MHC Class II Deficiency: A Disease of Gene Regulation : Medicine (original) (raw)

Introduction

Primary human immunodeficiencies constitute a heterogenous group of inborn errors of the immune system due to a variety of genetic abnormalities. The study of patients with primary immunodeficiency diseases has expanded our understanding of immunity. Recent progress in immunobiology and genetics has identified with increasing precision the causes of many primary immunodeficiencies; diagnosis and therapy, as a result, can be more specific and effective (26,87).

Among the primary immunodeficiencies, MHC class II deficiency (MHC-II deficiency) is caused by the absence of MHC-II expression on the cell surface. Patients suffering from this disease were first identified in the late 1970s and early 1980s (31,35,36,51,55,90,101,102). Since then, more than 70 patients have been clearly described. The lack of MHC-II expression results in a severe defect in both cellular and humoral immune responses to foreign antigens and is consequently characterized by an extreme susceptibility to viral, bacterial, fungal, and protozoal infections, primarily of the respiratory and gastrointestinal tracts. Severe malabsorption with failure to thrive ensues, often leading to death in early childhood (see below and references 32, 50).

The disease was formally named “major histocompatibility complex class II deficiency” by the World Health Organization (87). It is also frequently referred to as the “bare lymphocyte syndrome” (BLS). However, the term BLS was first used to describe a defect in MHC class I (MHC-I) expression in patients in whom MHC-II expression was not examined (102), and it is now often used synonymously for all defects involving expression of MHC-I (BLS type I), MHC-II (BLS type II), or both (BLS type III) (103). Only the immunodeficiency syndrome associated with a constant and profound defect of MHC-II expression will be discussed here, and the term “MHC-II deficiency” will therefore be used.

Structure, Function, and Regulation of MHC Class II Molecules

MHC-II molecules, also called human leukocyte antigens (HLA) in humans, are heterodimeric transmembrane glycoproteins consisting of α and β chains. There are 3 different human MHC-II isotypes (HLA-DR, -DP and -DQ) encoded by distinct α chain (A) and β chain (B) genes that are clustered on the short arm of chromosome 6. MHC-II genes are characterized by a high level of polymorphism. For example, more than 160 alleles have been described for the HLA-DRB1 locus. MHC-II molecules are expressed at the cell surface of various different cell types and they play a pivotal role in 4 processes of the immune response (Figure 1):

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Fig. 1:

Structure and function of MHC class II molecules. MHC-II molecules are composed of 2 chains (α and β). They present peptides derived from exogenous antigens (Ag) to CD4 + T cells, which recognize the MHC-II/peptide complex via their T-cell receptors (TCR).

Two modes of MHC-II expression are generally recognized: constitutive and inducible (60,99). Constitutive expression of MHC-II molecules is largely restricted to epithelial cells in the thymus and to professional antigen presenting cells, such as B lymphocytes and dendritic cells. The majority of other cell types are MHC-II negative. In many of these, however, expression of the MHC-II genes can be induced by certain stimuli, particularly by interferon gamma (IFN-γ) (4,29,60,80), and other cytokines such as IL-4, TNF-α, prostaglandins, and glucocorticoids (29,33,60,80,104). The 3 isotypes DR, DP, and DQ are coordinately regulated.

Considering the key function of MHC-II molecules, it is not surprising that correctly regulated MHC-II expression is important for the control of the immune response. This is clearly demonstrated by the fact that a lack of MHC-II expression severely cripples the immune system (50,60,80), while aberrant or inappropriate expression may be implicated in certain autoimmune diseases (1,6,33). For over a decade, there has been, therefore, a considerable amount of interest in the molecular mechanism controlling the expression of MHC-II genes. Both the constitutive and inducible modes of MHC-II expression are controlled primarily at the level of their transcription by a short promoter proximal enhancer region consisting of 4 highly conserved cis-acting DNA sequences referred to as the S, X, X2, and Y boxes. These 4 regulatory sequences are well conserved in all MHC-II genes in human and other species (4,29,60,80) and are sufficient for MHC-II gene expression. Different studies also suggest that polymorphisms within this well-conserved promoter can affect the level of MHC-II gene expression (57,58,93).

A considerable amount of effort has been devoted to the identification and isolation of DNA-binding proteins that control transcription of MHC-II genes by interacting with the S, X, X2, and Y boxes. Three of the MHC-II promoter binding complexes identified by biochemical methods, RFX, NF-Y, and X2BP, have turned out to be particularly relevant to the regulation of MHC-II genes (Figure 2).

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Fig. 2:

MHC-II promoters. Many different proteins can bind to the X, X2, and Y cis-acting elements of MHC-II promoters. The names of these proteins are indicated. However, it is now believed that the RFX, X2BP, and NF-Y complexes, which bind together cooperatively (double-headed arrow), are the major DNA-binding proteins implicated in MHC-II gene regulation.

RFX binds cooperatively with X2BP (39,66) and NF-Y (82) to generate a very stable higher order protein-DNA complex and this stable binding is required for promoter activation (22,59,66,79,82). Formation of this higher order complex is clearly required for occupation of MHC class II promoters in vivo, because these promoters remain bare (47,48) in cells in which formation of the higher order complex is abrogated by mutations destroying RFX (60,97) or by mutations in the Y box of MHC-II promoters (112).

In addition to the RFX complex, another protein called CIITA (class II transactivator) is essential for the MHC-II molecule expression (Figure 3). CIITA is a non-DNA-binding transactivator that represents the “master regulator” for the expression of MHC-II genes (38,64,80). Recent experiments have demonstrated that CIITA functions as a coactivator. Although CIITA activates transcription of MHC-II genes via the promoter proximal region, it does not seem to bind directly to the DNA. This implicated that CIITA is recruited to MHC-II promoters by protein-protein interactions with DNA-bound factors. We and others have recently been able to demonstrate these interactions (20,37,38,70,115). Chromatin immunoprecipitation experiments have revealed that CIITA is indeed physically associated in vivo with MHC-II promoters and with the promoters of the Ii and HLA-DM genes. Furthermore, in vitro recruitment experiments have demonstrated that the association of CIITA with MHC-II promoters is mediated by multiple synergistic protein-protein interactions with components of the MHC-II enhanceosome (37,64).

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Fig. 3:

Molecular defects in MHC-II deficiency. MHC-II promoter occupancy and transcription status of MHC-II genes (MHC-II, invariant chain [Ii] and DM) in normal MHC-II-positive B cells and in B cells from complementation groups A, B, C, and D. The gray boxes represent the S, X, X2, and Y regulatory DNA sequences present in the promoter proximal regions of all MHC-II genes. The protein complexes RFX, X2BP, and NF-Y bind, respectively, to the X, X2, and Y boxes. In addition, the protein CIITA is essential for the MHC-II gene expression. CIITA is mutated in complementation group A; mutations in CIITA do not modify promoter occupation in vivo. In complementation groups B, C, and D, the RFXANK, RFX5, or RFXAP subunits of RFX are mutated, respectively. A deficiency in RFX leads to a bare promoter in vivo.

MHC-II Deficiency

Much of what we know today about the highly complex molecular mechanisms regulating MHC-II gene transcription derives from a detailed molecular dissection of the genetic defects responsible for primary MHC-II deficiency. MHC-II deficiency is a severe autosomal recessive immunodeficiency disease resulting from a selective lack of MHC-II expression, and an absence of CD4 + T-cell-dependent cellular and humoral immune response (60,80,83,84).

MHC-II deficiency is a rare disease; only approximately 70 patients from 57 unrelated families have been reported worldwide. The majority of patients are of North African origin (Algeria, Tunisia, Morocco) (32,50,56). The remaining patients are of diverse ethnic backgrounds including Spain, Italy, Turkey, France, the Netherlands, the United States, Israel, Saudi Arabia, and Pakistan (9,14,34–36,44,51,56,71). As expected for a rare disease, there is a high incidence of consanguinity in the affected families (56). The disease has an autosomal recessive mode of inheritance. A comparison between the pattern of inheritance of the disease and the MHC genotype in affected families has demonstrated that the genetic lesions responsible for the MHC-II deficient phenotype lie outside of the MHC locus (18,32). This represented the first indication that the disease is due to defects in transacting regulatory factors required for expression of MHC-II genes. The affected genes are now indeed known to encode for at least 4 distinct regulatory factors controlling transcription of MHC-II genes.

Clinical manifestations

Clinical manifestations include primarily septicemia and recurrent infections of the gastrointestinal, pulmonary, upper respiratory, or urinary tracts. Patients are prone to bacterial, fungal, viral, and protozoal infections. These start within the first year of life, and subsequent evolution of the disease is characterized by an inexorable progression of the infectious complications until death ensues. Few children reach puberty; the majority die between the ages of 6 months and 5 years (Table 1).

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TABLE 1:

Clinical manifestations of MHC-II deficiency *

Bacterial infections in various locations are dominant. These include intestinal infections, pneumonitis, bronchitis, and septicemia. The most frequently isolated bacteria include Pseudomonas, Salmonella, E. coli, Streptococcus, and Staphylococcus. Haemophilus and Proteus species have also been isolated. In almost all patients, bacterial infections of the intestinal tract, together with Candida albicans, Giardia lamblia, or Cryptosporidium infection, are responsible for protracted diarrhea, malabsorption, and failure to thrive. Intestinal and hepatic involvement due to Cryptosporidium colonization appears to be more frequent in MHC-II deficiency than it is in other immunodeficiencies.

The intestinal mucosa typically exhibit a variable degree of villous atrophy, and an intraepithelial infiltration by lymphocytes, macrophages, and some plasma cells. Hepatic involvement is frequent, but the manifestations are not uniform. Many patients exhibit symptoms suggestive of viral hepatitis. The most frequent cause of hepatitis is infection with CMV. Sclerosing cholangitis associated with Cryptosporidium infection, and bacterial cholangitis due to Pseudomonas, Enterococcus, and Streptococcus infections have been diagnosed in a number of patients.

Recurrent bronchopulmonary infections have been observed in all patients. The infectious agents identified include viruses (CMV, respiratory syncytial virus, enterovirus), bacteria (Streptococcus, Haemophilus, Staphylococcus, Pseudomonas, Proteus), Pneumocystis carinii, and Candida albicans.

Neurologic manifestations due to viral infections have been diagnosed in a number of patients. Coxsackie virus, adenovirus, and poliovirus were frequently responsible for meningoencephalitis. Two patients developed poliomyelitis despite previous vaccination with inactivated virus. Another patient died of postvaccinal poliomyelitis with encephalitis after vaccination with live attenuated virus. Several patients developed a severe autoimmune cytopenia (anemia, neutropenia, and/or thrombocytopenia).

In addition to severe and recurrent systemic infections due to a wide variety of pathogens, which are common to all SCID patients, sclerosing cholangitis has been reported in MHC-II deficiency patients but not in other SCID patients (50).

Comprehensive accounts of the clinical manifestations associated with MHC-II deficiency have also been published elsewhere (32,50,103).

Immunologic features

The immunologic manifestations characteristic of MHC-II deficiency have been described in detail elsewhere (32,50,103), and are summarized in Table 2. All of the immunologic manifestations can be accounted for by the absence of antigen presentation via MHC-II molecules. The most striking and constant consequence of the defect in MHC-II expression is, as expected, the absence of cellular and humoral immune responses to foreign antigens. All patients are unable to mount T-cell-mediated immune responses to specific antigens, as assessed by delayed type hypersensitivity skin tests. This correlates with an absence of T cell responses in vitro in the presence of antigens with which the patients had been immunized, or sensitized to by infections. Also consistent with the absence of MHC-II expression is the finding that lymphocytes from the patients have a decreased capacity to stimulate HLA-nonidentical lymphocytes in the mixed lymphocyte reaction.

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TABLE 2:

Immunologic findings of MHC-II deficiency *

Humoral immunity is severely impaired. The majority of patients are panhypogammaglobulinemic, almost agammaglobulinemic, or have a decrease in 1 or 2 immunoglobulin isotypes. Antibody responses to immunizations and infections by microbial agents are generally absent or strongly reduced. It is noteworthy that autoantibodies associated with autoimmune disorders have been found in several patients.

Patients have normal numbers of circulating T and B lymphocytes. In the majority of patients, however, CD4 + T cell counts are reduced, while CD8 + T lymphopenia is observed in one-third of patients. This presumably reflects abnormal selection and maturation of CD4 + T cells resulting from a lack of MHC-II expression in the thymus.

The immunologic features summarized above exhibit considerable variability from 1 patient to another. It is remarkable, however, that this variability does not show any correlation with the genetic heterogeneity in the cause of the disease.

Genetic and Biochemical Heterogeneity in MHC Class II Deficiency

Somatic cell fusion studies have permitted the classification of MHC-II deficiency patients into 4 distinct complementation groups (A, B, C, and D) indicating that the disease is genetically heterogeneous (3,56,91). In addition to the patients, certain in vitro-generated regulatory mutants having similar MHC-II-negative phenotypes have also been classified into complementation groups (3,56,91).

Three independent approaches (in vitro DNA-binding studies, mapping of DNase I hypersensitive sites, and in vivo footprinting experiments) have revealed the existence of 2 distinct biochemical phenotypes in MHC-II deficiency patients. A multimeric X box binding complex, the RFX complex, was first identified in nuclear extracts from MHC-II-positive B cell lines on the basis of its ability to bind in vitro to the X box of MHC-II promoters. This binding activity was found to be deficient in the majority of MHC-II deficiency patients (22,42,81,100). Moreover, 2 DNAse I hypersensitive sites flanking the MHC-II promoter in MHC-II-positive cells were found to be absent in RFX-deficient MHC-II deficiency cell lines (30). The lack of RFX binding activity and the altered chromatin structure revealed by DNAse I hypersensitivity studies were shown by in vivo footprinting experiments to be correlated with an unoccupied promoter phenotype (47,48).

MHC-II deficiency patients in complementation groups B, C, and group D exhibit the characteristic deficiency in RFX binding activity, the absence of DNAse I hypersensitive sites, and a bare promoter (47,48,60,80). In contrast, MHC-II deficiency patients from complementation group A exhibit a wildtype biochemical phenotype (47,48,60,80) (see Figure 3;Table 3).

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TABLE 3:

Genetic, biochemical, and molecular heterogeneity in MHC-II deficiency

Molecular Basis for MHC Class II Deficiency

CIITA, the gene affected in complementation group A

A genetic approach based on cDNA expression cloning was developed to identify the genes affected in MHC-II deficiency. By this method, complementation of a cell line from group A led to the isolation of CIITA (class II transactivator) (98). CIITA is a 1,130-amino acid protein exhibiting no extensive homology to any other known proteins (Figure 4a). It functions as a non-DNA-binding coactivator (38,64,80) that mediates both constitutive and IFN-γ-inducible expression of MHC-II genes (98,99). The CIITA gene represents the “master regulator” for the expression of MHC-II genes (see Figure 3) (38,64,80), and, in most cases, the expression of CIITA and MHC-II is tightly correlated. For example, the constitutive expression of MHC-II genes in B cells is sustained by constitutive expression of CIITA. The differentiation of B cells into mature plasma cells is accompanied by silencing of the CIITA gene, resulting in the loss of MHC-II expression (94). The majority of cell types do not express basal levels of CIITA, and are consequently MHC-II negative. In such cells, the expression of CIITA, and thus of MHC-II genes, can generally be induced by stimulation with IFN-γ(11,99). This has been demonstrated in a wide variety of different cell types, including fibroblasts, melanoma cells, macrophages, microglia, and astrocytes (52,67,68,75,76).

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Fig. 4:

a) CIITA: CIITA is a protein composed of 1,130 amino acids. CIITA contains an ATP/GTP-binding domain, an acidic domain, 3 proline/serine/threonine-rich regions, and a leucine-rich repeat region (LRR). b) RFXANK: RFXANK is a 260-amino acid protein. RFXANK contains an ankyrin repeat region and an acidic region (DE) suggested to be a potential PEST domain. c) RFX5: RFX5 is a 616-amino acid protein. RFX5 contains a DNA-binding domain (DBD) and 2 proline-rich regions of unknown function. d) RFXAP: RFXAP is a 272-amino acid protein. RFXAP contains an acidic domain (DE) rich in aspartic acid and glutamic acid, a glutamine-rich domain (Q), and a putative nuclear localization signal (NLS).

CIITA is tightly regulated and several distinct and independent promoters control transcription of the CIITA gene. Four promoters (I, II, III and IV) have been identified in the human CIITA gene (68). Three of these (I, III, and IV) are strongly conserved in the mouse. The study of these promoters has demonstrated that it is their differential activation that ultimately determines the cell-type specificity and modulation of MHC-II gene expression (28,53,68,75,76). Two of the promoters direct constitutive expression in professional antigen presenting cells. Promoter I is highly specific for dendritic cells while promoter III is used primarily in B cells. A third promoter (IV) mediates IFN-γ-induced expression. The latter is activated by IFN-γ in a wide variety of professional and nonprofessional antigen presenting cells, including monocytes, macrophages, microglia, astrocytes, fibroblasts, and endothelial cells. While promoter IV is the major IFN-γ-inducible promoter in many cell types, induction of promoter III has also been reported. The dependence on promoters III and IV for IFN-γ-induced expression may vary as a function of the cell type.

Four patients and 1 in vitro-generated mutant cell line have been classified in complementation group A (Table 4) (5,8,72,77,98).

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TABLE 4:

CIITA mutations in patients and a mutant cell line classified in complementation group A

RFXANK, the gene affected in group B

The gene that is defective in patients in complementation group B was identified by a biochemical approach (23). The RFX complex was purified, and peptide sequences derived from the 33 kD subunit were used to identify and isolate the corresponding gene.The gene was called RFXANK because the protein it encodes contains a C-terminal protein-protein interaction domain consisting of 3 ankyrin repeats (63) (Figure 4b). The N-terminal extremity is rich in acidic amino acids, and it has also been reported to resemble a PEST (proline/glutamic acid/serine/threonine) domain (69). PEST domains are found in many proteins that have short half-lives (86). Whether or not this region of RFXANK functions as a PEST domain is unknown. The RFXANK gene has also been called RFX-B to indicate that it is mutated in complementation group B (69).

Transfection of the RFXANK cDNA into cell lines from patients in complementation group B restores expression of all MHC-II isotypes (63,69). Group B accounts for almost 70% of all known patients, and mutations in RFXANK thus represent the most frequent molecular defect in the disease. Seven different mutations of the RFXANK gene have been characterized in 27 unrelated patients (19,63,69,109). All of these mutations affect the integrity of the ankyrin repeat region. One is a missense mutation lying within the third repeat. The remaining 6 are nonsense or splice site mutations leading to proteins lacking all or part of the ankyrin repeat region. Twenty-two patients have the same mutation, indicating the existence of a founder effect (109; Picard et al, unpublished data) (Table 5). Within this group a certain heterogeneity of clinical course was observed. Two affected boys homozygous for this mutation have survived to 14 and 22 years of age, respectively, without bone marrow transplantation (BMT). Therefore, no correlation can be observed between the genotype and the clinical course of the disease (109,110).

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TABLE 5:

RFXANK mutations in patients classified in complementation group B

RFX5, the gene affected in group C

The same complementation strategy used to isolate CIITA was subsequently applied to cell lines exhibiting a defect in binding of the RFX complex (complementation group B, C, and D). Complementation of a cell line from a patient (SJO) in complementation group C led to the isolation of RFX5, the 75 kD subunit of RFX (97). RFX5 was found to be mutated in all MHC-II deficiency patients and an in vitro-generated mutant in complementation group C (7,73,74,97,108,110) (Figure 4c). RFX5 belongs to a novel family of related DNA-binding proteins; other members of this family are not involved in the control of the MHC-II gene expression (24). RFX proteins have been conserved throughout evolution in a wide variety of species. They have been recruited in a diverse spectrum of unrelated biologic systems, including regulation of the mitotic cell cycle in fission yeast, the expression of various mammalian genes including MHC-II genes, and the control of viral genes such as those of the highly pathogenic hepatitis B virus (24). All members of the family are characterized by a 75–77 amino acid segment known to encode the DNA-binding domain. The consensus sequence for this domain shows no significant homology to any other known DNA-binding motif (24,25). Via its C-terminal domain, RFX5 play a key role in the cooperative binding between the RFX complex and the NF-Y complex (107). Transactivation of MHC-II genes is dependent on the C-terminal region of RFX5 (20,107), which was also found to interact with CIITA (20,89). Five cell lines derived from MHC-II deficiency patients and 1 in vitro-generated cell line (G1B) have been classified in complementation group C (Table 6).

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TABLE 6:

RFX5 mutations in patients and a mutant cell line classified in complementation group C

RFXAP, the gene defective in group D

The gene that is defective in patients in complementation group D was identified by a biochemical approach (23). The RFX complex was purified, and peptide sequences derived from the 36 kD subunit were used to identify and isolate the corresponding gene. The gene was called RFX-associated protein (RFXAP). The primary sequence of RFXAP contains an acidic region, a glutamine-rich region, and a putative bipartite nuclear localization signal (Figure 4d). RFXAP was found to associate independently with both RFX5 and RFXANK and could act to bridge RFXANK and RFX5. In doing so, RFXAP may place the RFX complex in direct contact with the X1 box (20). Before the cloning of RFXAP, no patients were classified in complementation group D. The identification of RFXAP permitted patients to be classified in group D and to conclude that mutations in RFXAP lead to the same clinical picture of immunodeficiency as in patient in the other groups (23,27,106). Three different mutations disrupting the RFXAP gene have been identified in 6 unrelated families in complementation group D. All 3 of these mutations lead to the synthesis of severely truncated proteins. Mutations affecting the RFXAP gene in an in vitro-generated mutant (6.1.6) have also been defined: each allele in this cell line contains a frameshift mutation resulting from the insertion of a single G nucleotide (23) (Table 7).

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TABLE 7:

RFXAP mutations in patients and a mutant cell line classified in complementation group D

Atypical form of MHC-II deficiency

Twin brothers (KEN and KER) exhibiting an atypical and less severe form of MHC-II deficiency have been described (21,40,111). In contrast to the situation observed in the “classical” form of MHC-II deficiency, defective expression in the new patients does not concern all MHC-II genes equally, and does not affect all cell types to the same extent. In EBV-transformed B cells from these patients, the DRB, DQB, and DPA genes are silent while the DRA, DQA, and DPB genes are expressed. In mononuclear cells, on the other hand, there is also a significant level of DRB, DQB, and DPA expression. Moreover, impairment of the immune response is much less evident than in classical MHC-II deficiency. In fact, investigations of MHC-II-dependent immune functions in these patients indicate the presence of competent MHC-II-positive antigen presenting cells (40,111). As expected from their atypical phenotype, KEN and KER represent a fifth complementation group (group E) that is distinct from groups A-D (21).

Binding of RFX and DNAse I hypersensitive sites has not been studied in the atypical patients assigned to complementation group E (KEN and KER). However, in vivo footprint experiments have demonstrated that these patients exhibit an unusual promoter occupancy phenotype. Promoters of genes that are silent (DRB, DQB) exhibit a bare promoter, while those of genes that are expressed (DRA) are occupied normally (21). The affected genes have not been identified.

In addition to KEN and KER, several other patients with an atypical clinical course have been identified during the last few years. In 5 patients (3 families) from group A, 3 from group B, and 2 as yet unclassified patients, clinical manifestations were less severe or even absent, and patients’ survival was found to be longer. In CIITA-deficient patients this might be explained by leakiness of the mutation responsible for the MHC-II expression defect. Indeed, in 2 families missense mutations of the CIITA gene (F961S and L469P) do not fully abrogate its transactivation activity, as shown both in vivo and in vitro (110 and Steimle, personal communication). Among 3 atypi-cal patients from group B, now aged 21, 14, and 26 years, respectively, 2 share the 26 bp deletion of the RFXANK gene that has been detected in 20 other patients (Picard at al, unpublished data). These 2 patients’ unusual capacity to cope with infections must depend on genetic, immunologic, and environmental differences that remain to be defined. In the third patient, the RFXANK gene harbors a splice site mutation leading to a partial capacity for MHC-II transactivation (Prud’homme et al, unpublished data). These newly observed patients demonstrate that with the better diagnostic techniques now available, physicians should be able to detect less severe cases. It is likely that such patients will not require the same aggressive treatments used for typical cases of MHC-II deficiency.

Therapy for MHC-II Deficiency

Symptomatic and prophylactic treatment of infections and other complications can at best reduce the frequency and severity of the clinical problems associated with MHC-II deficiency. Optimal therapy consists of the administration of prophylactic antibiotics, intravenous immunoglobulins, and parenteral nutrition. However, in most of the cases, these means do not prevent progressive organ dysfunction and ultimately death, generally between the ages of 5 and 18 years.

As for other combined immunodeficiency disorders, allogeneic BMT is considered the treatment of choice for MHC-II deficiency. When an HLA-identical sibling is available, the chances of success are now high. The success rate is considerably lower when BMT is performed with matched unrelated donors, or with partially HLA-compatible related donors. The 2 main obstacles are intractable persistent viral infections and graft failure or rejection. Nevertheless, several patients have now been cured by BMT with such non-HLA-identical donors, although the success rate remains lower than in other immunodeficiency syndromes (49) (Table 8).

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TABLE 8:

Outcome in MHC-II deficiency *

Three conclusions can be drawn from the current experience with BMT in MHC-II deficiency. First, despite the lack of MHC-II expression, the risk of graft versus host disease is similar to that observed in patients with other forms of immunodeficiency. Second, CD4 + T cell counts remain low (albeit functional) in long-term survivors. This is probably due to defective MHC-II expression by the thymic epithelial cells of the host. Third, the lack of MHC-II expression in nonhematopoietic cells does not appear to be detrimental for patients having undergone successful allogeneic BMT.

Now that the 4 genes affected in MHC-II deficiency have been identified, gene therapy becomes a potential alternative to BMT. Introduction of the wildtype CIITA, RFX5, RFXAP, and RFXANK genes into hematopoietic stem cells of patients in complementation groups A, B, C, and D, respectively, would represent a logical therapeutic strategy. The validity and strength of this type of approach has recently been emphasized by its resounding success in curing SCID infants carrying mutations in the common γ-chain (γc) gene: hematopoietic stem cells were isolated from these infants, transduced ex vivo with a retroviral vector carrying the γc gene, and then re-infused. Immune functions in the patients were restored by the corrected stem cells (10). MHC-II expression is tightly controlled in a cell-type-specific and -inducible manner, and ectopic or nonphysiologic levels of MHC-II expression induced by the transgene should therefore be avoided in the patients. This should not represent a major problem in the case of gene therapy with RFX5, RFXANK, and RFXAP, which are expressed ubiquitously at relatively constant levels in all cell types. Expression of CIITA, on the other hand, is tightly regulated by several alternative promoters that differ in their tissue specificity and inducibility by IFN-γ(68). Physiologic expression of a CIITA transgene will thus be difficult to obtain.

Correction of the disease by gene therapy can be imagined in 3 forms:

Gene therapy is an attractive option but remains an experimental therapy that must be developed and optimized before being proposed to the patients (16). One of the key steps is the correction of the defects in a mouse model of the disease. Two models of MHC-II deficiency exist, and both are very similar to the human disease. These models are the CIITA and RFX5 knockout mice, which will be invaluable for evaluating the feasibility of gene therapy for MHC-II deficiency (12,13).

Summary

Primary human immunodeficiencies are a heterogenous group of inborn errors of the immune system. Among them, MHC class II deficiency (MHC-II deficiency) is caused by the absence of MHC-II expression on the cell surface. The disease was named “major histocompatibility complex class II deficiency” but it is also frequently referred to as the “bare lymphocyte syndrome” (BLS). The disease is due to defects in transacting regulatory factors required for expression of MHC-II genes. The affected genes are now known to encode at least 4 distinct regulatory factors controlling transcription of MHC-II genes. These transacting factors, called CIITA, RFXANK, RFX5, and RFXAP, are essential and specific for the MHC class II gene expression. Thus, while all patients have very similar clinical findings, the genetic defects are heterogenous, with mutations in 1 of these 4 transacting factors. Here, we review the clinical and molecular features that characterize MHC-II deficiency and discuss therapy options.

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