsible for antigen presentation in the patients remained to be defined. Wolf et al. (2001) investigated MHC class II expression on epidermal Langerhans cells, monocyte-derived dendritic cells, dermal microvascular endothelial cells and fibroblasts compared with B cells, peripheral blood monocytes, and activated T cells in order to search for antigen-presenting cells that might be responsible for the cellular and humoral immune responses observed in the twins. The results showed residual surface membrane expression of functional MHC class II molecules on epidermal Langerhans cells and monocyte-derived dendritic cells, but not on B cells, monocytes, or activated T cells, indicating a cell-specific defect of MHC class II expression. Thus, the defect encountered in these patients was not expressed to the same extent in different cell lineages, which is relevant to the understanding of the patients' phenotype, and also illustrated that only small amounts of MHC class II are needed to mount a functional cellular immune response in vivo.

Nekrep et al. (2002) identified an arg149-to-gln mutation (R149Q; 601863.0005) in the DNA-binding domain of RFX5 in cell lines (termed 'Ker' cell lines) derived from the histoidentical twins lacking MHC class II transcription reported by Wolf et al. (1995) and Douhan et al. (1996). Functional and structural modeling analyses indicated that the mutant protein was incapable of binding the X box of the HLA-DRA promoter, whereas expression of wildtype RFX5 in the Ker cell lines rescued MHC class II expression.

Kovats et al. (1995) demonstrated that the function of antigen-presenting cells is deficient in multiple genetic complementation groups of BLS type II. They demonstrated this by studying antigen-presenting cell (APC) function in DR-transfected BLS cells derived from multiple complementation groups. Each BLS cell line displayed the same defective APC phenotype: an inability to mediate class II-restricted presentation of exogenous protein antigens and structurally altered class II alpha/beta dimers. Expression of the HLA class II-like genes DMA (142855) and DMB (142856), previously implicated in antigen presentation, was reduced or absent in the BLS cells. Fusion of BLS cells with a cell line that has a genomic deletion of HLA class II genes coordinately restored class II structural gene and DM gene expression and a wildtype APC phenotype. Thus, each of the molecular defects that silences class II structural gene transcription also results in a defective APC phenotype, providing strong evidence for coregulation of these 2 functionally linked pathways.

DeSandro et al. (1999) reviewed the molecular bases of the several forms of BLS.

According to a review by de la Salle et al. (1999), 3 types of HLA deficiency, types I, II, and III, resulting from the absence of HLA class I molecules, class II molecules, and both class I and class II molecules, respectively, had been described. A review of the HLA class I deficiencies was provided by de la Salle et al. (1999) and of the class II deficiencies by Reith et al. (1999). Only 9 well-documented cases of HLA class I deficiency with normal expression of class II molecules were found by de la Salle et al. (1999). Contrary to types II and III bare lymphocyte syndrome, which are characterized by the early onset of severe combined immunodeficiency, class I deficiencies are not accompanied by particular pathologic manifestations during the first years of life, although chronic lung disease develops in late childhood. In contrast to type II or type III bare lymphocyte syndrome, pathology of the gut (diarrhea) is not observed. Systemic infections have not been described in HLA class I-deficient patients. Chronic bacterial infections, often beginning in the first decade of life, are restricted to the respiratory tract and extend from the upper to the lower airway. Most authors report bronchiectasis, emphysema, panbronchiolitis, and bronchial obstruction. High frequency of involvement of the nasal sinuses and of nasal polyps, uncommon in non-cystic fibrosis children, was noted. Some cases of type I bare lymphocyte syndrome have deficiency in the TAP2 gene (170261). Reith et al. (1999) stated that approximately 70 patients from 57 unrelated families had been reported worldwide. Most of the patients were of North African origin (Algeria, Tunisia, Morocco). There was a high incidence of consanguinity in the affected families.

In patient FZA with bare lymphocyte syndrome type II, complementation group B, Nagarajan et al. (2000) identified homozygosity for a missense mutation (L195P; 603200.0005) in the RFXANK gene. The patient's unaffected parents were heterozygous for the mutation.