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Clinical and Diagnostic Laboratory Immunology, September 2001, p. 984-992, Vol. 8, No. 5
Department of Anatomy and Cell Biology, Fels
Institute for Cancer Research and Molecular
Biology,1 and Department of Microbiology
and Immunology,2 Temple University School of
Medicine, Philadelphia, Pennsylvania 19140; and Department of
Pediatrics, MCP Hahnemann University,3 and
Section of Neurology,4
Department of Pathology and Laboratory
Medicine,5 St. Christopher's Hospital for
Children, Philadelphia, Pennsylvania 19134
Received 20 November 2000/Returned for modification 26 February
2001/Accepted 22 June 2001
We have investigated the clonality of Multiple sclerosis (MS) is an
inflammatory, demyelinating disease of the central nervous system (CNS)
(2, 32, 66-68). The etiology and pathogenesis of the
disease and its relationship to other less common demyelinating
disorders, such as acute disseminated encephalomyelitis (ADEM), remain
poorly understood (4, 59, 76). The natural history of MS
and its geographic distribution suggest that it may be due to a virus
contracted during childhood by susceptible individuals. There is a
general agreement that MS is an autoimmune disease of the CNS mediated
by T cells (21, 45, 73, 74, 80, 82). How the virus may
trigger the autoimmune response to neuroantigen(s) or other
self-antigen(s) is not fully understood. Analysis of T-cell responses
in patients with long-standing MS revealed that these T cells
recognized certain host myelin proteins, such as myelin basic protein
(MBP), proteolipid protein (PLP), and myelin-associated glycoprotein
(MAG) (17, 27, 39, 50, 52, 53, 72, 77). These T cells may
have been generated long after the onset of the disease. However, the
specificity, either viral or host, of the T cells that trigger the
disease and are present at the onset of the disease needs to be
elucidated. Analysis of T cells at the earliest possible time likely
holds the key to our understanding the immunopathogenesis of MS. In this context, the relationship (if any) between MS and ADEM (also known
as perivenous encephalomyelitis) becomes important in terms of
the immunopathogenesis of MS. There are considerable similarities between ADEM and experimental allergic encephalomyelitis (EAE), which
is traditionally considered to be a relevant animal model for MS
(4, 59, 76).
With the objective of identifying antigen-driven clonally expanded
populations of T cells, we amplified, cloned, and sequenced The clinical symptoms and signs, and the CSF and MRI findings observed
in this patient indicate the presence of multiple, metachronous,
predominantly white matter demyelinating lesions widely spread
through neuraxis. These findings resemble either the multiphasic
variant of ADEM or a transitional form of demyelinating disease
bearing features of ADEM and MS (32, 59, 62, 76). Extrahepatic manifestations of the infection with hepatitis A virus are
rare. However, a number of reports have previously suggested an
association of hepatitis A virus infection with neurological symptoms
(i.e., encephalitis, transverse myelitis, cervical myelopathy, or optic
neuritis) (6, 10, 15; P. J. Hughes, I. K. Saadeh, J. P. Cox, and L. S. Illis, Letter, Lancet 342:302,
1993). To our knowledge, this is the first case of infection with
hepatitis A virus that preceded the onset of demyelinating disease of
the CNS, in which a clonal expansion of T cells has been demonstrated.
(This work was presented at the 5th Symposium on the Neurovirology and
Neuroimmunology of Schizophrenia and Bipolar Disorders, Bethesda,
Md., 4 to 6 November 1999.)
The patient was a 7-year-old female who had two episodes of
diffuse and focal neurologic deficits separated by 5 months. The first
episode presented with fever, headache, tiredness, vomiting, jaundice,
pruritus, and mild, tender hepatomegaly. Five days later, she developed
lower extremity weakness and progressive lethargy. Her condition
deteriorated to coma and flaccid quadriplegia over 72 h. Liver
function tests revealed elevated aspartate aminotransferase (AST; 100 U/liter) alanine aminotransferase (ALT; 333 U/liter), and bilirubin
(total bilirubin, 3.2 mg/dl; direct bilirubin, 2.8 mg/dl).
Anti-hepatitis A virus total antibody and IgM antibody were found in
the serum. No clinical or laboratory evidence of hepatic coma was found
(normal blood ammonia level). Serum antibody titers for
Mycoplasma pneumoniae, Epstein-Barr virus, cytomegalovirus, and Borrelia burgdorferi were all negative. Human herpes
virus 6 (HHV-6) antibody titers were not measured. CSF studies
revealed a lymphocytic pleocytosis (197 lymphocytes), normal
glucose (65 mg/dl), elevated protein (62 mg/dl), and elevated IgA (2 mg/dl), IgG (28 mg/dl), and IgM (2.4 mg/dl) levels. CSF did not contain herpes simplex virus, as determined by PCR. Routine oligoclonal banding
studies were negative. CSF cultures were sterile. Hepatitis A virus RNA
was present in both serum and CSF as determined by reverse
transcription-PCR (RT-PCR) and sequencing. The diagnosis of hepatitis A
virus infection was also supported by epidemiological data. The patient
traveled to her hometown in Peru 3 weeks prior to the initiation of the
clinical symptoms. She had gone to the municipal swimming pool, and,
retrospectively, it was found that other people in town who used the
pool had developed symptoms compatible with the diagnosis of hepatitis
A virus infection. MRI studies were carried out and demonstrated
diffuse white matter changes in the brain, involving the cerebrum and
the brain stem, as well as in the spinal cord (Fig.
1). These white matter changes were
consistent with demyelinating disease. The patient received intravenous
(i.v.) methylprednisolone, plasmapheresis, and i.v. Ig therapy. Her
clinical status improved over 4 months to near baseline.
1071-412X/01/$04.00+0 DOI: 10.1128/CDLI.8.5.984-992.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Presence of Oligoclonal T Cells in Cerebrospinal Fluid of a Child
with Multiphasic Disseminated Encephalomyelitis following Hepatitis
A Virus Infection
ABSTRACT
Top
Abstract
Introduction
Case Report
Materials and Methods
Results
Discussion
References
-chain T-cell receptor
(TCR) transcripts from the cerebrospinal fluid (CSF) and peripheral blood from a 7-year old child who developed a multiphasic disseminated encephalomyelitis following an infection with hepatitis A virus. We
amplified -chain TCR transcripts by nonpalindromic adaptor (NPA)-PCR-V-specific PCR. TCR transcripts from only five V
families (V13, V3, V17, V8, and V20) were detected in
CSF. The amplified products were combined, cloned, and sequenced.
Sequence analysis revealed in the CSF substantial proportions of
identical -chain of TCR transcripts, demonstrating oligoclonal
populations of T cells. Seventeen of 35 (48%) transcripts were 100%
identical, demonstrating a major V13.3 D2.1 J1.3 clonal
expansion. Six of 35 (17%) transcripts were also 100% identical,
revealing a second V13 clonal expansion (V13.1 D2.1 J1.2).
Clonal expansions were also found within the V3 family (transcript
V3.1 D2.1 J1.5 accounted for 5 of 35 transcripts [14%]) and
within the V20 family (transcript V20.1 D1.1 J2.4 accounted
for 3 of 35 transcripts [8%]). These results demonstrate the
presence of T-cell oligoclonal expansions in the CSF of this patient
following infection with hepatitis A virus. Analysis of the CDR3 motifs revealed that two of the clonally expanded T-cell clones exhibited substantial homology to myelin basic protein-reactive T-cell clones. In
contrast, all V TCR families were expressed in peripheral blood
lymphocytes. Oligoclonal expansions of T cells were not detected in the
peripheral blood of this patient. It remains to be determined whether
these clonally expanded T cells are specific for hepatitis A viral
antigen(s) or host central nervous system antigen(s) and whether
molecular mimicry between hepatitis A viral protein and a host protein
is responsible for demyelinating disease in this patient.
INTRODUCTION
Top
Abstract
Introduction
Case Report
Materials and Methods
Results
Discussion
References
-chain
T-cell receptor (TCR) transcripts from the cerebrospinal fluid (CSF)
and the peripheral blood of a 7-year-old female who developed
multiphasic demyelinating disease shortly after infection with
hepatitis A virus. Sequence analysis revealed substantial proportions
of identical -chain TCR transcripts in the CSF, suggesting the
presence of oligoclonal T cells. The patient exhibited two episodes of
neurological symptoms 5 months apart. The first episode occurred 5 days
after hepatitis A virus infection, which was serologically confirmed,
and deteriorated to coma and quadriplegia. Hepatitis A virus
transcripts were present in the CSF and the peripheral blood of this
patient during the first neurological episode. Anti-hepatitis A virus
total antibody and immunoglobulin M (IgM) antibody were detected in the
serum of this patient during the first neurological episode.
Magnetic resonance imaging (MRI) studies demonstrated diffuse white
matter changes consistent with demyelinating disease. Five months after
the first episode, the patient developed a second neurological episode,
characterized by aphasia and optic neuritis.
CASE REPORT
Top
Abstract
Introduction
Case Report
Materials and Methods
Results
Discussion
References
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FIG. 1.
(A) First demyelinating episode. T1-weighted MRI of
axial section 5 days after the onset of neurological symptoms.
Multiple, multifocal, hyperintense lesions of various sizes are
disseminated throughout the cerebral white matter. There is a
distributional predilection of these lesions for the subcortical
(convolutional) white matter at the corticomedullary junction (arrows).
A smaller hyperintense focal area is also present in the left
periventricular white matter. (B) First demyelinating episode.
T2-weighted MRI of a parasagittal section of the spinal cord. Diffuse
spinal cord swelling associated with confluent, ill-defined,
high-signal intra-axial lesions. (C and D) Second demyelinating
episode. T2-weighted MRI of axial sections 3 days after the onset of
neurological symptoms. Diffuse heterogeneous areas of abnormal signal
are seen in the frontal and temporal lobes bilaterally. Contiguous
high-signal lesions are particularly predominant in the left opercular,
insular, and superior temporal white matter and the mesial frontal
convolutional white matter bilaterally (C). In addition, heterogeneous
high-signal abnormalities are detected in the thalamic region
bilaterally (from right to left) (D).
Five months after initial presentation, the patient exhibited a second neurological episode, characterized by acute onset aphasia and bilateral visual loss secondary to retrobulbar optic neuritis. Levels of AST, ALT, and bilirubin in blood were normal. CSF studies demonstrated a normal cell count (5 lymphocytes) and glucose level (69 mg/dl), with mildly elevated protein (44 mg/dl). The MRI revealed diffuse heterogeneous areas of abnormal signal on T2-weighted images in the frontal and temporal lobes bilaterally that were also enhanced with gadolinium, again consistent with demyelinating disease. The patient received i.v. methylprednisolone for 3 days followed by oral prednisone with subsequent clinical improvement and resolution of the MRI abnormalities.
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MATERIALS AND METHODS |
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Top
Abstract
Introduction
Case Report
Materials and Methods
Results
Discussion
References
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Amplification of hepatitis A virus RNA. The VP3-VP1 junction (positions 2132 to 2451) of the hepatitis A virus genome was amplified from serum and spinal fluid specimens by RT-PCR, as previously described (34). The sensitivity, specificity, and validation of the RT-PCR hepatitis A virus VP3-VP1 junction test is described elsewhere (9).
Nucleic acid sequencing of amplified hepatitis A virus. PCR products of amplified hepatitis A virus were purified with a Qiaquick PCR purification kit (Qiagen, Inc., Valencia, Calif.). Sequencing reactions were performed with a prism dye terminator cycle sequencing kit (Applied Biosystems, Foster City, Calif.) and an automated sequencer (ABI model 373 or 377; Applied Biosystems) following the instructions of the manufacturer. Preliminary sequence analysis was performed with ABI software, and further analysis was performed with GCG (Genetics Computer Group, Madison, Wis.) software (18).CSF and PBMCs. Cells in the CSF of this patient were collected by centrifugation at 400 × g for 15 min at 4°C and immediately used for RNA isolation.
Peripheral blood mononuclear cells (PBMCs) from this patient or normal donors were isolated from heparinized peripheral blood by centrifugation on a Ficoll-Hypaque density cushion, following established methods. PBMCs were collected from the interface and were washed twice before preparation of RNA. These studies have been approved by the Institutional Review Board of Temple University Hospital.Preparation of RNA from mononuclear cells. Total RNA was prepared either from mononuclear cells isolated from CSF or from PBMCs by the guanidinium thiocyanate phenol-chloroform single-step extraction method, following the procedure recommended by the manufacturer (Stratagene, La Jolla, Calif.) as described previously (58). Phenol extraction was performed at least twice on all specimens. To check the purity of the isolated RNA, the rRNA 28S and 18S bands were visualized after agarose gel electrophoresis.
Synthesis of cDNA.
Total RNA isolated from PBMCs (5 µg) or
from the CSF was used for double-stranded cDNA synthesis, as previously
described (12, 13, 43, 61). The first strand was
synthesized (in a 20-µl reaction volume) by using Superscript RTase
(Gibco-BRL) and either a NotI-oligo(dT)15 primer
or a NotI-human constant region -chain
(NotI-hC) primer (Table 1)
and incubated at 42°C for 1 h. The second-strand cDNA was
synthesized in a reaction volume of 160 µl by adding directly to the
first-strand reaction mixture 5 U of Escherichia coli DNA
ligase, 40 U of E. coli DNA polymerase, 1.5 U of RNAse H,
0.19 mM deoxynucleoside triphosphates (dNTP), and 3.8 µM
dithiothreitol in second strand buffer and incubating for 2 h at
16°C. Ten units of T4 polymerase was added, and the mixture was
incubated for 45 min at 16°C. The double-stranded cDNA was extracted
with equal volume of phenol-chloroform (1:1) precipitated with 0.5 volume of NH4OAc (4 M) and 2.5 volumes of 100% ethanol,
was washed once with 70% ethanol and resuspended in 10 µl of sterile
water.
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Adaptor ligation and NotI digestion. A nonpalindromic double-stranded adaptor (Table 1) comprised of the 5'-AATTCGAACCCCTTCGAGAATGCT-3' nucleotide and its complementary 5' end nucleotide 5'-pCGCATTCTCGAAGGGGTTCG-3' were ligated onto the 5' and 3' blunt ends of the cDNA with 1.4 U of T4 DNA ligase (Gibco-BRL) and incubated overnight at 14°C. This adaptor is a modification of the one that we have described previously (12, 13, 43, 61). The adaptor was removed from the 3' end of the cDNA by digestion for 3 h with 7.5 U of NotI restriction nuclease (GIBCO-BRL) in a 50-µl reaction volume. The NotI nuclease-digested cDNA was purified with a G-50 spin column, by centrifugation for 5 min at 1,100 × g, according to the procedure recommended by the manufacturer (5 Prime to 3 Prime, Boulder, Colo.).
Amplification by NPA-PCR-V-specific PCR. (i) First cycle of
amplification by NPA-PCR.
Nonpalindromic adaptor-PCR (NPA-PCR) was
carried out essentially as described previously (12, 13, 43,
61) with minor modifications. NotI-digested cDNA (1/5
to 1/10 volume), purified by centrifugation with G-50 spin columns, was
denatured by heating at 94°C for 3 min (in a reaction volume of 100 µl) and amplified by 35 cycles of PCR with Taq polymerase
(Promega, Madison, Wis.) at 94°C for 1 min, 45°C for 1 min, and a
final extension at 72°C for 10 min. The NPA
5'-AATTCGAACCCCTTCGAGAATGCT-3' was used as the 5'
amplification primer. A human C oligonucleotide, designated hC3
(5'-CAGGCAGTATCTGGAGTCATTGA-3') (Table 1), was used as
the 3' amplification primer, and it is located 5' to the hC primer used for cDNA synthesis (nested design). The hC3 primer was located in the C region starting at nucleotide 208. The amplified
transcripts were purified with a G-50 spin column.
(ii) Second cycle of amplification by individual V-specific
PCR.
A second cycle of amplification was carried out using as a
template -chain TCR cDNA (5 to 10 µl) amplified by NPA-PCR, as described in the previous paragraph. Oligonucleotides from each of 24 V families (V1 to V24) (22) were used as a 5' end
amplification primer in 24 separate amplification reactions (Table 1).
A human C primer designated hc2
(5'-ACCAGCACTCAGCTCCACGTGGTC-3') was used as a 3'
amplification primer, and it was located 5' of the hc3 primer used
for the first amplification (nested design). This oligonucleotide was
located in the C region starting at nucleotide 113. The reaction
mixture (50 µl) was denatured by heating at 94°C for 3 min and
amplified by 35 cycles of PCR with Taq polymerase (Promega),
at 94°C for 1 min, 55°C for 1 min, 72°C for 1 min, and a final
extension at 72°C for 10 min.
Cloning of TCR transcripts.
Ten microliters from each of the
products of each V-specific PCR amplification was run on 1% agarose
gel. The DNA bands corresponding to similar molecular weights were
excised, purified by Geneclean kit (Bio 101, Vista, Calif.) as
recommended by the manufacturer, and mixed, and 2 µl of the mixture
was ligated with 50 ng of vector pCR2.1 (Invitrogen, San Diego, Calif.)
with 2 U of T4 ligase (Gibco-BRL) in a total volume of 10 µl.
DH5
competent cells (Gibco-BRL) were transformed, and white
colonies were picked up.
Sequencing of TCR transcripts. Plasmids were isolated with the Perfect Prep kit according to the procedure provided by the manufacturer (5 Prime to 3 Prime). Sequencing was carried out by the dideoxy chain termination method with Sequenase 2.0 (U.S. Biochemicals, Cleveland, Ohio).
The maximum theoretical number of potentially unique-chain TCR
transcripts has been estimated (7) to be approximately 1012. Theoretically, the probability of randomly finding
two identical copies of a single -chain TCR transcript within a
given independent sample population is negligible. During
transformation of DH5 competent cells, the plasmid-cell mix was
subjected to heat shock (at 42°C for 45 s) followed by
incubation on ice for 2 min and growth for 1 h in SOC
medium (29) at 37°C before plating. Under ideal
conditions (log phase), E. coli has a doubling time of 20 min, which would result in two doublings after 60 min
(29). After heat shock, though, the cells do not
immediately enter log phase. However, the unlikely possibility that a
few of the transformed cells may double before plating does exist.
Therefore, identical TCR sequences from two different colonies (a
doublet) may indicate a clonal expansion or could be the result of a
singly transfected E. coli cell that doubled before plating.
Therefore, two identical copies of a single -chain TCR transcript
may or may not represent a clonal expansion. The odds of a triplet
(three identical transcripts) being due to this heat shock artifact are negligible.
The NPA-PCR-V-specific PCR-mixed ligation-mixed
transformation-mixed cloning method that we employed here has been
designed to determine whether there are clonal expansions of T cells in the CSF rather than to quantitate with accuracy these clonal
expansions. Equal volumes of each of the V-specific PCR
amplification products are mixed after purification, and before
ligation, transformation, and cloning. Comparison of this method to the
NPA-PCR-V-specific PCR-separate ligation-separate
transformation-separate cloning method (which is considerably more
laborious) resulted in the identification of the same clonal
expansions, which were found to be present in similar proportions (data
not shown). However, two important assumptions affect the ability of
PCR amplification methods to permit quantitation: (i) all amplification
reactions must be in the linear phase, and (ii) the efficiencies of the amplification reactions must be equal for all primers. Therefore, the
method employed here can provide a general approximation of the
relative frequency of the clonally expanded TCR transcripts, and in
that sense is rather a semiquantitative than a quantitative method.
Computer analysis of DNA sequences. The nucleic acid and the deduced amino acid sequence obtained were compared to those in the GenBank/EMBL/SWISS PROT databases by using FASTA, BLAST, and PSI-BLAST software (3). There is no information on the maximum number of CDR3 amino acid differences that permit substantial CDR3 homology. Differences of two conservative amino acids and one nonconservative amino acid were chosen arbitrarily in this study as the maximum number of differences allowed between CDR3 motifs from different T-cell clones in order to define substantial CDR3 homology.
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RESULTS |
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Top
Abstract
Introduction
Case Report
Materials and Methods
Results
Discussion
References
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Hepatitis A virus transcripts were detected by RT-PCR in both serum and CSF of this patient during the first neurological episode. The PCR product obtained from the serum and the CSF were sequenced to confirm the specificity of the amplified product. Sequences obtained from the serum and the CSF were identical and belong to genotype 1a. Anti-hepatitis A virus total antibody and IgM antibody were found in the serum of this patient during the first neurological episode.
To investigate the clonality of -chain TCR transcripts from the CSF
of this patient, we amplified -chain TCR transcripts from CSF
lymphocytes by the NPA-PCR-V-specific PCR method described in
Materials and Methods. CSF was obtained during the second neurological episode of this patient. -Chain TCR transcripts from only 5 (V13, V3, V17, V8, and V20) out of 24 V families were detected in the CSF. The amplified products were combined, cloned, and sequenced
as described in Materials and Methods. Sequence analysis revealed
substantial proportions of identical -chain TCR transcripts in the
CSF of this patient (Table 2),
demonstrating the presence of oligoclonal populations of T cells.
Seventeen of 35 transcripts (48%) were 100% identical, demonstrating
a major V13.3 D2.1 J1.3 clonal expansion (clone 1; CDR3
[CASSLEVYSGNT]). Six of 35 transcripts
(17%) were also 100% identical, revealing a second V13 clonal
expansion (clone 2; V13.1 D2.1 J1.2; CDR3: CASSYRGDGYT). Furthermore, clonal expansions were found within the V3 family (clone 3; V3.1 D2.1 J1.5; 5 out of 35 [14%] transcripts
were identical; CDR3: LCASSSVGQPQH) and within the V20
family (clone 7; V20.1 D1.1 J2.4; 3 out of 35 [8%]
transcripts were identical; CDR3: YLCAWGRSGTANIQY).
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In contrast to these findings with CSF lymphocytes, similar analysis
revealed that all V TCR families were expressed in PBMCs from this
patient. Sequence analysis after PCR amplification and cloning revealed
that PBMC -chain transcripts from this patient were unique when
compared to each other (with the exception of clones V5.1 D2.1
J2.7 and V13.7 D1.1 J1.1, which appear twice in the
peripheral blood but not in the CSF), suggesting polyclonal populations
of T cells (Table 3). As
discussed in Materials and Methods, the appearance of a transcript only
in duplicate may not necessarily indicate the presence of a clonal expansion. This duplicate transcript may appear because of E. coli division during 1 h of the cloning process (described
above). Similarly, sequence analysis of -chain TCR transcripts from
the CSF of a healthy subject without any neurological diseases revealed unique TCR transcripts when compared to each other, typical of polyclonal populations of T cells (data not shown).
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Comparison of the nucleic acid and deduced amino acid sequences
of these -chain TCR transcripts to those in the
GenBank/EMBL/SWISS PROT databases revealed that these sequences were
typical of -chain TCR, have not been previously identified and
therefore are novel.
Analysis of the CDR3 motifs of the clonally expanded sequences
(Table 2) by using the gapped BLAST and PSI BLAST protein database search programs (3) revealed that clone 1 (V13.3 D2.1 J1.3; CDR3: CASSLEVYSGNT)
exhibited substantial CDR3 homology to a T-cell clone derived
from connective tissue disease, reactive with small nuclear
ribonucleoprotein (snRNP), AAB42075; CDR3: CASSLRRFSGNT). The two
T-cell clones were different in the CDR3 only by two conservative
amino acids and one nonconservative amino acid. These differences have
been chosen arbitrarily in this study as the maximum number of
differences allowed between CDR3 motifs from different T-cell clones in
order to have substantial CDR3 homology.
Clones 2 and 3 (Table 2) exhibited substantial CDR3 homology to myelin
basic protein (MBP)-reactive T-cell clones. Clone 2 (V13.1 D2.1
J1.2; CD3: CASSYRGDGYT) was homologous to clone AAD15105
(CDR3: SSYQGMGYTL) (79). Clone 3 (V3.1
D2.1 J1.5; CDR3: CASSSVGQPQH) was homologous to clone
AAB31432 (CDR3: CASSIPGQPGHFG) (83). Clone 3 (V3.1 D2.1 J1.5; CDR3: CASSSVGQPQH) also exhibited substantial CDR3 homology to clone AAD15172 (CDR3: CASSSTGGQPQH) of unknown specificity, identified in human thymocytes
(37).
Clone 5 (V17.1 D2.1 J1.2; CDR3: CASSITYL) exhibited
CDR3 homology to human TCR clone AAB03951 (CDR3: CASSITVV)
of unknown specificity, identified in the brain of a patient with
chronic encephalitis of Rasmussen (42). Clone 6 (V8.1
D2.1 J1.2; CDR3: CASSSANY) exhibited substantial CDR3
homology to three different human TCR clones of unknown
specificity: (i) AAD29450 (CDR3: CASEESANY), (ii)
SO3496 (CDR3: CASSQATDY) (38), and (iii)
AAF24066 (CDR3: CASSPTVNY). Clone 7 (V20.1 D1.1
J2.4; CDR3: LCAWGRSGTANIQY) exhibited substantial
CDR3 homology to two different human TCR clones of unknown
specificity: (i) AAC97292 (CDR3: LCAWGTSGTS) and
AAC97254 (CDR3: LCAWSGTS).
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DISCUSSION |
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Top
Abstract
Introduction
Case Report
Materials and Methods
Results
Discussion
References
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We have demonstrated the presence of oligoclonal expansions
of T cells in the CSF of a patient with demyelinating MS-like disease,
consistent with multiphasic disseminated encephalomyelitis, which
followed an initial hepatitis A virus infection. Out of 24 V
families of TCR examined, only 5 V families were detected in the CSF
of this patient after relapse. A major clonal expansion has been
detected within the V13 family where 17 of 35 (48%) of V13 TCR
transcripts were identical (V13.3 D2.1 J1.3). Another V13
TCR clonal expansion has also been detected (V13.1 D2.1 J1.2;
6 of 35 [17%] identical transcripts). Clonal expansions were also
found within the V3 and V20 families. In contrast, all V TCR
families were expressed in PBMCs from this patient and were polyclonal.
Clonal expansions of T cells have been identified in the CSF of certain
patients with chronic progressive MS (27, 39, 44, 81). In
contrast, patients with encephalitis of Rasmussen (42), a
patient with subacute sclerosing panencephalitis, a patient with herpes
zoster meningoencephalitis, and a patient with atypical MS, which was
fatal within 8 months, did not exhibit oligoclonal T cells in the CSF
(27).
Analysis of the CDR3 motifs obtained in this study revealed that two of
the clonally expanded T-cell clones (clones 2 and 3) (Table 2)
exhibited substantial homology to MBP-reactive T-cell clones. These
findings are in contrast with those obtained with TCR transcripts from
brain plaques from a patient with acute MS, which did not exhibit any
homology to CDR3 motifs specific for MBP (E. L. Oleszak, J. Pappas, C. A. Slachta, W. L. Lin, L. I. Sakkas, and
C. D. Platsoucas, unpublished data). These results suggest that
perhaps different T-cell responses may be involved in brain plaques and
in CSF of patients with acute MS. Studies with additional patients are
needed to examine this possibility. Little information is available in
the literature on the homology of clonally expanded T-cell clones in
the CSF and of MBP-specific T-cell clones (1, 39, 44, 81).
Allegretta et al. (1) reported CDR3 homology and common
V usage between clonally expanded T cells from the brain and CSF of
patients with MS and T cells mediating EAE.
Hepatitis A virus transcripts were identified by RT-PCR and sequencing of the VP3-VP1 junction (position 2132 to 2451) of the hepatitis A virus genome in the serum and the CSF of this patient during the first neurological episode. Anti-hepatitis A virus IgM antibody and total antibody were found in the serum of this patient during the first neurological episode. There is epidemiologic evidence supporting the diagnosis of hepatitis A virus infection. Hepatitis A virus is a common cause of food-borne disease (hepatitis) and does not manifest often as neurological syndrome (26, 41, 48). However, hepatitis A virus is a picornavirus, and these viruses are known to infect the CNS (49).
The clinical symptoms and signs, including the presence of quadriparesis, combined with the serum and CSF biochemical findings, the MRI changes, and the absence of fulminant hepatic failure, firmly rule out hepatic encephalopathy in the setting of hepatitis A virus infection. Importantly, the structural and anatomical changes seen by MRI were distinctly multifocal, albeit confluent, and were accompanied by perilesional as opposed to diffuse cytotoxic edema and/or secondary sequelae (hemorrhages and/or hypoxia), typifying hepatic encephalopathy.
Extrahepatic manifestations of hepatitis A virus infections are rare. However, meningoencephalitis, transverse myelitis, Guillain-Barré syndrome, and optic neuritis have been all described as complications of hepatitis A virus infections, quite often without clinically obvious liver diseases (6-8, 10, 11, 15, 16, 28, 33, 46, 51, 78; Hughes et al., Letter, 1993; J. L. Parajna, M. Riera, and M. J. Garcia, Letter, Med. Clin. 97:279, 1991). Hepatitis A infection has been also associated with exacerbation of MS symptoms in patients with quiescent MS (60).
There are a number of reports describing MS in children. However, the incidence of MS in children before the age of 10 is low and has been estimated as 1.5 to 7 per 1,000 (20, 47, 64). Poser examined 812 patients with MS, and only one of them had an onset before age 10 (65). Furthermore, childhood MS may present different neuropathological picture from adult MS (14, 19, 23, 25, 30, 64, 70). Poser (63) has reported large, tumor-like, inflammatory demyelinating lesions in the area of the centrum semiovale in children with MS. Similar large, tumor-like brain lesions have been described by Kepes in his study of 31 patients, including children (36). Although large, focal tumor-like lesions are rather characteristic of ADEM, such lesions have been seen also in adult patients with MS (24, 48, 84). There are instances in which the clinical, imaging, and pathological distinction between ADEM and MS in children is difficult if not impossible to ascertain (32, 36, 59, 62, 76). Absent a pathological evaluation, the case at hand is best characterized as a recurrent disseminated encephalomyelitis (involving the cerebrum, brain stem, and spinal cord) with MRI futures compatible with demyelinating-type lesions. Some of these lesions were quite large, probably the result of confluent expansion bordering the cortical mantle. The lesions were distributed extensively throughout the hemispheric white matter but had a distinctive predilection for the subcortical convolutional white matter (corticomedullary junction). That said, deep periventricular white matter hyperintense signals on T1-weighted images and focal areas of thalamic enhancement on T2-weighted images were also present (Fig. 1). This distributional pattern by anatomical imaging, in the absence of oligoclonal bands, and the apparent recovery of the patient would favor the diagnosis of either a multiphasic variant of ADEM or a transitional form between ADEM and childhood MS (32). On the other hand, a number of investigators pointed out recently that discrimination between ADEM and MS is difficult, and ADEM may very well be a part of the MS spectrum (31, 35, 69).
The presence of substantial proportions of -chain TCR transcripts in
the CSF of this patient suggests the presence of oligoclonal T cells in
the CSF. These T cells have very likely expanded in the CSF in response
to particular antigens, viral (hepatitis A) or host. Alternatively, it
is possible that the clonaly expanded T cells identified
in this study have been generated in a process known as epitope
spreading (40, 71, 77), in response to CNS self-antigens,
which may have been released during the first neurological episode
because of viral and immunologic damage resulting in cell death. These
perhaps previously sequestered CNS self-antigens may be presented now
by antigen-presenting cells of the host. Because of the injury during
the first neurological episode, tolerance against these self-epitopes
may be broken and an immune response is generated. It is also possible
that the clonally expanded T cells in the CSF may recognize as viral
host determinants cross-reacting with the virus due to molecular
mimicry. Molecular mimicry is defined as the sharing of common
antigenic epitopes between microorganisms (bacteria, viruses, etc.) and
host proteins (21, 54-57, 75), and it is responsible for
the development of several autoimmune diseases. It has been reported
that a hepatitis B virus polymerase peptide, which shares six
consecutive amino acids with the encephalitogenic site of rabbit MBP,
is able to induce EAE (21). Although functional studies with hepatitis A virus peptides have not been reported, it is
important to note that VP3 structural protein of hepatitis A virus
shares with MBP seven common tripeptides (5). Therefore, molecular mimicry between hepatitis A virus antigens and host proteins
may be responsible for demyelinating disease.
In conclusion, it remains to be established whether the clonally expanded T cells in the CSF of a patient with hepatitis A virus infection recognize hepatitis A peptides or are specific for host antigen(s) of neuronal and/or glial origin. This case may allow us to determine how a ubiquitous virus can trigger demyelinating disease.
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ACKNOWLEDGMENTS |
|---|
We express our most sincere thanks to Harold S. Margolis and Omana Naiman, Hepatitis Branch, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, Ga., for evaluating our patient's serum and CSF for hepatitis A virus transcripts.
This work was supported in part by a grant from the National Multiple Sclerosis Society and grant T32 AI07101 from the National Institute of Allergy and Infectious Diseases.
| |
FOOTNOTES |
|---|
* Corresponding author. Mailing address: Department of Anatomy and Cell Biology, Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, 3307 North Broad St., Philadelphia, PA 19140. Phone: (215) 707-7657. Fax: (215) 829-1320. E-mail: eoleszak{at}astro.temple.edu.
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REFERENCES |
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Top
Abstract
Introduction
Case Report
Materials and Methods
Results
Discussion
References
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Clinical and Diagnostic Laboratory Immunology, September 2001, p. 984-992, Vol. 8, No. 5
1071-412X/01/$04.00+0 DOI: 10.1128/CDLI.8.5.984-992.2001
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