Major histocompatibility complex class II deficiency: a clinical review

Blood Reviews (1996) 10,242-248 0 1996 Pearson Professional Ltd

State of the art

Major histocompatibility complex Class II deficiency: a clinical review

R. Elhasid, A. Etzioni Major histocompatibility complex Class II deficiency or bare lymphocyte syndrome is a rare combined immunodeficiency that accounts for 5% of all casesof severecombined immunodeficiency. The syndrome is characterized by a lack of human leucocyte antigen Class II geneexpression, absenceof cellular and humoral T-cell immune responseto foreign antigens, and impaired antibody production, resulting in extreme susceptibility to viral, bacterial and fungal infections. In some patients, there is a reducedcell surface expression of human leucocyte antigen Class I molecules also. Major histocompatibility complex Class II deficiency is an autosomal recessivedisease,most frequent in the Mediterranean area. The diseaseis causedby impaired generegulation involving trans-acting proteins. Somatic cell geneticsusing cell fusion experiments identified four complementation groups, all resulting in the same clinical manifestation. Two regulatory geneshave been identified so far: Class II tram activator and regulatory factor X5. Supportive treatment includes intravenous gammaglobulin and prophylaxis against Pneumocystis carinii. The only curative treatment is bone-marrow transplantation.

INTRODUCTION

heavy chains, but the same microglobulin (p2m) light chain. They are expressed on the surface of all nucle-

Major histocompatibility complex (MHC) genes, locatedon the short arm of chromosome6, encodes two classesof proteins- MHC ClassI and ClassII that are involved in the immune response.In the human,thesegenesaretermedhumanleukocyteantigens(HLA Class I and ClassII). Both ClassI and ClassII moleculesare transmembranedimers,composedof glycoproteinchains.

atedcells.’ HLA ClassII moleculesarecomposedof an a and

There are three major types of HLA Class I antigens, HLA-A, -B and -C, characterized by distinct Ronit Elhasid MD and Amos Etzioni MD, Department Pediatrics and Pediatric Hematology - Oncology Unit, Rambam Medical Center, Haifa, Israel 31905. Tel: 00972-4-852-2193; Fax: 00972-4-854-2441; Correspondence

to Professor

p chain of three specificities: HLA-DR,

HLA-DQ

and HLA-DI? Class II molecules are present on the surface of B lymphocytes, activated T lymphocytes, monocytes, dendritic cells, Langerhans cells,

and epithelialcellsin the thymusandintestine.2 Thesetwo classes of MHC proteins, which present antigen to T cells, interact with different classes of T lymphocytes: CD4’ cells appear to recognize antigen in association with MHC Class II molecules, whereas CD8’ T cells recognize antigen in association with MHC Class I proteins.3 Presentation of foreign antigen to CD4’ T helper cells requires co-ordination of both the endocytic pathway which generates and delivers antigenic peptides, and

of

Etzioni.

242

MHC Class II deficiency

the biosynthetic pathway which provides the MHC Class II molecules, all within specialized antigen-presenting cells. Class II molecules are o.@ dimers that assemble in the endoplasmic reticulum with a third protein, invariant chain (Ii). The Ii blocks binding of endogenous antigens to the Class II molecules and stabilizes them. After removal of Ii in the acidic and proteolytic environment of the endosomal compartment, the Class II molecules can bind foreign antigen, transport it to the cell surface and present it to T cells. This compartment, where Class II molecules are loaded with their antigenic peptide, is unique and biochemically distinct from early and late endosomes and lysosomes, being a specialized subset of the endosomal compartment4 In addition to their role in antigen recognition and in antibody response to foreign protein antigens, HLA Class II molecules are necessary in cell-to-cell interactions involved in delayed-type hypersensitivity, intrathymic differentiation of pre-T cells and selfrecognition.5+j HLA Class I molecules are specific targets for allorecognition by allogenic T lymphocytes (of the CD8 type). They also present viral or parasite peptide antigens to autologous CDS lymphocytes, which act as cytotoxic T lymphocytes (CTLs). Defects affecting the expression of those surface molecules, especially MHC Class II molecules, results therefore in the total failure of immune recognition by CD4’ T cells. The available CD4’ cells cannot mount delayed-type hypersensitivity response, nor can they provide help for the B cells to generate antigen-specific humoral responses, resulting in a severe combined immunodeficiency. The first case of combined immunodeficiency disease associated with abnormal HLA Class I antigen expression was reported by Touraine et a1.7 They described a male infant, 5 months of age, who had pneumonia leading to respiratory failure. Bronchial secretions were positive for Pneumocystis cavinii. In spite of intensive treatment and fetal thymus transplantation, the child died of respiratory failure. No HLA-A and -B antigens were present on lymphocyte and platelet surfaces. His parents were first cousins of Algerian origin. Six siblings were alive, four were dead. The fourth child, a female infant, died of intractable pneumonia at one year of age. They named this form of immunodeficiency the ‘bare lymphocyte syndrome’, although HLA Class II expression had not been analyzed and was assumed to be normal. Later, it was found that these patients did express Class II molecules. The same membrane abnormalities were described by Payne et al8 and Maeva et al9 in non-immunodeficient or normal individuals. The syndrome discussed in this review is a rare severe primary immunodeficiency characterized by a

243

lack of HLA Class II gene expression in all tissues, a complete lack of cellular and humoral immune response to foreign antigens, and a reduced cell surface expression of HLA Class I molecules in certain cases. This disease was named MHC Class II deficiency by the WHO committee.‘O However, the term ‘bare lymphocyte syndrome’ has now been used to categorize patients with MHC Class II deficiency, irrespective of the status of HLA Class I expression.”

CLINICAL AND IMMUNOLOGICAL MANIFESTATIONS MHC Class II deficiency is characterized by combined immunodeficiency, absence of cellular and humoral T-cell responses on antigen challenge and impaired antibody production, resulting in extreme susceptibility to viral, bacterial and fungal infections. Usually, the infections begin in the first year of life, often leading to death in early childhood. Since the first description, more than 40 cases have been reported. li Klein et al analyzed 30 patients retrospectively in order to define the clinical and immunologic characteristics, outcome and natural history of MHC Class II deficiency. l2 Diagnosis was based on the family and personal history of recurrent pulmonary and gastrointestinal infections, and was confirmed by the finding of a defective expression of MHC Class II antigens on peripheral mononuclear blood cells. Mean age at first infection was 4.5 months (range 2-12 months). Clinical manifestations included recurrent infection of the gastrointestinal, pulmonary, upper respiratory, urinary tract and septicemia. The most frequently isolated bacteria included Pseudomonas and Salmonella species. Other organisms were pathogenic Escherichia coli, Streptococcus, Staphylococcus, Haemophilus and Proteus species. Twenty-three patients had severe, persistent viral infections, the most common being cytomegalovirus (CMV), enterovirus, adenovirus and herpes simplex virus (HSV). Some had invasive Candida infections. Almost all patients had severe intestinal infections with diarrhea, malabsorption and failure to thrive. Candida, Giardia lamblia and Cryptosporidium were the main organisms found in the gastrointestinal tract. Hepatic abnormalities were frequent; 27 patients had hepatomegaly or elevated transaminase activity or both, suggestive of viral hepatitis. Ten patients had evidence of biliary tract disease and sclerosing cholangitis was proven histologically in four patients. Cryptosporidial infection was associated with sclerosing cholangitis in three of four patients. The risk of biliary tract involvement seemed to increase with age.

244 Blood Reviews All patients had recurrent bronchopulmonary infections (CMV, respiratory syncytial virus, enterovirus, Pneumocystis carinii, Candida, Streptococcus species, Haemophilus, Staphylococcus, Pseudomonas and Proteus.) Neurologic manifestations were due to central nervous system viral infections. Oral poliovirus vaccination led to poliomyelitis and fatal meningoencephalitis in one child. Viral meningoencephalitis was the cause of death in six children. One patient died of disseminated HSV infection and two patients died with progressive encephalitis of probable viral origin. No case of malignancy was reported in those patients. The clinical course was characterized by progression of infectious complications. Few children reached puberty. The mean age at the time of death was four years (range six months-16 years). The oldest patient reported by Klein et all2 is 15 years of age. All received regular immunoglobulin substitution and prophylactic antibiotics. In most patients, MHC Class II expression could not be detected on B lymphocytes or monocytes. Some patients showed residual MHC Class II expression on B lymphocytes and monocytes. Regarding MHC Class I expression, significant abnormalities were detected by human leucocyte antigen (HLA) typing techniques. Decreased absolute CD4 counts were found in 22 of 26 patients that were tested, with proportional increment in subset of CD8’ cells. Immunophenotyping of peripheral blood lymphocytes showed normal numbers of CD3’ T and B cells. Delayed-type hypersensitivity skin tests and in vitro stimulation by tetanus toxoid, tuberculin and other antigens were negative in all patients. Response to various mitogen stimulation was intact, due to their ability to activate T cells regardless of HLA expression. Humoral immunity was impaired. Nine patients had panhypogammaglobulinemia, eight could not be evaluated because of prior administration of immune globulin infusion, and 12 had a decrease in one or two immunoglobulin isotypes. Most patients were unable to mount specific antibody response during and after infectious episodes by known pathogens. Nonetheless, a normal specific antibody response was observed in two twins, suggesting that some patients may be treated more conservatively.13 Recently, the primary and secondary humoral response to phage 174 was evaluated in three patients.14 Immunoglobulin production in the patients was only l-2% of levels observed in the control. Furthermore, no switch from immunoglobulin M (IgM) to immunoglobulin G (IgG) response was found. MHC Class II deficiency accounts for 5% of all cases of severe combined immunodeficiency (SCID).15 Usually, this type of combined immunodeficiency has

a milder course compared with other types of SCID syndromes, and the immune system maintains some function. In contrast to patients with other SCID syndromes, who have absence of tonsils and other lymphoid tissue despite chronic infections, patients with MHC Class II deficiency often have normal or enlarged peripheral lymph nodes and a thymus shadow is usually seen on radiographs of the chest.16 Because T cells capable of responding to alloantigens are present in these patients, the potential risk of graft rejection during allogenic bone-marrow transplant (BMT) exceeds that for patients with other SCID disorders and pre-transplant immune ablation is indicated. Transfusion with blood products that have not been irradiated may lead to severe graft-versus-hostdisease (GVHD) in patients with SCID. Klein et all2 described three patients with MHC Class II deficiency who had received non-irradiated blood product transfusions before diagnosis, without the development of GVHD, presumably due to residual immune function. When given bacille Calmette-GuCrin (BCG) in infancy, they survived, in contrast to infants with other forms of SCID who die of progressive infection.” In addition to severe and recurrent systemic infections due to a wide variety of pathogens, which are common to all SCID patients, sclerosing cholangitis described in MHC Class II deficiency patients has not been reported in other types of SCID. In Klein’s series,12three out of four patients with sclerosing cholangitis had concomitant gastrointestinal Cryptosporidium infection.

INHERITANCE MHC Class II deficiency is an autosomal recessive disease, as evidenced by equal numbers of males and females whose parents did not show any sign of the disease.12 Most children were of North African origin - Moroccan, Algerian, Tunisian; others were of Spanish, Italian, Kurdish or French origin, Consanguinity was present in two thirds of patients. As regards HLA Class I phenotype, two affected siblings had different HLA Class I phenotype in three families, and an affected individual had a HLA Class I identical to healthy sibling or father in nine other families.16These findings suggest segregation between factors regulating expression in HLA Class II molecules and HLA locus.

GENETIC

AND MOLECULAR

ANALYSIS

Complete absence of HLA Class II gene expression in all tissues is the cause of the clinical manifestation of

MHC

the disease. However, in certain cases this phenotype is somewhat leaky, with some residual expression of Class II molecules.17 This may be due to the heterogeneity in the genetic defects responsible for the disease. In certain cases, reduced expression of HLA Class I molecules has been described, but the significance of this remains unclear. MHC Class I and II chains are synthesized in the endoplasmic reticulum and transported to the cell membrane. Previously, it was thought that the defect in this disease is due to a lack of intracellular assembly of Class II a and p chains, or to a block in the transport of HLA Class II molecules from the endoplasmic reticulum to the cell surface. But it has been shown that lymphocytes from patients do not synthesize any HLA Class II a and B chains.‘* It seems that the genetic defect is the inability to synthesize HLA Class II polypeptide chains. When the messenger ribonucleic acids (mRNAs) of HLA Class II genes were analyzed by northern blot hybridization procedures in patients’ lymphocytes, no mRNAs were found, suggesting that a genetic abnormality in gene expression affecting HLA Class II genes, is the primary defect. It is worth noting that the expression could not be restored by stimulation with y-interferonI a known inducer of HLA Class II gene expression. As no deletion in the HLA Class II region took place in these patients, it was concluded that the genetic defect must be located outside the MHC region and outside chromosome 6. Support for this idea is the fact that the inheritance of HLA Class I alleles segregate independently of the disease. Also investigated is the possibility of abnormalities in the processing and splicing of RNA transcripts or stability of RNA; however, assays performed with control and cell lines from patients showed that there was complete absence of HLA Class II gene transcription.20 The global lack of expression of the entire HLA Class II gene family suggested a general defect in the regulation of these genes, involving one or several trans-acting factors. The regulation of Class II MHC gene expression is essential for a carefully controlled immune response. This control is due mainly to a promoter region that contains several conserved DNA elements or ‘boxes’ called the X, X2 and Y elements. All of these ‘boxes’ are essential for the proper transcription of Class II genes. All boxes must be occupied by DNA binding proteins to promote the expression of Class II genes. Apart from these occupied boxes, there is a need for another factor for normal expression and this is the Class II tram activator (CIITA)1sJm23 Extensive studies have been performed on MHC Class II promoters. These promoters contain several sequences, called the W, X, X2 and Y boxes. All are

Class II deficiency

245

required for normal or y-interferon induction of Class II expression on cell surface. Studies of the MHC Class II deficient cell lines showed the importance of the X box binding factor regulatory factor X (RFX) which is absent in certain patients.20 Binding of other factors like NF-Y (binding to the Y box) and X2bp (binding to the X2 box) were unaffected.24 On the basis of binding of RFX, two types of MHC Class II-deficient cells were demonstrated: one that has normal RFX binding and the other lacking RFX binding. I* Subsequently, it was revealed that patients with normal binding of RFX belong to the same complementation group whereas RFX-deficient cells fall into the other two complementation groups. It has been shown that patients with a defect in RFX binding have ‘bare promoter’ phenotype, including the X, X2 and Y boxes, while patients with normal RFX binding have occupied Class II promoter.25 Thus, it was concluded that binding of RFX is required for occupancy of all promoter boxes.‘* Somatic cell genetics using cell fusion experiments between different patients and in vitro generated cell lines, showed a number of complementation groups.26 Three complementation groups were demonstrated and a fourth complementation group is suggested (Fig.).27 This implies that, although the clinical manifestations are the same, there are mutations in at least three distinct genes that control the disease. Patients from complementation group A have normal RFX binding in vitro and normal HLA Class II promoter occupancy in vivo, while patients in complementation groups B and C have defective RFX binding in vitro and unoccupied Class II promoters in vivo. The genetic complementation approach has led to the identification of the MHC Class II transactivator (CIITA) the gene that is mutated in patients from complementation group A.2g CIITA is a 4.5 KB complementary deoxyribonucleic acid (cDNA) that can restore expression of HLA-DR,-DQ and -DP in cell lines from complementation group A. CIITA codes for a protein of 1130 amino acids, and the gene encoding CIITA maps to chromosome 15.‘9 There is no evidence for direct binding of CIITA to the MHC Class II promoter. Two models of CIITA function have been proposed.22 In the first model, CIITA directly interacts with Class II-specific DNA binding factors on the DNA, namely RFX. There is no evidence yet showing biochemical interactions between RFX and CIITA, but the fact that CIITA in cells that lack RFX does not revert the Class II-negative phenotype, suggests that RFX and CIITA interactions are necessary for activation. An alternative model suggests that CIITA regulates or modifies RFX, which allows it to activate transcription following binding.

246 Blood Reviews

NormalClassII expression MJXClass II genes

Promoter region

GroupB

Normal Class II gene expression and known complementation defects groups. In group A, a defect in CIITA was found. In groups B and C, no RFX-binding occurs. In C, a specific defect in RFXS is observed.

Fig.

Mutations in CIITA include deletions of the CIITA gene or splice site mutation that lead to a deletion in CIITA mRNA, all representing the genetic basis for MHC Class II deficiency in complementation group A. The CIITA gene itself is induced by y-interferon, and is the mediator of inducible MHC Class 11 gene expression by y-interferon.30 CIITA-deficient mice that do not express MHC Class II molecules can be utilized as a model system for the human bare lymphocyte syndrome.31 Complementation groups B and C are characterized by lack of binding of RFX, which is a heterodimer.” Mutation in either of the two RFX subunits provides an explanation for the fact that it is deficient in two different genetic complementation groups. Again, genetic complementation approach has led to the cloning of candidate cDNA, RFXS, which restores normal binding of the RFX complex in cell lines from group C but not group B, and thus may represent the regulatory gene responsible for HLA Class II deficiency of patients in group C. 32 This protein maps to chromosome 2.29 To date, no regulatory gene has been identified in group B.

A new complementation group has recently been found in a few patients. 33In this group, normal expression of both CIITA and RFX5 exist and no defect in RFX binding is detected. The primary genetic defect in this new complementation group is still unknown (Table 1). Two complementation groups - A and B accounted for two thirds of cases of MHC Class II deficiency. Group B is predominant. The fact that the patients originate from only two ethnic groups and the high incidence of consanguinity could explain this phenomenon. Most of the North African patients fall into complementation group B, while most of the Spanish patients belonged to group A.3” Table

1

Class II deficiency: complementation groups

Complementation

group

RFX

binding

Defect

A(-20%)

+

B(-60%) C(-10%) X(rare)

+

CIITA ? RFXS ?

MHC

Table

2 BMT

in MHC

Class

II deficiency

Age*

HLA Mismatched Surviving disease-free

Total

4 (40%)

13

9

*Age

is reported

in months

as median

with

247

(23 patients)

HLA Matched Total

Class II deficiency

the range

HLA matched unrelated donor

Age*

Surviving disease-free

(Z9)

4(20%)

Total

Age”

1

8

Surviving disease-free 1

in parentheses.

Although different genetic and molecular defects are found, they all result in the same disease with no clinical features that discriminate one from the other, and no correlation with complementation groups. The two regulatory genes, CIITA and RFX5 have no effect on HLA Class I expression, and thus do not explain the reduced level of the HLA Class I expression reported in certain patients.

TREATMENT MHC Class II deficiency has a poor prognosis with a life-expectancy of only a few years. Supportive treatment with intravenous immunoglobulin, antibiotics for documented infections, and prophylaxis against Pneumocystis carinii should be provided to all patients. The only curative treatment today is BMT. The first report on BMT for MHC Class II deficiency came from a European survey carried out between 1968 and 1985.35There were six patients who had HLA-matched transplant and four who had HLA-mismatched related transplant. Only one, who had an HLAmatched transplant, survived. They died from CMV infection or other infections that are uncommon after BMT, such as adenovirus, enterovirus and respiratory syncytial virus. In most cases, the patients were latent carriers of the viruses, which were activated with the protracted BMT immunosuppression. The authors concluded that, regardless of the diagnosis, the age at the time of BMT has an important role in the prognosis and justifies early treatment. Successful treatment with an unrelated-donor BMT in an X-month-old girl was reported by Casper et a1.36The patient was conditioned with busulfan and cyclophosphamide, followed by infusion of T-cell-depleted bone-marrow cells. This was the first successful unrelated BMT in a patient with HLA-deficient immunodeficiency, and the only one reported to date (Table 2). A second report from the European Group for BMT (EGBMT) and Immunodeficiency included

eight patients with an HLA-matched donor and twelve patients with a partially matched related donor who were transplanted since 1986.37 Three patients survived out of eight with matched HLA and four out of twelve with partially matched HLA, results that are far better than those reported in the earlier European survey. The improvement in outcome was mainly due to a higher engraftment rate and a decrease in the frequency of fatal infections. The latest and largest single-center study of 19 patients with MHC class II deficiency analyzed the results of their BMT.38 Of the seven patients who underwent HLA-matched BMT, three died in the immediate post-transplant period of severe viral infections, whereas the remaining four were cured. Of the twelve patients who underwent HLA-haploidentical BMT, three were cured, one was improved by partial engraftment and seven died of infectious complications. One is still immunodeficient because of engraftment failure. Here again, a favorable outcome was associated with an age of less than two years at the time of transplantation, before the acquisition of chronic virus carriage and sequelae of infections. A summary of all reported patients undergoing BMT is given in Table 2. Various conditioning regimens were used. Four out of seven patients who had HLA-matched BMT and survived, received busulfan (20 mg/kg) and cyclophosphamide (200 mg/kg). Patients who had HLA-mismatched BMT and survived received the same regimen, including anti-lymphocyte function-associated antigen 1 (LFA-1) antibody and anti-CD2 antibody. Full hematopoietic chimerism was only observed after using anti-LFA-1 and anti-CD2 antibodies to reduce engraftment failures. Anti LFA-I antibody may prevent interaction between recipient effector cells and donor bone-marrow cells, and help to achieve successful engraftment.39 Until gene therapy becomes available, BMT remains the treatment of choice in MHC Class II deficiency - a rare disease with dismal prognosis.

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