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PLENARY PAPER
From the Institute of Cancer Genetics and the
Departments of Pathology and of Genetics and Development, Columbia
University, New York, NY.
The IRTA1 and IRTA2 genes encode
immunoglobulinlike cell surface receptors expressed in B cells and
involved in chromosome 1q21 translocations in B-cell malignancy. We
have now characterized and comparatively analyzed the structure and
expression pattern of the entire family of IRTA genes, which includes 5 members contiguously located on chromosome 1q21. The IRTA messenger
RNAs are expressed predominantly in the B-cell lineage within discrete
B-cell compartments: IRTA1 is specific to the marginal
zone, IRTA2 and IRTA3 are found in the germinal
center light zone and in intraepithelial and interfollicular regions,
and IRTA4 and IRTA5 are expressed predominantly
in the mantle zone. All IRTA genes code for transmembrane receptors
that are closely related to Fc receptors in their most amino-terminal extracellular domains and that possess cytoplasmic domains containing ITIM (immunotyrosine inhibition motifs)- and, possibly, ITAM
(immunotyrosine activation motifs)-like motifs. These
structural features suggest that the IRTA receptors may play a role in
regulating activation of normal B cells and possibly in the development
of neoplasia.
(Blood. 2002;99:2662-2669) The immunoglobulin (Ig) superfamily
encompasses hundreds of distinct molecules and is one of the major
classes of surface receptors. Ig superfamily domains consist of
sequences of approximately 100 amino acids homologous to Igs that form
2 disulfide-bonded B cells express more than 20 Ig superfamily proteins (IgSPs), which
fulfill specific roles as both positive and negative regulators of the
humoral response. Many of these molecules deliver activating signals,
such as the B-cell receptor (BCR) with its associated IgSPs Ig We recently identified the IRTA1 and IRTA2 genes,
2 new members of the Ig receptor superfamily that are located on
chromosome 1q21 and are expressed in B cells.28 In B-cell
malignancy carrying 1q21 abnormalities, IRTA2 gene
expression is frequently deregulated, while IRTA1 was found to be
involved in a chromosomal translocation that fused it to the Ig C Complementary DNA library screening and cloning
Sequence analyses
Northern blotting PolyA-enriched RNA was prepared from previously described cell lines using Oligotex beads (Qiagen, Valencia, CA) separated on a 1% agarose 3-(4-morpholino)propanesulfonic acid (MOPS)/formaldehyde gel, blotted downward onto Duralose-UV membranes (Stratagene, La Jolla, CA) in 20 × SSC, cross-linked at 120 000 µJ/cm2, and hybridized to 32P-dCTP-labeled random-primed probes in
fomamide-containing solution with 10% dextran sulfate. DNA probes,
generated by polymerase chain reaction or restriction enzyme digestion,
were purified from 0.8% agarose TAE (tris-acetate
ethylenediamine tetraacetic acid [EDTA]) gels using GFX spin columns
(Amersham Pharmacia Biotech, Piscataway, NJ) and corresponded to the
following regions of the cDNA sequences: IRTA1 (3'
untranslated region [UTR]) nucleotides (nt) 1641 to 2225;
IRTA2 (5' end) nt 1 to 743; IRTA3 (3'
end) nt 2337 to 2970, (5' end) nt 1 to 745; IRTA4 (5' end)
nt 1 to 750; IRTA5 (3' end) nt 1271 to 1900, (5' end) nt 1 to 726. Filters were washed at a final wash of 0.1 × SSC at 65°C,
exposed to Kodak XAR film, developed on a Kodak 1000A XOMAT processor,
digitized with an AGFA T1200 duoscan, and rendered in Adobe
Photoshop 5.5.
In situ hybridization Digoxygenin-labeled probes encompassing the entire cDNA and 5' UTR of each IRTA gene were transcribed with T7, SP6, or T3 bacteriophage RNA polymerases, as appropriate, to generate antisense RNA probes from linearized plasmid template. A sense RNA-negative control probe of similar length was made from similarly purified plasmid DNA containing the Bcl6 cDNA. Human tonsil tissue was snap-frozen in dry ice/isopentane, and 12 µm serial cryostat sections were prepared. Sections were not treated with proteinase K but were acetylated and then hybridized at 68°C in 50% formamide-containing solution, washed, probed with an alkaline phosphatase-conjugated antidigoxygenin antibody, and developed, all as described.31
Cloning of IRTA cDNAs and structure of predicted IRTA proteins Cloning of IRTA1 and IRTA2 has been previously described.28 BLAST search of the GenBank database with the IRTA2 sequence identified an expressed sequence tag (EST) (AA63g02) showing 89% homology to IRTA2 over 250 bases within the extracellular domain encoding region. The insert of that clone (IMAGE: 825650) was used to probe a gt11 human tonsil cDNA library at high stringency (see
"Materials and methods"). Twenty-eight clones were sequenced, which
segregated into 4 contigs: IRTA2 (2 clones),
IRTA3 (GenBank AF459027) (9 clones), IRTA4
(GenBank 459633) (5 clones), and IRTA5 (GenBank AF459634)
(12 clones). The 3 IRTA sequences not identical to the probe
were identified despite the high stringency of library screening,
because each contains regions of about 90% nt sequence identity with
the probe, which fell into the IRTA5 contig. The 5' ends of
IRTA4 and IRTA5 were cloned by 5' RACE. BLAST
searches of GenBank databases and of the Celera human genome sequence
failed to identify additional homologous genes, suggesting that there
are no outstanding members of the IRTA family.
The domain organization of the IRTA RNAs is shown schematically in
Figure 1. As previously
reported,28 IRTA1 undergoes alternative polyadenylation, and IRTA2 undergoes alternative splicing at
the last exon to generate 3 protein isoforms that either have no
membrane tether (IRTA2a), have a putative
glycosyl-phosphatidyl inositol linkage (IRTA2b), or
have transmembrane and cytoplasmic domains (IRTA2c). In
addition, premature termination within the second Ig domain gives rise
to IRTA2d.28 For IRTA3, IRTA4, and
IRTA5, only transmembrane-encoding isoforms were found by
cDNA cloning and database searches. The 2 bands seen by Northern blot
analysis of IRTA5 (see below) are consistent with
alternative polyadenylation within the 3' UTR (at nt 146315 and nt
148601 of the genomic contig AL356276), where multiple ESTs sequences
initiate. These bands were seen with both 5' end and proximal 3' UTR
probes, ruling out the possibility of an unrecognized alternative
terminal exon. Whereas predominantly fully processed messenger RNAs
(mRNAs) were seen in cultured cell lines (see below), several longer
species representing incompletely processed mRNA were seen in RNA from tonsil and spleen, most notably for IRTA5. Recently, based
upon sequences of 3 cDNA clones, Xu et al proposed 3 distinct protein isoforms of a putative gene designated SPAP132 (AF319438).
The SPAP1a nt sequence is identical to our IRTA4 sequence
starting at nt 931 of IRTA4 but is missing the first 5 exons
that encode the signal peptide and the first 3 Ig-like domains.
IRTA proteins identify a subfamily of IgSP molecules related to Fc receptors The predicted IRTA proteins each have 3 to 9 extracellular Ig-like domains, followed by transmembrane and cytoplasmic domains (Figure 2), while IRTA2 also has secreted and glycosylphosphatidyl inositol-linked isoforms. After signal peptide cleavage, the predicted molecular weights of the unglycosylated polypeptides are 55.7 kd (IRTA1), 104.9 kd (IRTA2c), 78.9 kd (IRTA3), 53.4 kd (IRTA4), and 45.2 kd (IRTA5). The extent of sequence identity of corresponding Ig-like domains varies within the range of 45% to 83% among IRTA family members (Figure 2). Amino acid sequence alignment (Figure 3A) allows 5 Ig-like domain subtypes to be defined based upon homology within the IRTA family (Figure 2A-E). Domain subtypes A and B are similar (37% amino acid similarity) to domains present in the high-affinity Ig receptor Fc RI as well as FcRII and FcRIII, which are
low-affinity Ig receptors that have only 2 Ig-like domains. Not all of
the IRTAs have domains of each subtype. However, a feature common to
all of the IRTAs is the presence of domain subtype C, which is 70%
preserved among the various IRTA members. Domain C is also 47%
identical to the third domain of FcRI. The adjacent domain, subtype
"D," shows 55% identity among IRTA members and is absent from
FcRI. In IRTA2, however, the "D" consensus sequence is split
into 3 parts that are spread over 2 adjacent domains. The most highly
conserved domain, domain subtype E, is reiterated with 83% identity in
IRTA2c (3 times), IRTA3 (twice), IRTA4 (once), and IRTA5 (once), but it
is absent entirely from FcRI and from IRTA1.
The various domains of the IRTA members are encoded by a pattern of
exons that is conserved among members of the family: 2 exons encode the
signal peptide, 1 exon encodes each Ig domain, and 5 exons encode each
cytoplasmic region. IRTA5 is unique among the IRTAs in that it has a
charged residue (glutamic acid) in the transmembrane region, suggesting
that it may heterodimerize with a protein containing a positively
charged amino acid in nearby position, as is the case for many
ITAM-bearing proteins, including Fc Each cytoplasmic domain contains 3 to 5 tyrosine residues, which
suggests the presence of ITIM- or ITAM-like motifs. Based on a
consensus sequence for ITIM (V/L/I-X-Y-X-X-L/V),33 7 canonical ITIMs can be found in the IRTA molecules (boxed, bold in
Figure 3B), while 14 additional sequences differ from the consensus
ITIM at the IRTA genes are located within a 300 kilobase region on chromosome 1q21 BLAST search of IRTA3, IRTA4, and IRTA5 against the human genome revealed that they all lie within a single P1 phage artificial chromosome (PAC) contig (AL356276). All 5 IRTA genes are contained within a 300 kilobase (kb) genomic region (Figure 4), and all have a telomere-to-centromere transcriptional orientation. The IRTA locus lies between 2 genes identified at translocation breakpoints in lymphomas: Bcl-9, which was found to be deregulated in a single case of pre-B-cell acute lymphoblastic leukemia35 on the centromeric end, and FcRIIB, which was found to be up-regulated in 2 cases of follicular
lymphoma and in one cell line36 on the telomeric end. Also
centromeric to the IRTA locus lies the MUC-1 (EMA) gene, deregulated in 6% of non-Hodgkin lymphomas that have a 1q21
abnormality.36 The IRTA genes are midway between 2 Fc
receptor loci, consistent with an evolutionary relationship of the IRTA
and the FcR gene families. The IRTA locus also contains a 5 exon
pseudogene that is highly homologous to IRTA2; lack of EST
sequences derived from this region and the presence of in-frame stop
codons in 2 of the exons serve as evidence of its obsolescence. On the
telomeric end of the region, the transcriptional start site of
IRTA5 lies 11 kb downstream of the polyadenylation signal of
the CD5 antigen-like (scavenger receptor cysteine rich family)
gene.
IRTA genes are expressed in topographically distinct B-cell compartments The pattern of expression of the IRTA genes in normal human tissues was examined by Northern blot analysis (Figure 5). IRTA2, IRTA3, IRTA4, and IRTA5 are all expressed predominantly in the spleen. IRTA1 was detected in normal tonsil tissue (see below; Figure 6) but is expressed at very low levels in the spleen. Significant heterogeneous signals corresponding to higher molecular weight (incompletely processed) species were seen using probes to IRTA4 and IRTA5 in RNA from tissues but not from cell lines (see below; Figure 6). Expression of IRTA3, IRTA4, and IRTA5, like IRTA1 and IRTA2,28 is restricted to lymphoid tissue, with predominance in the B-cell-rich spleen over the T-cell-rich thymus.
The expression pattern of the IRTA genes within the B-cell compartment
was examined by in situ hybridization of hyperplastic human tonsil
tissue (Figure 7). IRTA1 is
expressed outside of lymphoid follicles in a "marginal zone"
pattern and in intraepithelial lymphocytes28 (Figure 7A).
This region contains a population of mature/memory B cells that,
in lymph nodes of patients with certain infectious conditions (eg,
toxoplasmosis and human immunodeficiency virus lymphadenitis), are rich
in monocytoid B cells.35
IRTA228 and IRTA3 mRNAs were detected in a polarized pattern within the germinal center, with highest expression in the centocyte-rich light zone and little to no signal in the dark zone (Figure 7B). Outside the germinal center, the highest levels of these mRNAs were detected in intraepithelial lymphocytes and in interfollicular regions. These results indicate that transcriptional activation of these genes occurs during the maturation of centroblasts to centrocytes, with maintenance of expression in postgerminal center B cells. A weak signal for IRTA2 and IRTA3 RNA was detected in the follicular mantle zones. IRTA4 and IRTA5 are expressed in a third, distinct pattern, with highest levels seen within the mantle zones (Figure 7C). IRTA5 mRNA was not detected outside this region, while IRTA4 signal was slightly above background levels outside the mantle zone. Thus, these 2 genes are expressed almost exclusively in naive B cells. To more broadly assess IRTA gene expression, we performed Northern blot analysis using a panel of cell lines representative of the major hematopoietic lineages (Figure 6). Expression of all IRTA family members is B lineage-restricted, in that no signal was seen in RNA from HeLa (epithelial) or representative erythroid, myeloid, monocytic, or T-cell lines. As shown here and previously,28 IRTA1 and IRTA2 are expressed in some lymphoblastoid cell lines that also weakly express IRTA3. Among B-cell lines examined, all IRTAs are widely expressed in Burkitt lymphoma (BL) lines, each having a unique expression profile. The BL and multiple myeloma lines shown in Figure 6 are grouped according to the presence or absence of a cytogenetic abnormality of 1q21, further defined by fluorescence in situ hybridization as trisomy of the locus in 90% of cases.28 For all of the IRTA mRNAs, expression in BL cell lines can be considered a deregulation of gene expression relative to their presumed cell of origin, the centroblast. However, for IRTA2, this deregulation also correlates with the presence of a 1q21 abnormality in the 24 cell lines shown in Figure 6. The levels of IRTA2 are on average 10-fold higher in 1q21 abnormal BLs than in 1q21 normal BLs.28 IRTA2 is also expressed by one of the 1q21 abnormal multiple myeloma lines. The other IRTA genes' expression levels do not correlate with the presence of a chromosomal defect in the IRTA region.
The IRTA genes encode glycoproteins within the Ig superfamily of
receptors. Their closest relatives are the Ig-like receptors for the Fc
portions of Ig. These Fc receptors trigger various functions of
effector cells,7 such as antibody-dependent cellular cytotoxicity and anaphylaxis. The most extensive homology is to Fc Recently, using an approach to identify sequences of Fc receptor homologs, Davis et al38 describe the sequences and expression patterns of FcRH1 (IRTA5), FcRH2 (IRTA4), and FcRH3 (IRTA3). Our Northern results are essentially in agreement for IRTA3 and IRTA4, but we find a more restricted expression and transcript size pattern (3 and 5.5 kb, as opposed to multiple transcripts ranging from 1 to 8 kb) for IRTA5.38 This discrepancy may be due to a different probe used for Northern blot analysis; we note that the 3' UTR of IRTA5 contains sequences (including a sine/alu repeat element) that cross-hybridize to other transcripts. Thus, the inclusion of these sequences in the probe (not described in detail by Davis et al) may have generated a cross-hybridization. Regarding the assignment of ITIM and ITAM motifs, our analysis agrees with the one by Davis et al38 for ITIM, while we have been more conservative in ITAM assignment because we do not detect any bona fide ITAM motifs (see "Results"). However, tyrosine motif identification based on consensus sequences cannot be conclusive and needs functional validation. Despite the homology to Fc receptors, however, the strong conservation by all of the IRTA members of the carboxy-terminal Ig-like domains, along with the reiteration of domain subtype E up to 3 times within an individual IRTA protein, suggests that the IRTA proteins bind through this region to a common or closely related ligand(s) that may be distinct from Ig. In addition, approximately 40% of the amino acid residues in this domain are similar to a domain of PECAM-1 (CD31), an ITIM-containing molecule that plays lineage- and stage-specific roles in intercellular recognition and adhesion. Thus, despite the similarity to Fc receptors, we cannot rule out other functions for the IRTA proteins, such as a role in intercellular signaling via interaction with other cell-bound ligands or even association with the BCR itself. The functional consequences of IRTA ligation on the cell surface are under investigation and hinge upon the nature of the cytoplasmic tyrosine motifs. Where ITIMs are present in the IRTA proteins, they may bind a phosphatase, possibly SHP-1,32 to repress B-cell activation. Alternatively, ITIMs could provide activating signals, by analogy to the ITIM-bearing IgSPs PECAM12 and signaling lymphocytic activation molecule,39 which are thought to interact with the physiologically activating phosphatase SHP-2.40 However, based upon primary structure alone, we cannot rule out the possibility that several pairs of tyrosine-containing motifs (Figure 3B) function together as ITAMs to recruit a src family protein kinase to the receptor. The IRTA mRNAs are expressed on distinct B-cell subsets as defined architecturally within human tonsil tissue. IRTA4 and IRTA5 are expressed in a pattern that corresponds to naive B cells, which suggests a unique role for these molecules in the early stages of B-cell activation or in turnover and migration of this population prior to specific antigenic stimulation. IRTA1 is expressed in the marginal zone and in intraepithelial lymphocytes; this, together with its affinity for IgA, suggests a role in mucosal immunity. IRTA2 and IRTA3 are expressed mainly within the germinal center light zone and in postgerminal center cells, which may imply regulation in the context of T-cell-dependent immune responses. Thus, the IRTA family may provide a means for fine regulation of the immune response at various stages in response to a similar molecule or complex. Because of their B-cell subtype-specific expression, discovery of the IRTA proteins may have clinical implications in diagnosis and therapy. For instance, the marginal zone/intraepithelial pattern of IRTA1 has been confirmed by immunohistochemistry (not shown), and it is present in the monocytoid B cells of human immunodeficiency virus lymphadenitis as well as in most lymphomas of mucosa-associated lymphoid tissue (G.C., manuscript in preparation). Analogously, the other IRTAs may define lymphoma subtypes of distinct cellular derivation, which may prove to be useful in diagnosis. Finally, as B-cell subtype-specific surface markers, the IRTAs may serve as specific targets in immunotherapy of B-cell lymphomas and nonmalignant disorders, analogous to anti-CD20 antibodies.41,42
Submitted September 10, 2001; accepted December 3, 2001.
Supported in part by a grant from the National Institute of Health (CA-37295 to R.D.-F).
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Riccardo Dalla-Favera, Institute of Cancer Genetics, Columbia University, Russ Berrie Science Pavilion, 1150 St Nicholas Ave, Room 303B, New York, NY 10032; e-mail: rd10{at}columbia.edu.
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 A. G. Polson, B. Zheng, K. Elkins, W. Chang, C. Du, P. Dowd, L. Yen, C. Tan, J.-A. Hongo, H. Koeppen, et al. Expression pattern of the human FcRH/IRTA receptors in normal tissue and in B-chronic lymphocytic leukemia Int. Immunol., September 1, 2006; 18(9): 1363 - 1373. [Abstract] [Full Text] [PDF]
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C.-M. Leu, R. S. Davis, L. A. Gartland, W. D. Fine, and M. D. Cooper FcRH1: an activation coreceptor on human B cells Blood, February 1, 2005; 105(3): 1121 - 1126. [Abstract] [Full Text] [PDF]
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 T. Ise, H. Maeda, K. Santora, L. Xiang, R. J. Kreitman, I. Pastan, and S. Nagata Immunoglobulin Superfamily Receptor Translocation Associated 2 Protein on Lymphoma Cell Lines and Hairy Cell Leukemia Cells Detected by Novel Monoclonal Antibodies Clin. Cancer Res., January 1, 2005; 11(1): 87 - 96. [Abstract] [Full Text] [PDF]
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R. S. Davis, R. P. Stephan, C.-C. Chen, G. Dennis Jr., and M. D. Cooper Differential B cell expression of mouse Fc receptor homologs Int. Immunol., September 1, 2004; 16(9): 1343 - 1353. [Abstract] [Full Text] [PDF]
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R. S. Davis, H. Li, C.-C. Chen, Y.-H. Wang, M. D. Cooper, and P. D. Burrows Definition of an Fc receptor-related gene (FcRX) expressed in human and mouse B cells Int. Immunol., September 1, 2002; 14(9): 1075 - 1083. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
sheets, each composed of 3 or 4 
2 or +3 position relative to the tyrosine (ITIM-like; boxed, italicized in Figure 
domains for cell surface recognition.
Annu Rev Immunol.
1988;6:381-405