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Blood, Vol. 95 No. 12 (June 15), 2000:
pp. 3878-3884
NEOPLASIA
Salivary gland mucosa-associated lymphoid tissue lymphoma
immunoglobulin VH genes show frequent use
of V1-69 with distinctive CDR3 features
John A. Miklos,
Steven H. Swerdlow, and
David W. Bahler
From the Department of Pathology, University of Pittsburgh,
Pittsburgh, PA.
 |
Abstract |
Salivary gland mucosa associated lymphoid tissue (MALT)
type lymphomas are B-cell neoplasms that develop out of a reactive infiltrate, often associated with Sjögren's syndrome. Previous reports from our laboratory involving 10 patients suggested these lymphomas expressed a restricted immunoglobulin (Ig)
VH gene repertoire with over use of
V1-69 gene segments. To better determine the frequency of
V1-69 use and whether there may also be selection for CDR3
structures, we sequenced the VH genes from
15 additional cases. Over half of the potentially functional VH genes (8 of 14) used a
VH1 family V1-69 gene
segment, whereas the other cases used different gene segments from the VH1 (V1-46),
VH3 (V3-7, V3-11, V3-30.3,
V3-30.5), and VH4
(V4-39) families. The 8 V1-69 VH
genes used 5 different D segments in various reading frames, but all
used a J4 joining segment. The V1-69 CDR3s showed remarkable
similarities in lengths (12-14 amino acids) and stretches of 2 to 3 amino acids between the V-D and D-J junctions. They did not resemble
CDR3s typical of V1-69 chronic lymphocytic leukemias. This
study extends our earlier work in establishing that salivary gland MALT
lymphomas represent a highly selected B-cell population. Frequent use
of V1-69 appears to differ from MALT lymphomas that develop at
other sites. The high degree of CDR3 similarity among the V1-69
cases suggests that different salivary gland lymphomas may bind
similar, if not identical epitopes. Although the antigen specificities
are presently unknown, similar characteristic CDR3 sequences are often
seen with V1-69 encoded antibodies that have anti-IgG or
rheumatoid factor activity.
(Blood. 2000;95:3878-3884)
© 2000 by The American Society of Hematology.
| |
Introduction |
Salivary gland mucosa associated lymphoid tissue (MALT)
type lymphomas are neoplasms of CD5 negative B cells that appear to arise out of a reactive infiltrate termed "lymphoepithelial
(myoepithelial) sialadenitis" (LESA).1,2 LESA is seen in
all patients with Sjögren's syndrome but may also be seen in
salivary gland biopsy specimens from patients who do not have
Sjögren's syndrome. Previous studies have suggested that direct
antigen stimulation through surface immunoglobulin (Ig) molecules may
be playing an important role in the development of salivary gland MALT
lymphomas.3,4 For example, more than half of the different
clonal LESA-associated VH genes we have
sequenced from 10 different patients use a V1-69 gene
segment.4,5 Because there are a total of approximately 50 different functional VH gene segments in
the human genome that can potentially be used,6 these
studies suggested that B cells with heavy chains encoded by
V1-69 are preferentially selected for transformation in the
salivary gland, presumably because of their enhanced ability to bind
some, as yet unidentified, antigen relative to other B cells that are present.
Recent studies have shown that the use of V1-69 gene segments
by normal B cells and other types of B-cell malignancies may also be
biased or nonrandom.7 Multiple, closely related alleles of
V1-69 have been identified that can be classified as 51p1-like or 1263-like, based on several nucleotide differences in
CDR2.8 Moreover, different VH
gene haplotypes have been described that can contain 0, 1, or 2 copies
of V1-69 genes.7 Studies using the G6
anti-idiotypic antibody, which identifies B cells expressing heavy
chains encoded by 51p1-like alleles, indicated that the expression of
these V1-69 genes can be proportional to the germline copy
number, with 1 copy accounting for up to 4% of IgD positive normal
tonsillar B cells.7 Analyses of individual peripheral blood
B cells, however, found that only approximately 1.6% had productive
V1-69 rearrangements, split approximately equally between
CD5 positive and CD5 negative B cells, which is close to the value
expected for random use of a single copy VH gene.9 Compared with normal B-cell populations,
V1-69 expression in CD5 positive B-cell chronic lymphocytic
leukemia (CLL) appears to be increased being found in 10% to 20% of
cases.10-12 In addition, the expression of 51p1-like
alleles appears to be strongly favored in CLL over 1263-like
V1-69 alleles.10
To better determine the frequency that V1-69 gene segments and
certain alleles are utilized by salivary gland MALT lymphomas compared
with normal B cells and other B-cell neoplasms, we sequenced the
VH genes from an additional 15 independent
cases. Besides more precisely quantitating the preferential use of
51p1-like V1-69 gene segments, this analysis also revealed that
salivary gland V1-69 genes often have remarkably similar CDR3s
with conserved amino acid sequence motifs at the V-D and D-J junctions.
Because of the importance CDR3-encoded residues often have in
determining the fine specificity of antigen binding,13,14
this observation further suggests that salivary gland lymphomas from
different patients may sometimes recognize the same or similar epitopes.
| |
Patients, materials, and methods |
Patient material
From a total of 18 different patients, paraffin-embedded salivary
gland biopsy specimens of LESA-associated lesions that demonstrated B-cell clones using a standard polymerase chain reaction (PCR) technique (see below), but had not been analyzed further for
VH gene use were available from our earlier
clinicopathological study.15 Histologically, 13 of the
biopsy specimens met criteria considered to be diagnostic of salivary
gland MALT lymphoma, 2 demonstrated LESA with halos of monocytoid cells
(a borderline lesion), and 3 demonstrated only LESA. Salivary gland
biopsy specimens from 2 additional patients who histologically
demonstrated MALT lymphoma and had clonal B cells by PCR were also used.
Polymerase chain reaction
DNA was isolated from unstained standard thickness tissue sections
as described.16 The presence of clonal B cells was
confirmed by amplifying the DNA with consensus 5'
VH gene framework region 3 (FW3) and
3' JH primers for 37 cycles, electrophoresing the
resultant products in 8% acrylamide gels, and staining with ethidium
bromide as described.4 More complete length
VH genes were first amplified for 37 cycles
from the DNA using a variety of 5' VH
leader primers, framework region 1 (FW1) primers, or framework region 2 (FW2) primer with a consensus 3' JH primer under
standard conditions as described.4 To increase the
sensitivity and obtain sufficient DNA for subsequent cloning, secondary
amplification for 15 cycles using 0.5 µL of the initial reactions as
a template was performed using the same conditions, only substituting
an internal JH primer (JH2 for JH1)
or occasionally internal FW1 primer as described.4 With the
exception of a consensus FW2 primer, 5'-TGGGTCCG(C, A)CAG(G,
C)C(T, C)CC(A, T)GG- 3', which was used in 2 cases to obtain the
VH genes, all the other 5' primers
were based on sequences for each of the different
VH families and have been previously
published along with the 3' JH
primers.4,5
Cloning and sequencing of polymerase chain reaction products
Isolation and purification of the clonal FW3-JH
generated PCR products from 8% acrylamide gels was performed as
described.4 Bands corresponding to more complete
VH genes were isolated from 1.5% low-melt
agarose gels and the DNA purified using Wizard DNA preps (Promega,
Madison, WI). Approximately one third of the purified DNA was cloned
using the PCR-Script kit (Stratagene, La Jolla, CA). Plasmid DNA used
for sequencing reactions was obtained from overnight cultures of
randomly selected bacterial colonies using Wizard mini-preps (Promega).
Dideoxy sequencing in both directions was performed using Sequenase
(Amersham, Cleveland, OH) with approximately one third of the plasmid
DNA, according to the manufacturer's protocol. Some of the PCR
products were directly sequenced as described.4 Sequence
analysis was performed using MacVector software (IBI, New Haven, CT)
and the VBASE database.6
| |
Results |
Polymerase chain reaction analysis and identification of B-cell
clones
Parotid gland biopsy specimens of MALT lymphomas and several related
LESA-associated lesions that demonstrated monoclonal bands using a
standard heavy-chain PCR technique were obtained from 20 different
patients. All the biopsies, except 2 recent cases of low-grade MALT
lymphoma, were included in our earlier clinicopathologic study that did
not analyze the VH genes used by the
clones.15 The PCR clonality technique involves
amplification across the highly variable CDR3 regions using consensus
FW3 and JH primers and has excellent sensitivity and
specificity, even with the poor quality DNA obtained from the
paraffin-embedded tissue, because the products are typically small,
being approximately 100 to 150 base pairs (bp) long.17,18
Similar to the representative results shown in Figure
1, single dominant monoclonal bands were identified in all 20 cases, along with polyclonal background ladders that reflect reactive B cells also present in the biopsy specimens, which generally have different sized CDR3s. Previous dilutional studies
indicated that the clonal B cells needed to represent approximately 5%
or more of the total B-cell population to be detected with this
technique (unpublished observations).
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| Fig 1.
PCR clonality analysis.
CDR3-related PCR products were obtained by amplifying lymphoma biopsy
DNA with consensus FW3 and JH1 primers. Small aliquots of
the resultant products were also secondarily amplified with FW3 and
more internal JH2 primer. Shown are products from both
FW3-JH1 and FW3-JH2 reactions for 2 cases and a
polyclonal control after electrophoresis in an 8% acrylamide gel and
staining with ethidium bromide. Prominent single monoclonal bands are
seen in each case, along with fainter polyclonal ladders that reflect
background B cells with different sized CDR3s that are also invariably
present. The smaller sizes of the FW3-JH2 generated
monoclonal bands simply reflect the more 5' location of
JH2 relative to JH1. Secondary amplifications
with JH2 were performed to potentially enhance weaker
monoclonal signals relative to the polyclonal background and to
determine whether the JH2 primer would work with the clonal
VH gene in PCR reactions to obtained more
full length VH products.
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Complete or nearly complete VH genes were
successfully amplified from 15 of the 20 cases using a variety of
VH leader, FW1, FW2, and JH
primers. Our failure in 5 of the cases appeared to be due to the
paraffin-extracted DNA being of lower quality, which prevented
amplification of longer products the size of
VH genes. VH
PCR products from selected reactions were cloned and repeat
VH gene sequences identified in all cases,
except in one, where the VH PCR products were directly sequenced. To ensure the repetitively isolated or clonal
VH sequences represented the same clones
identified earlier with the FW3-JH primers, the monoclonal
FW3-JH bands were also purified and independently sequenced
to obtain the "gold standard" CDR3 sequences (Figure
2). This is an important step when working
with paraffin-extracted DNA because repeat full-length VH sequences can occasionally be isolated
that do not match the more reliable FW3-JH-generated CDR3
sequences when the DNA is of poor quality (personal observation).
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| Fig 2.
Salivary gland lymphoma CDR3 sequences.
PCR products obtained from amplification with FW3-JH1 or
FW3-JH2 primers were either directly sequenced or cloned
and multiple clones sequenced as indicated on the right (additional
identical CDR3 sequences were also obtained from the more full length
VH PCR products). Each sequenced is compared with the
germline D and J segments showing the greatest homology where identity
is indicated by a dash. The bolded entries in the deduced amino acid
sequences from cases 1 to 5 highlight the conserved motifs at the V-D
and D-J junctions referred to in the text.
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Analysis of VH gene segments
Of the 15 clonal VH genes identified, 14 were potentially functional in that no stop codons were present and the CDR3 sequences were in frame (Figures 2 and
3). Comparing the clonal
VH sequences with the known germline genes
revealed that 8 of 14 were most homologous to a V1-69 gene
segment, whereas the other 6 were most closely related to different
VH genes from the
VH1 family (V1-46),
VH3 family (V3-7, V3-30.3, V3-11, V3-30), and VH4 family
(V4-39). Apparent point mutations were present in all but 1 of
the clonal VH consensus sequences, with the
average percentage homology being 95% (Table 1). The majority of substitutions in the
V1-69-derived genes appeared to be different from one another,
with the exception of an isoleucine to threonine change (I to T in
single letter amino acid code) in the third codon of CDR2, which was
found in 5 of 8 consensus sequences (Figure 3). In addition to point
mutations present in all the VH sequences
from a given case, 5 cases (nos 1, 2, 4, 12, and 14) had
VH genes that also showed significant
intraclonal sequence variation above our estimated Taq error rate of
approximately 0.2%, indicative of ongoing somatic hypermutation (Table
2). Although only one noncommon mutation was identified in the VH gene from case 9, it was present in 3 of 4 clones, suggesting it was acquired
sequentially and was not from a polymerase error. Many of the other
noncommon mutations in other cases were also shared among several
VH sequences.
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| Fig 3.
Deduced amino acid sequences of the consensus lymphoma
VH gene segments.
The sequences are compared to the amino acid sequences of the germline
VH gene segments showing the greatest
homology where identity is indicated by a dot. The positions of
mutations in the nucleotide sequences that would not result in a change
in amino acid sequence are indicated by small case letters. Complete
nucleotide consensus sequences for these cases are available from the
GenBank database (accession numbers AF216816-AF216829).
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Analysis of CDR3 sequences
The germline D and J segments assigned to the various clonal
VH genes are listed in Figure 2. All 8 of
the V1-69 derived chains used a J4 joining segment, whereas the
others used mainly J3 sequences (4 of 6 cases). Although a variety of
different D segments were used in different reading frames, 2 of the
V1-69-derived genes (patient 1 and patient 2) used D4-23 in
the same reading frame and had CDR3s that differed only by 3 of 14 amino acids. Several conserved amino-acid motifs that appeared to be
encoded mostly by N nucleotides are evident in many of the
V1-69 CDRs. For example, a glutamate, arginine, glycine motif
(ERG single letter amino acid code) is present in 5 of the 8 V1-69 CDR3 sequences at the V-D segment joint. In addition, an
asparagine, proline motif (NP single letter code) is present at the D-
J junction in 4 of the 8 sequences.
| |
Discussion |
This report greatly extends our earlier studies that suggested
salivary gland MALT lymphomas express a limited repertoire of
VH gene segments.4,5 Of the 28 functional LESA-associated clonal VH genes
now sequenced, 24 (86%) appear to be derived from only 3 VH gene segments (Table
3) and remarkably 17 (61%) use a
V1-69 gene segment. Because the clonal
VH gene CDR3 sequences were also obtained
independently from sequencing FW3-JH-generated products,
the limited repertoire cannot be accounted for by preferential
amplification of certain genes with our VH primers. As
mentioned above, multiple, closely related V1-69 alleles have
been described that are termed either 51P1-like or 1263-like, based on
several nucleotide differences within the CDR2 region.8 Of
the 14 salivary gland lymphoma V1-69-derived segments, 12 appear to be derived from the 51P1 allele and 2 from a 51P1-like allele termed "2 M7" that only differs from 51P1 by 1 nucleotide in FW3. Because the calculated gene frequency of 1263-like and 51P1-like alleles is approximately 30% and 70%, respectively,10
there also appears to be preferential use of specific V1-69
alleles by these lymphomas. As further discussed below, this highly
nonrandom repertoire suggests that an antigen is selecting certain B
cells for malignant transformation in the salivary gland. As
highlighted in Table 3, V1-69 has not been reported to be
frequently used by MALT lymphomas that develop in the
stomach.19-23 This suggests that gastric MALT lymphomas
recognize different antigens from salivary gland MALT lymphomas and
that pathogenesis of MALT lymphomas may have features that are specific
for certain sites or locations.
This report also establishes that salivary gland lymphoma-expressed
V1-69 genes often have remarkably similar CDR3 sequences. All 8 V1-69 CDR3s described in these studies use a J4 segment and were
between 12 and 14 amino acids long. Although a variety of different D
segments were generally used, 5 of the 8 V1-69 CDR3s had the
amino acid motif glutamate, glycine, arginine (EGR single letter amino
acid code) at the V-D junction that appeared to be encoded by mostly
different N-nucleotide sequences. Moreover, 4 of the 5 CDR3s that
contained an ERG motif also had a conserved NP motif located at the D-J
junction, that again appeared to be mostly encoded by N-nucleotides. In
part, because of these conserved N-nucleotides motifs and preferential
use of JH4, 2 of the unrelated lymphomas, which used the
same D segment in the same reading frame, had CDR3s that only differ by
3 of 14 amino acids. Our previously reported V1-69 salivary
gland lymphoma VH genes showed only
possible overuse of JH4 (7 of 9) sequences, without
revealing the conserved ERG motif (0 of 9) or NP motif (1 of
9).4,5
The heavy-chain CDR3 is the most variable part of the conventional
antigen binding site and often plays a critical role in determining
immunoglobulin binding specificity.13,14,24 Because of the
tremendous potential variability, different antibodies that recognize
the same antigen usually have dissimilar CDR3
sequences.25,26 Antigens that elicit antibodies with
similar CDR3 features have been described, but are mainly limited to
simple peptides, haptens, and polysaccharides.27 Therefore,
the high degree of similarity among the salivary gland lymphomas CDR3
sequences suggests that some may recognize similar or perhaps identical epitopes.
Although the antigen specificity of the salivary gland lymphoma
antibodies is presently unknown, our VH
gene analysis suggests that many may have rheumatoid factor activity or
reactivity toward IgG heavy chains. Borretzen et al28
reported that V1-69 rheumatoid factors have characteristic
CDR3s that are approximately 12 to 14 amino acids long, preferentially
use JH4, and have the conserved amino acid motifs EGR and
NP at the V-D and D-J junctions, respectively, similar to what we have
found for salivary gland lymphomas (Figure
4). It was also noted that these features
did not appear to be present in other nonrheumatoid factor
V1-69 CDR3 sequences. In addition, antibodies with rheumatoid
factor activity encoded by V3-7 VH
sequences were noted to have different characteristic CDR3 sequences
that are typically 16 to 17 amino acids long, preferentially
use JH3 and D3-22 segments, and have a glycine as the first
amino acid.28 Interestingly, salivary gland lymphomas
VH genes encoded by V3-7, one of
which was identified in this study, also appear to have CD3s with
similar characteristics as shown in Figure 4. The possibility that many of the salivary gland lymphoma immunoglobulins have rheumatoid factor
activity is also supported by reports of frequently finding local
salivary gland production of rheumatoid factor in patients with
Sjögren's syndrome29 and the frequent occurrence of
mixed type II cryoglobulins (monoclonal rheumatoid factors, as
described below) in these patients.30
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| Fig 4.
Comparison of 2 salivary gland lymphoma CDR3 sequences to
CDR3 sequences used by V1-69 and V3-7 encoded
antibodies with rheumatoid factor activity.
The rheumatoid factor sequences are from Borretzen et al.28
The gap in RF112 was made to highlight the sequence similarities.
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The frequent use of V1-69 and similar CDR3 sequences by these
lymphomas suggests that B cells with certain binding specificities are
selected for clonal expansion and transformation in the salivary gland.
This hypothesis is also supported by several considerations from
analyses of apparent point mutations present in all but 1 of the
lymphoma VH sequences described in this
report. First, the ratios of deduced replacement (R) and silent (S)
mutations found in CDR1 and CDR2 were generally lower than expected if
the mutations occurred randomly. This is particularly evident in the 5 most informative cases with 7 or more mutations in CDR1 and CDR2
(patients 2, 4, 5, 9, and 13; Table 1), in which the observed R/S
ratios were much lower than the R/S ratios expected by random mutation
alone.31 Finding lower R/S mutation ratios than expected by
chance suggests that there is selection against R mutations or negative
selection that can occur because certain CDR residues are necessary for
antigen binding and cannot be altered. Second, negative selection of R
mutations was also observed in the FWRs, which was again especially
evident in the VH genes with the greatest
number of mutations and potentially most informative (nos 2, 4, 5, 9, 12, 13, and 14). Evidence for negative selection of R mutations in FWRs
is often found in VH genes that encode
functional immunoglobulin molecules because certain amino acid residues
need to be preserved to maintain function.32 In this case,
it suggests that the maintenance of the immunoglobulin function is
important for lymphoma cell survival or growth.
In addition to mutations present in all the clonally related
VH sequences, some of the
VH genes from a given case showed
significant levels of intraclonal heterogeneity or mutations, not
common to all the related VH sequences indicative of ongoing Ig gene hypermutation. Ongoing Ig gene mutation suggests that antigen binding, which is thought to trigger the Ig gene
mutator, may still be simulating lymphoma cell growth in these
cases.33 Further support for active antigenic stimulation of lymphoma cell growth comes from analysis of the distribution and
type of noncommon mutations found in the 2 VH genes with the greatest number of
noncommon mutations described in this study. As highlighted in Table
4, there appears to be
selection against newly generated R mutations in both the
CDRs and FWRs. Evidence suggesting that newly generated R mutations in
the lymphoma VH genes can be negatively
selected was also described in our previous studies in which greater
numbers of these mutations could be evaluated.4
Besides salivary gland MALT lymphomas, V1-69 gene segments also
appear to be frequently used by CLL, although to a lesser degree, being
found in approximately 10% to 20% of cases.10-12 Unlike
salivary gland lymphomas, however, the V1-69 genes in most cases of CLL are usually unmutated.10-12 Cases of CLL using
V1-69 gene segments also have been reported to have CDR3s with
distinctive molecular features.10 It is clear, however,
that the distinctive V1-69 salivary gland lymphoma CDR3
sequences we have identified in this study differ from those described
for V1-69 CLL in typically being longer, using predominately
JH4 rather than JH6 joining segments, and also
showing conserved amino acid motifs at the V-D and D-J junctions (Table
5). These differences in expressed V1-69 genes
further support salivary gland lymphoma being distinct from CLL and
also suggest that the antigens recognized by CLL and salivary gland
MALT lymphomas that potentially may be involved in malignant
transformation will be different. Finding frequent use of V1-69
genes in malignancies with different characteristics CDR3s also raises
the possibility that heavy chains encoded by V1-69 segments may
have some superantigen-like feature that predisposes B cells to become
neoplastic.13
Hepatitis-C-associated immunocytoma appears to represent another
B-cell neoplasm that frequently uses V1-69 because 4 of 8 immunocytoma VH genes that were sequenced
in a recent study used V1-69.34 Immunocytomas,
which are also termed lymphoplasmacytic lymphomas in the recent WHO
lymphoma classification system,35 can sometimes be
difficult to differentiate histologically from MALT-type lymphomas,
have similar immunophenotypes, and may be closely related. Hepatitis-C
is thought to be the major cause of type II mixed cryoglobulins that
represent monoclonal IgM rheumatoid factors complex to polyclonal
IgG.36 Presumably, all the V1-69 hepatitis-C-associated immunocytomas in the previously mentioned study
by Ivanovski et al34 were producing monoclonal rheumatoid factors because these patients also had type II mixed cryoglobulins. Because of this, the use of V1-69 by hepatitis-C lymphomas was not completely unexpected because it is well known that monoclonal rheumatoid factors from mixed cryoglobulins frequently express the G6
cross-reactive idiotype that is a marker for 51p1-like alleles of
V1-69.10,37 Besides the frequent use of
V1-69, hepatitis-C-associated immunocytomas may also have CDR3
sequences similar to those seen in salivary gland lymphomas because 3 of the 5 used JH4, and 2 started with EG (none had EGR),
although none had an NP motif at the D-J junction. The
VH gene similarities and presumed rheumatoid factor reactivity of the hepatitis-associated immunocytomas support these neoplasms being closely related to salivary gland MALT
lymphomas in terms of pathogenesis. Because hepatitis-C virus does not
appear to be a likely cause of LESA or salivary gland lymphoma,38,39 the use of similar
VH genes may represent selection by a
similar antigen that is generated or up-regulated as a result of
localized chronic immune system stimulation.
In conclusion, this study helps to clearly establish that salivary
gland MALT lymphomas express an extremely limited repertoire of
VH genes with conserved CDR3 structures.
The data are consistent with a model in which only certain B cells are preferentially selected for transformation in the salivary gland which
have immunoglobulin molecules with the ability to bind an as yet
undefined antigen. Previous reports indicating there is an increased
frequency of B cells with the G6 and other nonactive idiotypes in
salivary gland biopsy specimens from patients with Sjögren's
syndrome who do not have lymphoma suggests the selection process is
chronic in nature.3,40 Our analysis of mutations in
salivary gland lymphoma VH genes also is
consistent with an antigen-driven selection process that may be
prevented from undergoing affinity maturation through normal tolerance
mechanisms similar to what has been described for V1-69
antibodies with rheumatoid factor activity.41 If it can be
shown that many of the salivary gland lymphomas do indeed have
rheumatoid factor activity, which is suggested by the distinctive
V1-69 and V3-7 CDR3 sequences, it will also be
important to determine what other antigens the lymphomas may recognize
because the rheumatoid factor activity could represent a
cross-reactivity.42,43 In addition, because heavy chains
from antibodies with rheumatoid factor activity can be encoded by a
variety different VH
genes,28,44 the mechanism whereby the limited
VH repertoire is selected would still need
to be explained.
| |
Footnotes |
Submitted November 2, 1999; accepted February 1, 2000.
Supported by the Pathology Educational and Research Foundation
(University of Pittsburgh) and a Translational Research Grant from the
Leukemia and Lymphoma Society (D.W.B.).
Reprints: David W. Bahler, Department of Pathology,
Presbyterian University Hospital, Rm C604, 200 Lothrop St, Pittsburgh, PA 15213; e-mail: bahlerdw{at}msx.upmc.edu.
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.
| |
References |
1.
Harris NL.
Lymphoid proliferations of the salivary glands.
Am J Clin Pathol.
1999;111(suppl 1):S94[Medline]
[Order article via Infotrieve].
2.
Hyjek E, Smith WJ, Isaacson PG.
Primary B-cell lymphoma of salivary glands and its relationship to myoepithelial sialadenitis.
Hum Pathol.
1988;19:766[Medline]
[Order article via Infotrieve].
3.
Kipps TJ, Tomhave E, Chen PP, Fox RI.
Molecular characterization of a major autoantibody-associated cross-reactive idiotype in Sjögren's syndrome.
J Immunol.
1989;142:4261[Abstract].
4.
Bahler DW, Swerdlow SH.
Clonal salivary gland infiltrates associated with myoepithelial sialadenitis (Sjögren's syndrome) begin as nonmalingant antigen-selected expansions.
Blood.
1998;91:1864[Abstract/Free Full Text].
5.
Bahler DW, Miklos JA, Swerdlow SH.
Ongoing Ig gene hypermutation in salivary gland mucosa-associated lymphoid tissue-type lymphomas.
Blood.
1997;89:3335[Abstract/Free Full Text].
6.
Cook GP, Tomlinson IM.
The human immunoglobulin VH repertoire.
Immunol Today.
1995;16:237[Medline]
[Order article via Infotrieve].
7.
Sasso EH, Johnson T, Kipps TS.
Expression of the immunoglobulin VH gene 51p1 is proportional to its germline gene copy number.
J Clin Invest.
1996;97:2074[Medline]
[Order article via Infotrieve].
8.
Sasso EH, van Dijk KW, Bull AP, Milner ECB.
A fetally expressed immunoglobulin V H1 gene belongs to a complex set of alleles.
J Clin Invest.
1993;91:2358.
9.
Brezinschek HP, Brezinschek RI, Dorner T, Lipsky PE.
Similar characteristics of the CDR3 of VH1-69/DP10 rearrangements in normal human peripheral blood and chronic lymphocytic leukaemia B cells.
Br J Haematol.
1998;1998:516.
10.
Johnson TA, Rassenti LZ, Kipps TJ.
Ig VH 1 genes expressed in B cell chronic lymphocytic leukemia exhibit distinctive molecular features.
J Immunol.
1997;158:235[Abstract].
11.
Fais F, Ghiotto F, Hashimoto S, et al.
Chronic lymphocytic leukemia B cells express restricted sets of mutated and unmutated antigen receptors.
J Clin Invest.
1998;102:1515[Medline]
[Order article via Infotrieve].
12.
Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK.
Unmutated Ig VH genes are associated with a more aggressive form of chronic lymphocytic leukemia.
Blood.
1999;94:1848[Abstract/Free Full Text].
13.
Li Y, Spellerberg MB, Stevenson FK, Capra JD, Potter KN.
The I binding specificity of human VH4-34 (VH4-21) encoded antibodies is determined by both VH framework region 1 and complementarity determining region 3.
J Mol Biol.
1996;256:577[Medline]
[Order article via Infotrieve].
14.
Martin T, Duffy SF, Carson DA, Kipps TJ.
Evidence for somatic selection of natural autoantibodies.
J Exp Med.
1992;175:983[Abstract/Free Full Text].
15.
Quintana PG, Kapadia SB, Bahler DW, Johnson JT, Swerdlow SH.
Salivary gland lymphoid infiltrates associated with lymphoepithelial lesions: a clinicopathologic, immunophenotypic, and genotypic study.
Hum Pathol.
1997;28:850[Medline]
[Order article via Infotrieve].
16.
Lister J, Miklos JA, Swerdlow SH, Bahler DW.
A clonally distinct recurrence of Burkitt's lymphoma at 15 years.
Blood.
1996;88:1407[Abstract/Free Full Text].
17.
Diss TC, Pan L, Wotherspoon AC, Isaacson PG.
Sources of DNA for detecting B cell monoclonality using PCR.
J Clin Pathol.
1994;47:493[Abstract/Free Full Text].
18.
Sioutos N, Bagg A, Michaud GY, et al.
Polymerase chain reaction versus Southern blot hybridization detection of immunoglobulin heavy-chain gene rearrangements.
Diagn Mol Pathol.
1995;4:8[Medline]
[Order article via Infotrieve].
19.
Du M, Diss TC, Xu C, Peng H, Isaacson PG, Pan L.
Ongoing mutation in MALT lymphoma immunoglobulin gene suggests that antigen stimulation plays a role in the clonal expansion.
Leukemia.
1996;10:1190[Medline]
[Order article via Infotrieve].
20.
Qin Y, Greiner A, Trunk M, Schmausser B, Ott M, Muller-Hermelink H.
Somatic hypermutation in low-grade mucosa-associated lymphoid tissue-type B-cell lymphoma.
Blood.
1995;86:3528[Abstract/Free Full Text].
21.
Du M-Q, Xu C-F, Diss TC, et al.
Intestinal dissemination of gastric mucosa-associated lymphoid tissue lymphoma.
Blood.
1996;88:4445[Abstract/Free Full Text].
22.
Chapman C, Dunn-Walters D, Stevenson F, Hussell T, Isaacson P, Spencer J.
Sequence analysis of immunoglobulin variable region genes that encode autoantibodies expressed by lymphomas of mucosa associated lymphoid tissue.
JCP Clin Mol Pathol.
1996;49:M29.
23.
Hallas C, Greiner A, Peters K, Muller-Hamerlink HK.
Immunoglobulin VH genes of high-grade mucossa-associated lymphoid tissue lymphomas show a high load of somatic mutations and evidence of antigen-dependent affinity maturation.
Lab Invest.
1998;79:277.
24.
Sanz I.
Multiple mechanisms participate in the generation of diversity of human H chain CDR3 regions.
J Immunol.
1991;147:1720[Abstract].
25.
Borretzen M, Chapmen C, Stevenson FK, Natvig JB, Thompson KM.
Structural analysis of VH4-21 encoded human IgM allo- and autoantibodies against red blood cells.
Scand J Immunol.
1995;42:90[Medline]
[Order article via Infotrieve].
26.
Mariette X, Brouet JC, Danon F, Tsapis A, Lassoued K.
Nucleotide sequence analysis of the VL and VH domains of five human IgM directed to lamin B.
Arthritis Rheum.
1993;36:1315[Medline]
[Order article via Infotrieve].
27.
Adderson E, Shackelford P, Quinn A, et al.
Restricted immunoglobulin VH usage and VDJ combinations in the human response to Haemophilus influenzae type b capsular polysaccharide.
J Clin Invest.
1993;91:2734.
28.
Borretzen M, Randen I, Natvig JB, Thompson KM.
Structural restriction in the heavy chain CDR3 of human rheumatoid factors.
J Immunol.
1995;155:3630[Abstract].
29.
Anderson L, Cummings N, Asofsky R, et al.
Salivary gland immunoglobulin and rheumatoid factor synthesis in Sjögren's syndrome: nature history and response to treatment.
Am J Med.
1972;53:456[Medline]
[Order article via Infotrieve].
30.
Tzioufas AG, Manoussakis MN, Costello R, Silis M, Papadopoulos NM, Moutsopoulos HM.
Cryoglobulinemia in autoimmune rheumatic diseases.
Arthritis Rheum.
1986;29:1098[Medline]
[Order article via Infotrieve].
31.
Chang B, Casali P.
The CDR1 sequences of a major proportion of human germline Ig VH genes are inherently susceptible to amino acid replacement.
Immunol Today.
1994;15:367[Medline]
[Order article via Infotrieve].
32.
Schlomchik MJ, Marshak-Rothstein A, Wolfowicz CB, Rothstein TL, Weigert MG.
The role of clonal selection and somatic mutation in autoimmunity.
Nature.
1987;328:805[Medline]
[Order article via Infotrieve].
33.
Denepoux S, Razanajaona D, Blanchard D, et al.
Induction of somatic mutation in a human B cell line in vitro.
Immunity.
1997;6:35[Medline]
[Order article via Infotrieve].
34.
Ivanovski M, Silvestri F, Pozzato G, et al.
Somatic hypermutation, clonal diversity and preferential expression of the VH 51p1/VL kv325 immunoglobulin gene combination in hepatitis C virus-associated immunocytomas.
Blood.
1998;91:2433[Abstract/Free Full Text].
35.
Jaffe ES, Narris NL, Diebold J, Muller-Hamerlink HK.
World health organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: a progress report.
Am J Clin Pathol.
1999;111(suppl 1):s8.
36.
Angelo V, Chung RT, Kaplan LM.
A role for hepatitis C virus infection in type II cryoglobulinemia.
N Engl J Med.
1992;327:1490[Abstract].
37.
Gorevic PD, Frangione B.
Mixed cryoglobulin crossreactive idiotypes: implications for the relationship of MC to rheumatic and lymphoproliferative disease.
Semin Hematol.
1991;28:79[Medline]
[Order article via Infotrieve].
38.
Aceti A, Talianai G, Sorice M, Amendolea MA.
HCV and Sjögren's syndrome.
Lancet.
1992;339:1425[Medline]
[Order article via Infotrieve].
39.
Royer B, Cazals-Hatem D, Sibilia J, et al.
Lymphomas in patients with Sjögren's syndrome are marginal zone B-cell neoplasms, arise in diverse extranodal and nodal sites, and are not associated with viruses.
Blood.
1997;90:766[Abstract/Free Full Text].
40.
Deacon EM, Matthews JB, Potts AJC, Hamburger J, Mageed A, Jefferis R.
Expression of rheumatoid factor associated cross-reactive idiotopes by glandular B cells in Sjögren's syndrome.
Clin Exp Immunol.
1991;83:280[Medline]
[Order article via Infotrieve].
41.
Borretzen M, Randen I, Zdarsky E, Forre O, Natvig JB, Thompson KM.
Control of autoantibody affinity by selection against amino acid replacements in the complementarity-determining regions.
Proc Natl Acad Sci U S A.
1994;91:12917[Abstract/Free Full Text].
42.
Williams RC Jr, Malone CC, Kao K-J.
IgM rheumatoid factors react with human class I HLA molecules.
J Immunol.
1996;156:1684[Abstract].
43.
Thorpe SJ, Borretzen M, Bailey SW, Randen I, Natvig JB, Thompson KM.
Human monoclonal rheumatoid factors: incidence of cross-reactions with tissue components and correlation with VH gene usage.
Immunology.
1994;83:114[Medline]
[Order article via Infotrieve].
44.
Thompson KM, Randen I, Borretzen M, Forre O, Natvig JB.
Variable region gene usage of human monoclonal rheumatoid factors derived from healthy donors following immunization.
Eur J Immunol.
1994;24:1771[Medline]
[Order article via Infotrieve].
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Abstract
Introduction