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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Division of Immunology, Beth Israel Deaconess
Medical Center, and the Division of Immunology, Children's Hospital,
Harvard Medical School, Boston, MA; the Division of Allergy and
Immunology, Department of Pediatrics, Duke University School of
Medicine, Durham, NC; and the Division of Pediatrics, Rambam Medical
Center, B Rappaport School of Medicine, Technion, Haifa, Israel.
X-linked lymphoproliferative (XLP) disease is a primary
immunodeficiency caused by a defect in the SH2D1A gene. At
least 3 major manifestations characterize its clinical presentation:
fatal infectious mononucleosis (FIM), lymphomas, and immunoglobulin deficiencies. Common variable immunodeficiency (CVID) is a syndrome characterized by immunoglobulin deficiency leading to susceptibility to
infection. In some patients with CVID, a defective btk or
CD40-L gene has been found, but most often there is no
clearly identified etiology. Here, 2 unrelated families in whom male
members were affected by CVID were examined for a defect in the
XLP gene. In one family previously reported in the
literature as having progressive immunoglobulin deficiencies, 3 brothers were examined for recurrent respiratory infections, whereas
female family members showed only elevated serum immunoglobulin A
levels. A grandson of one of the brothers died of a severe
Aspergillus infection secondary to progressive immunoglobulin deficiency, FIM, aplastic anemia, and B-cell lymphoma. In the second family, 2 brothers had B lymphocytopenia and
immunoglobulin deficiencies. X-linked agammaglobulinemia syndrome was
excluded genetically, and they were classified as having CVID. The
occurrence of FIM in a male cousin of the brothers led to the XLP
diagnosis. Because the SH2D1A gene was found altered in
both families, these findings indicate that XLP must be considered when
more than one male patient with CVID is encountered in the same family,
and SH2D1A must be analyzed in all male patients with CVID.
Moreover, these data link defects in the SH2D1A gene to
abnormal B-lymphocyte development and to dysgammaglobulinemia in female
members of families with XLP disease.
(Blood. 2001;98:1321-1325) X-linked lymphoproliferative (XLP) disease is
characterized by extreme complications of Epstein-Barr virus (EBV)
infection.1-5 Its identification was first reported more
than 25 years ago.1 XLP has 3 major phenotypes: fulminant
infectious mononucleosis (FIM) (50%), B-cell lymphoma (20%), and
dysgammaglobulinemia (30%).6,7 Aplastic anemia,
vasculitis, and pulmonary lymphomatoid granulomatosis are also often
associated with the syndrome.
The gene responsible for the disease has been cloned and named
SAP (for SLAM-associated protein) or
SH2D1A.8-10 The human and mouse
SH2D1A genes consist of 4 exons and 3 introns spanning approximately 25 kilobase (kb).8,11 In the mouse,
SH2D1A is highly expressed in thymocytes and peripheral T
cells with a prevalent expression on Th1 cells.11 Although
SH2D1A is also expressed by natural killer
cells,12,13 its presence in B lymphocytes is unclear.
The SH2D1A protein consists of 128 amino acids comprising an SH2 domain
and a 24-amino acid tail.8,10 It has been shown to bind a
family of surface immune receptors, the SLAM family, which belongs to
the immunoglobulin family of receptors.10,13,14 SLAM
(CD150), 2B4 (CD244), CD84, and Ly-9 are the molecules that bind
SH2D1A.10,13-15 An SH2D1A-like molecule named
EAT-216 interacts with the same SLAM family
members as SH2D1A in non-T hematopoietic cells (M.M. et al, manuscript
submitted, 2001).3,5
Among the different XLP phenotypes, FIM is the only one clearly
linked to EBV infection. However, immunoglobulin deficiencies and
non-Hodgkin B-cell lymphomas have been observed in patients with XLP
who were seronegative or polymerase chain reaction (PCR)-negative for
EBV.17,18 Immunoglobulin deficiency and chronic
respiratory infections associated with XLP clinically resemble common
variable immunodeficiency (CVID).19,20 CVID is a primary
immunodeficiency syndrome characterized by decreased, often fluctuating
serum immunoglobulins and clinical features of recurrent bacterial
infections.19,20 Atypical inflammatory gastrointestinal
diseases and autoimmune diseases, including autoimmune hemolytic
anemia, thrombocytopenia, rheumatoid arthritis, and pernicious anemia,
develop in some patients. Patients with CVID also have an increased
risk for cancer, particularly lymphoma.20
Our working hypothesis is that a subset of male patients with CVID that
lacks a clearly defined etiologic factor may have alterations in the
SH2D1A gene. In the past, X-linked agammaglobulinemia (XLA)
and X-linked and autosomal hyper-immunoglobulin (Ig)M syndrome (X-HIM
and HIM) disease genes have been found mutated in some CVID patients,
whereas most patients remain without a clearly identified etiologic
factor.19,21 Here, 10 males of 2 families in whom CVID had
been previously diagnosed were found to have alterations in the XLP
gene SH2D1A. Our results indicate that mutations in the
SH2D1A gene must be studied in all male patients with CVID.
Detection of mutations in the SH2D1A gene
Genomic polymerase chain reaction.
Peripheral blood lymphocytes from families were collected in
EDTA-containing test tubes. When lymphoblasts were available, they were
grown in RPMI 1640 supplemented with 10% fetal bovine serum under
standard culture conditions. DNA was isolated using standard
techniques.22 Coding sequences, 5' regulatory region (300 nucleotides from the transcription initiation site), and intronic
splice-site sequences were amplified by PCR (GeneAmp/XL PCR kit;
PerkinElmer, Branchburg, NJ). From each family, at least 2 affected
members, 2 carriers, and 2 healthy members were analyzed for mutations
in the SH2D1A gene. PCR was performed in 50 µL with a
GeneAmp PCR System 9700 (PE Applied Biosystems, Foster City, CA), under
the following conditions: 94°C for 3 minutes, 94°C for 1 minute,
60°C for 1.5 minutes, 72°C for 1 minute for 35 cycles; 72°C for
10 minutes; 4°C ( Reverse transcription-PCR.
Total RNA was isolated from peripheral blood lymphocytes of patients,
carriers, and healthy persons by TRIzol Reagent (BRL, Gaithersburg,
MA). One microgram total RNA was reverse-transcribed using a one-step
reverse transcription (RT)-PCR system (Access RT-PCR kit; Invitrogen).
The primer combinations used were F5'-GCC TGG CTG CAG TAG CAG CGG CAT
CTC CC-3' and R5'-ATG TAC AAA AGT CCA TTT CAG CTT TGA C-3'. Annealing
temperature for both primer pairs was 60°C.
Measurement of serum immunoglobulin levels
Clinical and immunologic presentation of the patients Family 1.
Patient C.L. (Figure 1A) was
born in 1996. After the first 6 months of life, the patient was
examined for recurrent infections of the upper and lower
respiratory tracts (bronchitis, pneumonia, and otitis media) and of the
gastrointestinal tract. Determination of serum immunoglobulin levels
indicated only elevated IgA at 6 months and slightly low IgM at 14 months (Table 1). Because of the family history of immunodeficiency, he
did not receive live vaccines. At the age of 17 months, serum
concentrations of IgG and IgA declined, and he had almost no detectable
antibody titer against tetanus and diphtheria toxoids despite repeated immunizations. B- and T-cell numbers were normal. Lymphocyte
proliferation tests at the age of 18 months indicated normal responses
to phytohemagglutinin and concanavalin A, with a low response to
pokeweed mitogen. At the age of 19 months, aspartate
aminotransferase, alanine aminotransferase, alkaline phosphatase, and
C.L.'s family is a well-studied sibship, previously reported by Buckley and Sidbury24 (Figure 1A), affected by a variety of progressive immunoglobulin abnormalities in male and female members. C.L.'s grandfather (C.G.), together with his 2 brothers C.E. and C.F., were first seen at Duke University Medical Center in 1963 because all 3 were affected with frequent respiratory infections that were particularly severe in C.E. C.G. had only a late onset of mild infections. When he was first seen at the age of 6.5 years, C.G.'s findings were reported to be normal, but by the time he was 8.5 years of age, splenomegaly and a low lymphocyte count were noted. Immunologic studies over a period of 4 years showed a progressive deficiency of all 3 immunoglobulin isotypes (Table 1). He had a normal number of B cells initially, but this declined with time. He was treated with IVIG, but a B-cell lymphoma of the small intestine developed. This was successfully treated, but he had chronic severe diarrhea and died of bacterial pneumonia at the age of 38 years. The oldest brother, C.E., was first seen at the age of 14 years. He was affected by severe repeated respiratory infections, and examination of his serum revealed marked deficiencies of IgA, IgM, and IgG. C.E. failed to respond to blood group A and blood group B substances and to diphtheria, tetanus, and polio vaccines. He had 4 episodes of acute pneumonia before the age of 11 and died at 15 years because of acute respiratory failure. Another brother, C.F., remained well until late childhood. After the age of 10 years, he had repeated episodes of acute pneumonia. Analysis of serum immunoglobulin (Table 1) showed progressive reduction of his IgM and IgG levels over a 4-year period beginning in 1963. He died at the age of 25 years from acute pulmonary infiltrates and carcinomatous meningitis. The mother of the 3 boys (C.B.) had no history of severe infections. Her immunologic study findings (Table 1) demonstrated marked polyclonal IgA hyperglobulinemia, selective unresponsiveness to blood group B substance injections, and poor responses to immunization with diphtheria and polio vaccines. Two maternal aunts (C.C. and C.D.) also had IgA hyperglobulinemia and low isohemagglutinin titers. The father of the 3 boys (C.A.) was healthy and had normal levels of serum immunoglobulins (Table 1). There was no history of conditions similar to those of the boys on either side of the family. Family 2. A 2.5-year-old boy (A.C.) (Figure 1B, 2-A) was brought to the Rambam Medical Center (Haifa, Israel) in 1988 after several episodes of pneumonia and Escherichia coli sepsis starting when he was 1 year old. His B-lymphocyte count was very low (1%-2%), as were his serum IgG and IgM levels, and serum IgA was undetectable (Table 1). A presumptive diagnosis of XLA was made, and he was started on IVIG therapy. B cell levels rose to 7% to 8% over years. He had no major medical problems until the present; he is now 12 years of age. In 1993, his brother (A.B.) (Figure 1B, 2-A) was born and was found to have a normal number of B cells. Nevertheless at age 10 months, pneumonia and hypogammaglobulinemia developed (Table 1). IVIG treatment was begun, and, like his brother, he is now doing well. A mutation in btk was ruled out (courtesy of Dr M. E. Conley), and, thus, CVID was diagnosed. In 1999, their cousin B.C. (age 2 years) (Figure 1B, 2-B) was admitted to the hospital with clinical signs and symptoms compatible with FIM. He had marked hepatosplenomegaly and rapid deterioration of liver function. Anti-viral caspid antigen (VCA) IgM was positive, and liver biopsy showed typical features of FIM. He was treated with high-dose methylprednisolone and VP-16, but, unfortunately, he died before bone marrow transplantation could be performed. Family history (Figure 1B, 2-B) revealed that 2 other brothers died of FIM at approximately the same age range. In one of them, EBV was detected by biopsy of the liver. His 2 sisters were healthy.Analysis of the SH2D1A gene in the 2 families Family 1.
Clinical and autopsy findings of C.L. led us to consider the
possibility that he and his ancestors could have had XLP. Genomic DNA
of C.G. and C.L. was extracted from B lymphocytes immortalized with EBV
virus. DNA sequencing results (Figure 2A)
indicated the presence of a single nucleotide substitution, C
Family 2.
The clinical presentation of B.C. (November 1999), compatible with XLP,
prompted us to examine his DNA and that of his cousins (A.C. and A.B.)
for mutations in the XLP gene. Genomic DNA was extracted
from peripheral blood lymphocytes of members of the 2 families (2-A and
2-B) to be tested for alterations in the SH2D1A gene. DNA
sequencing (Figure 2B) indicated that the male family members B.B.,
B.C., A.B., and A.C. had an 8-base pair (bp) deletion located in the
third exon (nucleotides 548 to 555). This alteration in the
SH2D1A gene was previously unreported. Curiously, the
sequence deleted in these patients (GCATTTCA) is repeated twice in the third exon, and this deletion is situated adjacent to an internal splice acceptor site located in the third exon. This low-frequency splice acceptor site generates a physiologically shorter form of the
SH2D1A protein, named SAP
CVID is a heterogeneous syndrome both clinically and
immunologically.19,20 A precise clinical and laboratory
definition of the disease has been difficult because of the
heterogeneity in phenotypes. In a large study of 248 patients with
CVID,20 40% had impaired T-cell proliferation to
mitogens. Based on B-lymphocyte responses to plate-bound Cellular immunologic alterations in patients with XLP are not well understood. T and B lymphocytes undergo sustained proliferation in XLP. Extensive tissue infiltration and multi-organ failure are the primary causes of death in these patients.6 The failure to eliminate EBV-transformed B cells in XLP does not seem to be caused by a defect in the B cell.28 SH2D1A expression in B lymphocytes is probably limited only to certain subpopulations.12 Moreover, no major B-lymphocyte defects have been found in SH2D1A null mice (C. Gullo, C. Terhorst, personal communication). On the contrary, variable defects in T cells and natural killer cells of patients with XLP have been reported. SH2D1A-deficient natural killer cells are unable to lyse appropriate target cells.29-33 B-lymphocyte developmental abnormalities were detected in one member of the 2 families. Such a defect in B cells has been described in the past.34 Whether these B-lymphocyte abnormalities and abnormal immunoglobulin levels result from a SH2D1A deficiency in B cells or from abnormal T-B lymphocyte interactions among SLAM-family members is unknown at this time. The SH2D1A-interacting molecules SLAM and CD84 and the 2B4-ligand CD48 are highly expressed in B cells,35 and their expression increases after cell activation or EBV infection. In particular, SLAM has been demonstrated to play a role in B-lymphocyte proliferation and immunoglobulin synthesis after ligation by its soluble form (sSLAM).36 The complex network of interactions among SH2D1A, EAT-2, and their ligands SLAM, 2B4, CD84, and Ly-9 may account for the clinical variability of manifestations in XLP. Recent data (M.M. et al, manuscript submitted, 2001) indicate that EAT-2 is probably the SH2D1A-like molecule functional in B lymphocytes. One could predict that mutations of EAT-2 might give rise to CVID. Decreases in serum immunoglobulin levels with time in patients C.L., C.E., C.G., and C.F. (family 1) suggest that a cumulative effect of sequential environmental factors must play a strong role in determining the expression of the SH2D1A mutations. Because SLAM has been recently identified as another receptor for the measles virus,37 a role for measles virus as a potential precipitant of disease expression in SH2D1A-deficient patients can be presumed. Dysgammaglobulinemia complicated by disseminated measles has been described in the past.38,39 Of particular interest is the fact that female members of family 1 had abnormal immunoglobulin levels. Female carriers of XLP have been reported to have abnormal antibody responses to EBV.40 In male patients with XLP, IgG1 and IgG3 serum levels are often low with elevated IgA and IgM classes.17 Therefore, in females with 1 of 2 altered SH2D1A alleles, a modest reduction in SH2D1A protein levels could result in mild laboratory alterations, such as the hyper-IgA reported in family 1. Decreased cellular levels of the SH2D1A protein could lead to immunoglobulin dysregulation through alterations in the T-B lymphocyte network. Patients with XLP who have reduced SH2D1A protein levels have been described. One patient had a critically reduced SH2D1A wild-type protein level because of a regulatory mutation in the 5' splicing acceptor site of the second exon.10 Family 1 is of further interest because all 3 major phenotypes
developed in C.L. in only few months, and he died before the age of 2 years. The other affected male relatives had hypogammaglobulinemia or
hypogammaglobulinemia and malignant lymphoma and lived until 15 years
and 38 years. This clinical variation in patients with the same SH2D1A
mutation indicates that other host or environmental factors are
important in determining disease expression. Environmental factors are
not limited to EBV infection because XLP phenotypes may develop in its
absence. Age may be a critical factor in determining disease
severity In conclusion, the work reported here indicates the presence of SH2D1A mutations in patients diagnosed with CVID. Therefore, together with btk, CD40-L, and AID genes, we suggest that SH2D1A must be included in the molecular diagnosis of CVID. Because of the high rate of new mutations occurring in other human X-linked immunodeficiencies, such as XLA,41 the SH2D1A gene should be studied in all male patients with CVID. Clinically polarized XLP presentations must be considered when patients with CVID are encountered. A similar conclusion could be drawn from data published elsewhere.42 This is particularly true when more than one male member of a family is affected. Besides allowing genetic counseling, a correct diagnosis of XLP will allow for the selection of more aggressive therapy (such as BMT) because the prognosis for XLP is much worse than for CVID syndrome in general.
Submitted February 16, 2001; accepted April 20, 2001.
Supported by National Institutes of Health grant PO1-AI-35714 (C.T.); National Foundation March of Dimes grant 1FY00-382 (C.T.); and a grant from the National Center for Research Resources, General Clinical Research Centers Program, NIH (MO1-RR-30, R.H.B.), and grants AI42951 and AI47605 (R.H.B.). M.M. is supported by an American-Italian Cancer Foundation Fellowship.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Cox Terhorst and Massimo Morra, Division of Immunology, RE-204, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, Boston, MA 02215; e-mail: cterhors{at}caregroup.harvard.edu; mmorra{at}caregroup.harvard.edu.
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| Copyright © 2001 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
Top
Abstract
Introduction
). Primer combinations were: exon 1 F5'-GCC CTA CGT AGT GGG TCC ACA TAC CAA CAG-3'; exon 1 R5'-GCA GGA GGC
CCA GGG AAT GAA ATC CCC AGC-3'; exon 2 F5'-GGA AAC TGT GGT TGG GCA GAT
ACA ATA TGG-3'; exon 2 R5'-GGC TAA ACA GGA CTG GGA CCA AAA TTC TC-3';
exon 3 F5'-GCT CCT CTT GCA GGG AAA TTC AGC CAA CC-3'; exon 3 R5'-GCT
ACC TCT CAT TTG ACT TGC TGG CTA CAT C-3'; exon 4 F5'-GAC AGG GAC CTA
GGC TCA GGC ATA AAC TGA C-3'; exon 4 R5'-ATG TAC AAA AGT CCA TTT CAG
CTT TGA C-3'. Genomic DNA from the Raji human cell line (American Type
Culture Collection, Manassas, VA) was used as a positive control, and
distilled water was used as a negative control. PCR products were
visualized on a 1.5% agarose gel and subjected to direct sequencing
procedure or to subcloning followed by sequencing (samples from
female donors).
bacteria (Invitrogen), and selection was performed through
blue-white screening on Luria Bertani (LB) plates containing ampicillin
(50 mg/mL) and X-Gal (40 µL of a 100mg/mL solution on each plate;
Sigma, St Louis, MO). White colonies were grown overnight in LB-Amp
liquid media. Plasmid was isolated using a Miniprep kit (Qiagen,
Valencia, CA). For each exon, at least 10 colonies were subjected to
sequencing. Sequencing data were analyzed using the programs EditSeq
and MegAlign (Dnastar Software, Madison, WI).
-glutamyltransferase liver enzyme levels were elevated. Abdominal
ultrasonography results were normal, and findings were negative for
hepatitis A, B, and C, cytomegalovirus, and human immunodeficiency
virus. Two months later, the patient was admitted to the hospital
because of fever, pneumonia, a diffuse morbilliform rash, and an
enlarged liver. Absolute neutropenia and thrombocytopenia then
developed, and the patient was found to be EBV positive by PCR testing
of his blood and cerebrospinal fluid. He was treated with acyclovir,
granulocyte transfusions, and intravenous immunoglobulin
(IVIG), but he died 5 weeks after admission because of an
overwhelming Aspergillus infection secondary to aplastic
anemia. Autopsy showed disseminated aspergillosis (involving lungs,
kidney, esophagus, large and small intestines, pericardium, and
diaphragm); acute and organizing bronchopneumonia; hypocellular bone
marrow; lymphodepletion of thoracic and abdominal lymph nodes (necrosis
with rare B cells and moderate number of T cells) positive for the EBV
antigens LMP and EBNA-2); severe thymic atrophy with no evidence of
thymopoiesis; acute and organizing splenic infarcts; centrilobular
liver congestion, cholestasis, and peritoneal serous effusion; and
large B-cell lymphoma involving peripancreatic lymph nodes only (LMP
and EBNA-2 positive).
T, in
position 462 of the SH2D1A gene. This substitution alters
the triplet CGA, which codes for amino acid R55, into the stop codon
TGA. Because of the premature stop signal, only a 54-amino acids
hypothetical SH2D1A protein (R55X) could be generated (Figure 
55, which is found in all healthy persons.
Because of a shift in the reading frame, this deletion leads to a
premature stop codon (at a position corresponding to residue 100). This
premature stop codon generates a short, altered SH2D1A protein of 99 amino acids (Y100X) (Figure 
hypogammaglobulinemia developed in C.L. at 17 months of age,
and he succumbed of FIM and aplastic anemia at 20 months of age.