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*
The Edward Jenner Institute for Vaccine Research, Compton, United Kingdom;
Imperial Cancer Research Fund Cancer and Immunogenetics Laboratory, Wellcome Trust Center for Human Genetics, University of Oxford, Oxford, United Kingdom; and
Medical Research Council Laboratories, Fajara, The Gambia
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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-chain (c) of cytokine receptors,
including those for IL-2, IL-4, IL-7, IL-9, and IL-15, are responsible
for an X-linked form of the disease, while mutations of several other
genes, including Janus-associated kinase-3, may cause autosomal
recessive forms of SCID. We investigated the first SCID patient to be
described with minimal cell surface expression of the leukocyte common
(CD45) Ag. CD45 is an abundant transmembrane tyrosine phosphatase,
expressed on all leukocytes, and is required for efficient lymphocyte
signaling. CD45-deficient mice are severely immunodeficient and have
very few peripheral T lymphocytes. We report here that a homozygous
6-bp deletion in the gene encoding CD45 (PTPRC, gene map locus
1q31–32), which results in a loss of glutamic acid 339 and tyrosine
340 in the first fibronectin type III module of the extracellular
domain of CD45, is associated with failure of surface expression of
CD45 and SCID. Molecular modeling suggests that tyrosine 340 is crucial
for the structural integrity of CD45 protein. This is the second
description of a clinically relevant CD45 mutation, provides direct
evidence for the importance of CD45 in immune function in humans, and
suggests that abnormalities in CD45 expression are a possible cause of
SCID in humans. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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CD45 Ag can potentially exist in at least eight different isoforms generated by alternative splicing in the N-terminal extracellular domain of the molecule (15, 16). The expression of different CD45 isoforms depends on the state of activation and differentiation of hemopoietic cells, and in humans has been used to distinguish naive and memory T lymphocytes (17, 18, 19, 20, 21). Variations in CD45 isoform expression exist as normal variants (22), but can also be associated with some human disorders of immune activation (23, 24, 25). However, the mechanisms linking the expression of different CD45 isoforms to T cell function and the regulation of CD45 activity remain unclear.
Cale et al. (26) described an SCID patient from consanguineous parents with minimal cell surface expression of CD45. Recently, a second SCID patient lacking surface CD45 expression has been investigated, and the genetic lesions in the CD45 gene identified (27). Here we show that the patient described by Cale et al. (26) has a homozygous 6-bp deletion in the CD45 gene, which results in a loss of glutamic acid 339 and tyrosine 340 in the first fibronectin type III module of the extracellular domain of CD45 and is responsible for the lack of cell surface expression of CD45. These findings confirm that CD45 is essential for lymphocyte development and signaling and that abnormalities in CD45 expression can be a cause of SCID in humans.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Fresh blood and frozen PBMC were obtained from the G. family from the Department of Immunology and Infectious Diseases, Great Ormond Street Hospital National Health Service Trust (London, U.K.) (26). EBV-transformed lymphoblastoid lines were derived from the parents. Fresh material from the SCID patient was very limited, and it proved impossible to derive an EBV line. Genomic DNA samples from European populations were provided by W. F. Bodmer (Institute of Molecular Medicine, University of Oxford, Oxford, U.K.). African pygmy samples were provided by L. L. Cavalli-Sforza (Department of Genetics, Stanford University School of Medicine, Stanford, CA). Samples from the Caucasus, Iran, and Central Asia were obtained as part of the anthropological expedition EurAsia ’98 (see http://popgen.well.ox.ac.uk/eurasia for more details).
Immunofluorescence
Liquid nitrogen-stored PBMC from members of family G, Chinese hamster ovary (CHO),2 and EL-4 CD45 transfectants were surface stained with the following mAbs against human isoforms CD45R0-PE, CD45RB-FITC, and CD45RA-PE (Dako, Carpenteria, CA) or with pan-CD45-PE (PharMingen, San Diego, CA) or pan-CD45 hybridoma supernatant (2D1, Imperial Cancer Research Fund, London, U.K.) with second layer F(ab')2 sheep anti-mouse Ig-FITC (Sigma, St. Louis, MO). Isotype-matched mAbs were used as controls. Ten thousand events were collected on a FACScan flow cytometer (Becton Dickinson, Mountain View, CA) and analyzed using CellQuest software.
Amplification and sequencing of CD45 cDNA
Total RNA was extracted from frozen PBLs using Tri-Reagent
(Sigma). First-strand cDNA synthesis on 4 µg of total RNA was
performed using random hexadeoxynucleotide primers and the First-Strand
cDNA Synthesis Kit (Pharmacia Biotech, Uppsala, Sweden). The CD45 cDNA
was amplified using four pairs of primers, each pair amplifying 
1-
to 1.3-kb overlapping parts of the CD45 cDNA: pair 1, 5' untranslated
region forward (5'-CCTCGTCTGATAAGACAACAG-3') and ex10 reverse
(5'-CATATTACCACACTGAAATC-3'); pair 2, ex10 forward
(5'-CAGTTACATGATTGTACAC-3') and ex17 reverse
(5'-CAAGCTCCTGCTGTTCATC-3'); pair 3, ex16 forward
(5'-GGCACTGATAGCATTTCTGGC3') and ex28 reverse
(5'-TCATCAGAGGATTCATCTGA-3'); and pair 4, ex27 forward
(5'-GAGGACACAGCACATTGGAA-3') and 3' untranslated region reverse
(5'-GTCTCTCACACAAACACACACC-3'). The PCR conditions for amplification of
CD45 cDNA included 4-min incubation at 94°C followed by 30 reaction
cycles (1 min at 94°C, 1 min at 55°C, 4 min at 72°C) and final
16-min extension at 72°C. The purified PCR products were subjected to
direct automated sequencing using gene-specific primers.
PCR analysis for detection of the 1168–1173del
One hundred nanograms of genomic DNA was amplified by PCR using forward (5'-AATTAGAAAACCTTGAACCCG-3') and reverse (5'-ACTTGCGTTAGTAAACTTGTGG-3') primers. The primers were in exon 11, on either side of the 1168–1173del and amplified fragments of 77 bp (mutant) or 83 bp (wild type). PCR conditions were as described above. The PCR products were analyzed on a 6% nondenaturing polyacrylamide gel or VisiGel Separation Matrix (Stratagene, La Jolla, CA). For amplification refractory mutation system-PCR analysis (28) the following primers were used: forward primers, CD45FDEL (5'-CTTGAACCCGAACATAAGTG3') and CD45F (5'-CTTGAACCCGAACATGAGTA-3'); and reverse primer, CD45R (5'-AGCAATTTTACATATAAATGCAAG-3'). CD45-FDEL is specific for 1168–1173del, while CD45F is specific for the unmutated sequence. Typing reactions were performed in a volume of 10 µl with the following buffer conditions: 67 mM Tris-HCl, 16.6 mM ammonium sulfate, 0.1% Tween 20, 177 µM of each dNTP, 2.3 mM magnesium chloride, 0.4 U of AmpliTaq Gold polymerase (Perkin-Elmer, Norwalk, CT), 70 ng of template DNA, and 10 pmol of each primer. PCR was performed on a Hybaid MBS multiblock PCR machine (Middlesex, U.K.), with a touchdown protocol (an initial 10-min denaturation at 95°C, then 10 cycles of 25 s at 95°C, 25 s at 65°C dropping by 0.5°C/cycle, 30 s at 72°C, followed by 25 cycles of 25 s at 95°C, 25 s at 60°C, 30 s at 72°C, and a final 5-min extension at 72°C); products were resolved on a 1.6% agarose gel.
Generation of 1168–1173del CD45 mutant cell lines
The retroviral expression vector pZipNeoSV-LCA.6 containing the full-length cDNA for the human high m.w. CD45RABC isoform was provided by Dr. M. Streuli (Dana-Farber Cancer Institute, Boston, MA) (29). The 1168–1173del was introduced into the pZIPNeoSV-LCA6 construct according to the QuickChange Site-Directed Mutagenesis Kit (Stratagene) using forward (5'-GAAAACCTTGAACCCGAACATAAGTGTGACTCAGAAATACTC-3') and reverse (5'-GAGTATTTCTGAGTCACACTTATGTTCGGGTTCAAGGTTTTC-3') primers. Clones containing the 6-bp deletion were identified by PCR as described above and sequenced to confirm that the correct mutation had been introduced. Exponentially growing CHO cells or EL-4 mouse thymoma cells (1 x 107) were mixed with 20 µg of wild or mutated pZIPNeoSV(X)-LCA6 cDNA constructs in 0.8 ml of PBS, then subjected to electroporation (Bio-Rad Gene Pulser, Bio-Rad, Hercules, CA) at 950 µF and 250 V. After 48-h recovery in medium, cells were selected for neomycin resistance in medium containing G-418 (1 mg/ml). Surviving clones were analyzed by immunofluorescence using PE-conjugated pan-human CD45 mAbs and Western blotting.
Western blot analysis
CHO cell transfectants (4 x 106) were lysed in 500 µl of RIPA buffer for 30 min on ice. The supernatant was clarified by centrifugation at 10,000 x g for 10 min at 4°C. An equal amount of protein from each of the cell lysates was loaded and separated by 10% SDS-PAGE. The gel was transferred onto nitrocellulose membrane, and the membrane was blocked in PBS, 0.1% Tween 20, and 5% nonfat dry milk overnight at 4°C. CD45 protein was detected using mouse anti-human CD45 mAb (3 µg/ml; clone H130, PharMingen) followed by anti-mouse IgG-HRP conjugate (1:25,000; Pierce & Warriner, Cheshire, U.K.), followed by reaction with SuperSignal WestPico Chemiluminescent Substrate (Pierce & Warriner) for 5 min.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We obtained material from an infant with SCID who exhibited minimal expression of CD45 Ag (26). The patient was the first child of consanguineous Kurdish parents. She was presented aged 2 mo with a rash, pyrexia, hepatosplenomegaly, lymphoadenopathy, pneumonitis, and pancytopenia. CMV was detected in buffy coats, a liver biopsy specimen, nasopharyngeal aspirates, and urine. On the basis of immunologic investigations (see below) and clinical phenotype, a diagnosis of SCID with postnatally acquired CMV was made. She responded well to anti-CMV treatment and at 8 mo underwent bone marrow transplantation (BMT) from a matched unrelated donor. T cell engraftment was demonstrated 3 wk after BMT. Despite continuous anti-CMV treatment her CMV reactivated, and she died 55 days after BMT. Analysis of PBLs showed absolute lymphopenia, low T cell number (0.26 x 109/L), with markedly low CD4+ (0.07 x 109/L) and low CD8+ (0.36 x 109/L) and normal B cell numbers (1.2 x 109/L). Ig production was impaired, with low concentrations of IgM and IgA compared with age-matched normal controls. Because of the very limited availability of blood samples from the patient, further phenotypic and functional analysis was not possible.
The most striking feature was the markedly reduced expression of CD45
Ag on all leukocytes. Fig. 1
shows the
expression of different CD45 isoforms on PBMC from the parents and the
SCID patient. Minimal CD45 expression was detected with pan-CD45 and
CD45RB Abs, and no expression was detected with CD45RA and CD45R0 Abs
in the SCID patient, while both parents showed normal CD45 expression
patterns.
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To identify the molecular basis of the abnormal CD45 expression in
the patient we performed RT-PCR and sequenced the CD45 cDNA. We found
one silent and two conservative substitutions in the cytoplasmic domain
and a 6-bp deletion in exon 11 in the extracellular domain of the
coding sequence of CD45. The 6-bp deletion is at nucleotide position
1168 of the CD45 cDNA, 1168–1173del (accession no. NM 002838,
huCD45RABC isoform). This does not produce a frame shift, but causes a
deletion of two amino acids, glutamic acid 339 and tyrosine 340,
E339Y340 (Fig. 2a). The
1168–1173del was also confirmed in genomic DNA from the patient by
amplification and sequencing of exon 11.
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b). The latter also shows normal CD45 expression, as
determined by FACS analysis (data not shown). These results indicate
that it is unlikely that the T cells in the SCID patient are of
maternal origin, as there was no evidence in the PCR products for the
presence of the normal allele. Other members of the family were not
available for analysis. The 1168–1173del is responsible for the lack of surface CD45 expression
To confirm directly that the 1168–1173del mutation is responsible
for the observed abnormal CD45 surface expression in the patient, we
introduced the 1168–1173del into a normal full-length CD45 cDNA in a
retroviral expression vector and transfected CHO cells. FACS analysis
showed lack of surface CD45 expression on the CD45 mutant CHO
transfectant (Fig. 3a). By
contrast, CHO transfected with a wild-type human CD45 cDNA construct
expressed high levels of CD45 Ag, providing direct evidence that the
1168–1173del is responsible for abnormal CD45 expression in leukocytes
of the SCID patient. The same results were obtained when the EL-4 mouse
thymoma cell line was transfected with these constructs (data not
shown).
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b).
These results suggest that the 1168–1173del may affect the proper
folding, stability, and correct cellular localization of the mutant
CD45 protein. Tyrosine 340 is crucial for the structural integrity of CD45
The deleted glutamic acid 339 and tyrosine 340 are part of the
first of three fibronectin type III modules believed to form part of
the extracellular domain of CD45 (30, 31). Tyrosine 340 is
conserved in all CD45 sequences (human, rat, mouse, chicken, shark, and
puffer fish), and the equivalent tyrosine is also highly conserved in
known fibronectin sequences (Fig. 4a). Although the crystal
structure of the extracellular domain of CD45 has yet to be solved, a
molecular model of the first fibronectin module could be constructed
using COMPOSER (32) based on known fibronectin structures
(Fig. 4b). The model suggests that this tyrosine makes
important contributions to maintenance of the packed core of the
fibronectin structure (33). Deletion of this residue is
likely to seriously destabilize the fibronectin module, leading to
unfolding and intracellular degradation.
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To rule out the possibility that the 1168–1173del mutation in the SCID patient represented a common genetic polymorphism, we analyzed its frequency in the general population. Using amplification refractory mutation system-PCR analysis (28) the 1168–1173del was not detected in 518 unrelated healthy controls from varied ethnic backgrounds, including Europe, Africa, and East and Central Asia. This analysis included samples from 39 Kurds as well as 176 individuals from related ethnic groups (Iranians, Armenians, Azeris, and Turkmen); all were negative for 1168–1173del. Therefore, the deletion does not appear to be a common genetic polymorphism and has only been detected in the patient and members of her family.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In addition, our study provides direct evidence, through the transfection of murine and hamster cells with wild-type and mutant alleles, that the 6-bp deletion is responsible for the failure of CD45 surface expression on the patient’s cells. The exact mechanism responsible for the lack of CD45 cell surface expression is unknown. RT-PCR analysis of CD45 cDNA in the patient’s family revealed comparable amounts of wild-type and mutant CD45 transcripts in the patient, her parents, and the healthy sibling, suggesting that the 1168–1173del may not affect CD45 expression at the transcriptional level. Furthermore Western blot analysis of the cell transfectants showed that CD45 protein is produced, although not expressed, at the cell surface. While it is difficult to extrapolate to the patient from cell culture studies, this suggests that the 1168–1173del may affect the proper folding, stability, and correct cellular localization of the mutant CD45 protein. This is in accord with the molecular modeling, which shows that tyrosine 340 has a crucial role in maintaining structural integrity of the first fibronectin type III of the extracellular domain of CD45. Tyrosine 340 is highly conserved topohydrophobic residue (33) responsible for key nonpolar interactions in the packed, hydrophobic core of the fibronectin module. Deletion of this residue would result in dramatic alterations in the thermodynamic stability of this module. This may lead to an inability of the fibronectin module to fold into a stable tertiary conformation, leading, through the exposure of otherwise buried, proteolytic cleavage sites in the unfolded protein, to a concomitant degradation by intracellular proteases (34). Further studies will be required to determine the precise mechanism for the lack of surface CD45 expression in the patient. For example, pulse-chase experiments could be used to follow the intracellular fate of the mutant molecules.
We have also examined the frequency of the mutant allele in 518 DNA samples, including 215 from ethnic groups related to the Kurdish patient. No examples of the 6-bp deletion were detected, suggesting that 1168–1173del is not a common genetic polymorphism. Very recently, another SCID patient lacking CD45 expression has been reported (27). This patient, similar to the case described here, was also presented at 2 mo of age and had greatly reduced numbers of peripheral T cells. The latter were unresponsive to mitogen, and despite normal B cell numbers, serum Ig levels decreased with age. Two separate genetic abnormalities, a large deletion on one allele and a point mutation at the other, distinct from that reported here, were shown to be associated with lack of CD45 expression on the patient’s cells. The fact that now two SCID patients with different genetic lesions in CD45 have been identified suggests that although disease-associated CD45 polymorphisms may be rare, they should be considered in SCID patients without any other known cause.
In addition to the association of SCID with the lack of CD45 surface expression, abnormalities of CD45 splicing have been recognized in humans. We and other have demonstrated that a point mutation in the fourth (A) exon of CD45 prevents normal splicing of the N-terminal region of the gene, so that activated lymphocytes of these individuals express both high and low m.w. CD45 isoforms, in contrast to the normal pattern of low m.w. isoform expression (22). While these individuals are apparently normal, no homozygotes have yet been identified. In contrast, families with a similar defect in CD45 splicing associated with hemophagocytic lymphohistiocytosis or erythrocytic hemophagocytosis have been described (23, 24). Recently, linkage of abnormal CD45 splicing with a 32-bp deletion in CCR5 (CCR5del32), which confers resistance to infection with HIV isolates that use CCR5 as a coreceptor, has been reported (25). Although in all these cases no abnormality in the CD45 gene has yet been identified, this is made difficult by the large size of CD45, which has been estimated to be >120 kb (35).
This study provides evidence for the crucial role of CD45 in immune functions in humans, identifies abnormalities in CD45 expression as a possible cause for SCID, and suggests that CD45 screening should be included in the investigation of SCID patients and other patients with unexplained immunodeficiency.
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Acknowledgments |
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Footnotes |
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2 Abbreviations used in this paper: CHO, Chinese hamster ovary; BMT, bone marrow transplantation.
Received for publication October 3, 2000. Accepted for publication October 11, 2000.
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References |
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subunit of the T lymphocyte receptor. N. Engl. J. Med. 327:529.[Medline]
32 mutation with a functional polymorphism of CD45RA. J. Immunol. 165:148.This article has been cited by other articles:
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  S. Kirchberger, O. Majdic, S. Bluml, C. Schrauf, J. Leitner, C. Gerner, W. Paster, N. Gundacker, M. Sibilia, and J. Stockl The cytoplasmic tail of CD45 is released from activated phagocytes and can act as an inhibitory messenger for T cells Blood, August 15, 2008; 112(4): 1240 - 1248. [Abstract] [Full Text] [PDF]
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J. L. Roberts, J. P. H. Lauritsen, M. Cooney, R. E. Parrott, E. O. Sajaroff, C. M. Win, M. D. Keller, J. H. Carpenter, J. Carabana, M. S. Krangel, et al. T-B+NK+ severe combined immunodeficiency caused by complete deficiency of the CD3{zeta} subunit of the T-cell antigen receptor complex Blood, April 15, 2007; 109(8): 3198 - 3206. [Abstract] [Full Text] [PDF]
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 Z. Liu, R. Dawes, S. Petrova, P. C. Beverley, and E. Z Tchilian CD45 regulates apoptosis in peripheral T lymphocytes Int. Immunol., June 1, 2006; 18(6): 959 - 966. [Abstract] [Full Text] [PDF]
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 F. Rieux-Laucat, C. Hivroz, A. Lim, V. Mateo, I. Pellier, F. Selz, A. Fischer, and F. Le Deist Inherited and somatic CD3zeta mutations in a patient with T-cell deficiency. N. Engl. J. Med., May 4, 2006; 354(18): 1913 - 1921. [Abstract] [Full Text] [PDF]
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E. Z. Tchilian, R. Dawes, L. Hyland, M. Montoya, A. Le Bon, P. Borrow, S. Hou, D. Tough, and P. C. L. Beverley Altered CD45 isoform expression affects lymphocyte function in CD45 Tg mice Int. Immunol., September 1, 2004; 16(9): 1323 - 1332. [Abstract] [Full Text] [PDF]
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trace of the modeled
fibronectin type III module.