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PubMed1991

Interaction of iC3b with recombinant isotypic and chimeric forms of CR2.

CR2 is a component of a signal transduction complex on B lymphocytes that augments B cell responses to Ag. We have quantitatively assessed binding by the two isotypic forms of CR2 for two of its ligands, the polymerized iC3b (p(iC3b)) fragment of C3, and gp350/220, the EBV membrane protein. The recombinant 15-SCR or 16-SCR forms of CR2 bound p(iC3b) with identical affinities. Full binding activity of CR2 for p(iC3b) was observed with a chimera comprised of SCR-1 and -2 of CR2 fused to SCR-17 through -30 of CR1. Therefore, the alternatively spliced SCR-10a has no role in binding p(iC3b), and the binding activity of wild type receptor for iC3b can be reconstituted with SCR-1 and -2 of CR2. The binding affinities of the two isoforms of CR2 for soluble gp350/220 were also similar. Additional sites in the C3c region of C3 have been postulated also to interact with CR2. However, monomeric iC3b and C3d were equally effective in inhibiting the binding of p(iC3b) to CR2, indicating that the C3c region of iC3b does not contribute to the interaction of iC3b with CR2. Finally, the relative abilities of C3b and iC3b to bind to CR1 and CR2 were compared. The conversion of C3b to iC3b generated a ligand with an approximate 100-fold decrease in affinity for CR1 and a 10-fold increased affinity for CR2, resulting in a 1000-fold greater likelihood for binding to the latter receptor that may then promote B cell activation.

Animals↗
PubMed1991

Intracellular interaction of EBV/C3d receptor (CR2) with p68, a calcium-binding protein present in normal but not in transformed B lymphocytes.

To analyze direct intracellular interactions of CR2 in normal human B lymphocytes, we used polyclonal anti-Id anti-CR2 antibodies (Ab2) prepared against the highly purified CR2 molecule (gp140) as original immunogen. We previously demonstrated that this Ab2 contained specificities that mimicked extracellular and intracellular domains of CR2 and was helpful for identifying CR2-specific ligands. Indeed, some Ab2 specificities recognized human C3d and EBV, two extracellular CR2 ligands. In addition, other Ab2 specificities interacted directly, as CR2, with the intracellular p53 antioncoprotein that is expressed in transformed cells and not in normal cells. We demonstrate herein that Ab2 detected in normal B lymphocytes a 68-kDa protein, p68, that was not expressed in transformed B cells. p68 was localized in purified plasma membranes and cytosol fractions. Direct interaction of purified CR2 with purified p68 was demonstrated. Competitive studies supported that CR2 and Ab2 interacted with identical sites on p68. These interactions were calcium dependent. p68 was identified as a calcium-binding protein by its ability to be solubilized from B lymphocyte membranes by EGTA, a calcium-chelating agent, to bind specifically on phenothiazine-Sepharose in a calcium-dependent interaction, and to be recognized by specific antibodies directed against human p68, a calcium-binding protein of the annexin VI family. Thus, demonstration of different intracellular interactions of CR2 with distinct regulatory proteins, such as p53, the antioncoprotein, and p68, a calcium-binding protein, supports involvement of two regulatory pathways of signal transduction through CR2, depending on the normal or transformed state of human B lymphocytes.

Annexin A6↗
PubMed1991

Identification of 5'-regions affecting the expression of the human CR2 gene.

Human CR2 has a restricted cellular distribution, being expressed on B lymphocytes, dendritic cells of the spleen, pharyngeal epithelial cells, and at low levels on some T lymphocytes. CR2 is expressed by mature B lymphocytes, but not by pre-B cells or by plasma cells, suggesting that mechanisms exist for positive and negative regulation of CR2 gene expression during B cell development. S1 nuclease digestion and primer extension analysis positioned the transcriptional start site between 92 and 94 bp upstream of the ATG codon. Nucleotide sequence analysis identified several sequences within the CR2 promoter region with homology to other known promoter sequences. These included a site similar to an AP-1 site, a sequence with 10 of 13 nucleotides identical to the X box of class II genes, and a TATA box. Genomic DNA starting immediately 5' of the sequence encoding the CR2 signal peptide was subcloned upstream of the bacterial chloramphenicol acetyltransferase gene for analysis of functional promoter and enhancer sites. The functional boundaries of the CR2 promoter were determined by deletion analysis, with both the X box-like sequences and the TATA box required for CR2 expression. This analysis revealed sequences with regulatory effects on CR2 gene expression, however, these transcriptional controlling sequences did not act in a tissue specific fashion.

Antigens, Differentiation, B-Lymphocyte↗
PubMed1990

Expression of the C3d/EBV receptor and of other cell membrane surface markers is altered upon HIV-1 infection of myeloid, T, and B cells.

Human cell lines (the T-cell lines H9, Jurkat, and HUT102, the myeloid lines U937 and HL60, and the Raji B cell line) were infected with HIV-1. HIV-1 antigen could be detected by immunofluorescence analysis in more than 50% of T cells and myeloid cells 15 days after infection. Infection of Raji cells took more than 2-3 months. Studies of cell surface marker expression revealed remarkable changes after HIV-1 infection of Raji cells: expression of CR2 (C3d/EBV receptor, CD19, CD20, CD22, CD23, CD10, and surface IgM) were highly reduced, in the case of CR2 and membrane-IgM from 100 to 0%, whereas levels of CD37 and CD38 remained unaltered by HIV-1 infection. U937 cells showed a reduction of CD4 expression from 14 to 5% after HIV-1 infection; the CR3 expression slightly increased from 25 to 30%. In contrast, HLA-DR was only expressed (21%) after HIV-1 infection but not in uninfected U937 cells. Expression of HLA-DR could be detected also in HL60 cells (33%) after HIV-1 infection. In H9 cells, CD4 was reduced from 60 to 30% after HIV-1 infection, whereas HLA-DR and CD25/IL-2 receptor expression increased from 16 to 90% and from 0 to 50%, respectively. CD4 was reduced from 70 to 0% from Jurkat cells after HIV-1 infection, whereas expression of CR2 was only slightly diminished from 8 to 4%. Expression of CR1 and HLA-DR was slightly increased in these cells (1 to 3%).(ABSTRACT TRUNCATED AT 250 WORDS)

Antigens, Differentiation, B-Lymphocyte↗
PubMed1990

Monovalent ligands of complement receptor 2 inhibit whereas polyvalent ligands enhance anti-Ig-induced human B cell intracytoplasmic free calcium concentration.

We have performed experiments to investigate the role of ligands for complement receptor 2 (CR2) in human B cell activation. Flow microfluorimetry was used to assess changes in free intracytoplasmic calcium concentration [Ca2+] in indo-loaded B cells, immediately after exposure to anti-mu antibody and to monovalent or polyvalent CR2 ligands. As monovalent ligands we used the C3d fragment and synthetic C3 peptides (peptides P14, residues 1201-1214, and P28, residues 1187-1214). As polyvalent ligands we used i) an intact monoclonal mouse anti-CR2 antibody (HB5) and its F(ab')2 fragment, ii) tetravalent P13 [residues 1202-1214) 4-template), and iii) P28 conjugated to BSA (molar ratio 5/1). Anti-CR2 antibody HB5, tetravalent P13, and P28 conjugated to BSA, enhanced the ability of F(ab')2 fragments of the IgG fraction of goat anti-human mu antibody to increase human B cell [Ca2+]i. In contrast, the monomeric CR2 ligands C3d and P28 inhibited the anti-mu-induced increase in human B cell [Ca2+]i. Multivalent P13, P28, and the HB5, by themselves, did not affect B cell [Ca2+]i. These experiments suggest that the valence of the CR2 ligands is crucial for the nature (synergistic vs antagonistic) of the message transmitted through the CR2.

Antigens, Differentiation, B-Lymphocyte↗
PubMed1990

The murine complement receptor gene family. IV. Alternative splicing of Cr2 gene transcripts predicts two distinct gene products that share homologous domains with both human CR2 and CR1.

The murine Cr2 gene encodes at least two related proteins. The first of these is predicted to include 1408 amino acids from a transcript including 4224 coding nucleotides. This protein is predicted to contain 21 60-amino acid repeats plus those residues encoding transmembrane and cytoplasmic regions for a total peptide m.w. of 155,307. The first six of these repeats are similar to human CR1 in sequence and organization. The second protein is encoded by an alternatively spliced Cr2 transcript that is lacking those sequences which encode the first six 60-amino acid repeats of the larger protein. This second, smaller protein, encoded by a transcript of 3096 coding nucleotides, is predicted to include 15 60-amino acid repeats, plus the transmembrane and cytoplasmic regions. This smaller protein contains 1032 amino acids for a peptide m.w. of 113,328. This second protein is extremely homologous in size and sequence to human CR2. Both proteins share the same signal sequence for membrane insertion. DNA sequence analysis, RNA protection studies and genomic phage mapping indicate the transcripts which encode these proteins are derived from the Cr2 gene via alternative splicing.

Amino Acid Sequence↗
PubMed1990

Loss of human CR1- and murine Crry-like exons in human CR2 transcripts due to CR2 gene mutations.

Analysis of the coding sequences of the murine Cr2 gene indicated that it contains two distinct regions of homology to the murine Crry, and human CR1 and CR2 genes. The last 15 short consensus repeats (SCR) of Cr2 are very similar to the 15 reported SCR of human CR2. These 15 SCR of Cr2, plus the transmembrane and cytoplasmic domains, make up a protein very similar in organization and sequence to the human CR2 gene product. Another Cr2 transcript contains the sequences encoding the previously described 15 SCR plus those encoding another six amino terminal SCR. These amino terminal SCR are very similar to those of Crry and the first six SCR seen within the CR1 long homologous repeats. Amino acid sequence similarity analysis, however, indicated that the sequences encoding the six amino terminal SCR of Cr2 evolved from a separate lineage of SCR than Crry and CR1, suggesting that the human counterparts to these additional Cr2 SCR had not been identified. Using the cDNA sequences specific for the amino terminal SCR of murine Cr2, the human counterparts were isolated and localized within the human CR2 gene between those nucleotides encoding the signal sequence and those encoding the first SCR of the mature human CR2 protein. Unlike the murine Cr2 gene products, these Crry/CR1-like sequences of the CR2 gene are not maintained in mature CR2 mRNA, and thus represent pseudoexons. DNA sequence analysis of the pseudoexon homologous to that encoding the first SCR of the murine Cr2 gene indicated that a stop codon has been introduced within the human coding sequence but that the 5' and 3' splice recognition sequences appear to be functional. Although the stop codon would block the translation of a transcript with this exon, it would not inhibit the incorporation of the exon within the mature CR2 transcript. Therefore, another mutation must have been introduced within the human CR2 gene such that both this exon and the other CR1/Crry-like exons are removed from mature CR2 transcripts.

Amino Acid Sequence↗
PubMed1990

A molecular and immunochemical characterization of mouse CR2. Evidence for a single gene model of mouse complement receptors 1 and 2.

The relationships between functional, biochemical, and genetic homologues of human and mouse C receptors 1 (CR1) and 2 (CR2) are incompletely understood. We have isolated and characterized a partial mouse CR2 cDNA clone and determined the exon-intron organization of the gene encoding it. Together they predict a form of mouse CR2 highly identical to the 15 short consensus repeat form of human CR2. Strong similarities in genomic organization and exon-intron junctions indicate that this mouse gene and human CR2 are evolutionary homologues. A polyclonal rabbit anti-mouse CR2 fusion protein, BRN-1, was prepared. BRN-1 immunoprecipitates bands of 155 to 160 kDa under nonreducing conditions in mouse CR2 expressing B cell lines. In mouse spleen a doublet of 155 kDa and 190 kDa under nonreducing and 165 and 205 kDa under reducing conditions is recognized by immunoprecipitation and Western blot analysis. Staphylococcus aureus V8 protease maps of these two proteins show many shared bands. Crossed immunoprecipitation using BRN-1 and 7E9, a previously described mAb reported to identify the 190-kDa mouse CR1 and a smaller 150-kDa protein, indicates that both antibodies react with the same proteins. Therefore, by using BRN-1 we have now linked the genetic mouse CR2 to its functional, biochemically characterized gene product. The observation that BRN-1 also recognizes a second 190-kDa mouse protein defined functionally as a homologue of human CR1, and that these proteins have very similar peptide maps, provides strong evidence that these two proteins are expressed by a single mouse CR2/CR1 transcription unit.

Amino Acid Sequence↗
PubMed1990

The analysis of the variation of the surface proteins of leukemic lymphocytes of B-chronic lymphocytic leukemia patients by high performance liquid chromatography.

Surface phenotypes of leukemic lymphocytes are analyzed by high performance liquid chromatography of the vectorially iodinated surface proteins and the variation of the phenotypes of B-chronic lymphocytic leukemia (B-CLL) lymphocytes from different individuals is studied. A number of surface molecules show a coordinated variation between patients in their level of expression. Some of these molecules belong to recognized clusters of differentiation, e.g., CD45 and CD21 and their variation can be confirmed by flow cytometry. But the HPLC also reveals other components that have not been assigned to known clusters, e.g., a component of Mr of around 300 kD. Two types of B CLL lymphocytes can be recognized by this set of molecules and the patients ranked according to the level of expression of these markers on their leukemic cells. The effects of TPA treatment on expression suggests that these molecules represent a maturational sequence and that the leukemias are derived from progressive stages along this process.

Antigens, Differentiation↗
PubMed1990

Structure and signalling functions of C3 receptors on human B cells.

CR1 (C3b receptor) and CR2 (C3d/EBV receptor) are two C3 receptors expressed on B lymphocytes. CR1 and CR2 have structural similarities and their cross-linking at the B cell surface by antibodies or specific ligands in multimeric forms induce B cell activation. However, activation of human B cells through cell surface interactions or by intracellular protein kinase C activators leads to phosphorylation of CR2 but not CR1. CR2 is phosphorylated on serine and tyrosine residues. Analysis of post-membrane events associated with CR2 revealed intracellular interactions of CR2 with p53, a plasma membrane anti-oncogene-encoded phosphoprotein, and with p120, a nuclear phosphoribonucleoprotein. These intracellular interactions probably represent important steps in the signalling functions of CR2.

Antigens, Differentiation, B-Lymphocyte↗
PubMed1990

Deficiencies of human C3 complement receptors type 1 (CR1, CD35) and type 2 (CR2, CD21).

CR1 (CD35) and CR2 (CD21) are structurally related integral transmembrane glycoproteins that function as cellular receptors for human C3b and C3dg, respectively. The primary sequence of the most common structural allotype of CR1 and that of CR2 have been established, and ligand binding on the molecules has been mapped. CR1 and CR2 genes are located in close vicinity in the RCA locus of chromosome 1. CR1 has a wide cellular/tissular distribution and mediates a variety of biologic functions, including the transport of C3-bearing immune complexes on erythrocytes, enhancement of phagocytosis, induction of IL-1 secretion and enhancement of B-cell differentiation. Expression of CR2 is restricted to B lymphocytes and follicular dendritic cells. The receptor modulates B-cell growth. CR2 also serves as the receptor for EBV and determines the cellular tropism of the virus. This review discusses the molecular biology and functional characteristics of CR1 and CR2. It focuses on alterations of expression of the receptors in disease, with particular emphasis on the genetic and acquired factors that contribute to the defective expression of CR1 in patients with systemic lupus erythematosus.

Amino Acid Sequence↗
PubMed1988

Structural and functional analysis of CR2/EBV receptor by means of monoclonal antibodies and limited tryptic digestion.

The receptor for the C3d fragment of the third component of complement, CR2, has recently been shown also to act as the receptor for the Epstein-Barr virus (EBV) and to be involved in the control of B-cell proliferation. In order to define functionally important domains on this molecule, we produced monoclonal antibodies to several distinct epitopes. CR2 was purified from a NP-40 lysate of human tonsils by a new method involving sequential chromatography on lentil lectin Sepharose 4B and DEAE-Sephadex and used to immunize mice. After fusion we obtained four stable hybridoma lines producing antibody to CR2. Specificity of these antibodies for CR2 was ascertained by immunofluorescence analysis on a panel of various cells known to possess CR2, by their reactivity in a recently described ELISA for C3 receptors, by Western blotting with purified CR2 and immunoprecipitation from 125I-labelled Raji cells. These four antibodies were found to recognize three distinct epitopes localized on the same fragments of 95,000, 72,000, 50,000, 32,000 and 28,000 MW obtained after mild tryptic digestion of CR2. The 72,000 MW fragment contains the binding site for C3d. Two monoclonal antibodies recognizing the same epitope did not inhibit the binding of C3d-coated sheep erythrocytes to Raji cells, whereas the other two antibodies against distinct epitopes did inhibit in the presence of a second antibody. All four monoclonal antibodies stimulated the proliferation of human peripheral blood B cells.

Antibodies, Monoclonal↗
PubMed1988

CR2 ligands modulate human B cell activation.

A considerable body of evidence from this and other laboratories indicates that complement receptor type 2 (CR2) modulates B cell activation and growth. In the present studies we have examined the effects of three different types of CR2 ligands, i.e., monomeric, aggregated, and latex-bound C3dg; mAb to different CR2 epitopes; and UV-inactivated, non-transforming EBV (EBVUV) for their actions on highly purified, high density resting tonsil B cells. Although none of these ligands induced B cells to enter the cell cycle or synergized with either anti-mu or low m.w. B cell growth factor in triggering B cell mitogenesis, aggregated C3dg, latex-bound C3dg, the OKB7 anti-CR2 mAb, and EBVUV-enhanced thymidine incorporation by phorbol ester-activated tonsil B cells. Such enhancement was not T cell or monocyte dependent. The major action of the CR2 ligands thus seems to be to enhance the transition of B cells activated by certain stimuli from the G1 to the S phase of the cell cycle. In contrast to the action of aggregated and latex-bound C3dg, monomeric C3dg was inhibitory for phorbol ester and aggregated C3dg-induced B cell activation. The HB-5 anti-CR2 mAb, which reacts with a different epitope on CR2 from that of OKB7, did not synergize with PMA in B cell activation. These data provide additional evidence for a role for the CR2 in the control of B cell growth and provide a useful model for studying the CR2-mediated signals that affect the growth of B cells.

Adjuvants, Immunologic↗
PubMed1988

Cell cycle control of a Burkitt lymphoma cell line: responsiveness to growth signals engaging the C3D/EBV receptor.

CR2, the receptor for the C3d fragment of the third complement component and for Epstein-Barr virus (EBV) has been shown, on mouse B cells, to be involved in the control of B-cell proliferation by acting as a receptor for macrophage-derived growth factors. We examined whether the growth of a Burkitt lymphoma cell line, RAJI, could be influenced by ligands of human CR2. In serum-free culture, purified human C3d, as well as three monoclonal antibodies to distinct epitopes on human CR2, were capable of enhancing the growth rate of RAJI cells two to five-fold. This effect could not be observed if even trace amounts of serum were present in the culture medium. Simultaneous addition of pairs of antibodies did not enhance the growth rate, suggesting that a particular engagement of CR2 may be critical in order to induce a stimulatory effect. These results indicate that in a homologous serum-free human B-cell system human C3d as well as monoclonal antibodies to human CR2 can induce B-cell proliferation and that CR2-mediated triggering of B cells can be induced via epitopes other than the C3d-binding site. In addition we conclude that--unlike normal human B cells--at least some human B-lymphoma cells respond to CR2-mediated stimuli in the absence of any T-cell derived factors. Therefore the control mechanisms exerted through CR2 must still be intact on these autonomously growing cells.

Antibodies, Monoclonal↗
PubMed1989

Analysis of epitope expression and the functional repertoire of recombinant complement receptor 2 (CR2/CD21) in mouse and human cells.

We transfected human complement receptor 2 (CR2/CD21) cDNA containing eukaryotic expression constructs into CR2-negative mouse L cells and human K562 erythroleukemia cells. We subsequently selected stably transformed cells that expressed human CR2, as assessed by flow microfluorimetry analysis and immunoprecipitation of 125I-labeled surface membranes using the monoclonal anti-CR2 antibody, HB5. Utilizing flow microfluorimetry analysis, epitopes recognized by anti-CR2 mAb HB5, OKB7, B2, and four other anti-CR2 antibodies were detected on CR2 expressing transfectants but not parental cells. In addition, CR2 expressing transfected cells efficiently formed rosettes with sheep erythrocyte intermediates bearing human C3bi and C3d, but not C4b or C3b, consistent with the known ligand specificity of CR2. CR2 containing transfectants were also demonstrated to specifically bind EBV. Infection with EBV of CR2 expressing L cells and K562 cells resulted in mean expression of Epstein-Barr nuclear Ag (EBNA) at 48 h in 0.35% of CR2 expressing L cells and 3.7% of CR2 expressing K562 cells. Parental L cells and K562 cells did not express EBNA after EBV infection. These results indicate that CR2 alone is sufficient to transfer both C and EBV receptor functions to heterologous cells. In addition, expression of EBNA was found to be significantly higher in human K562 than mouse L cells, both expressing the same recombinant receptor. These results suggest that mechanisms other than CR2 binding lead to inefficient EBV infection and/or EBNA synthesis in mouse fibroblasts.

Animals↗
PubMed1989

Lymphocytes stimulated by allogeneic B cell lines cleave the third component of complement and fix C3 fragments. Their nonspecific lytic capacity is elevated against complement receptor type 2-carrying targets.

Human blood lymphocytes stimulated in mixed cultures by allogeneic B cell lines were shown to cleave C3 molecules. The B cell lines were derived from Burkitt lymphoma patients: 1) established from their EBV-negative lymphoma, 2) the EBV-positive sublines converted in vitro, and 3) lymphoblastoid cell lines (LCL) i.e., B lymphocytes transformed in vitro by EBV. These cell lines differed considerably in their capacity to stimulate allogeneic lymphocytes. The split products of C3 were detected in the supernatants and on the surface of the activated lymphocytes at levels which correlated with the strength of stimulation. Lymphocytes cultured with LCL had the highest levels of thymidine incorporation blast transformation, C3 cleavage, and C3 fragment fixation. Lymphocytes exposed to the EBV-negative Burkitt lymphomas were stimulated weakly and their C3-activating capacity was low. Irrespective of the efficiency of lymphocyte stimulation induced in the cultures, 60 to 70% of the blasts were found to fix C3 fragments. The majority of the lymphocytes which fixed C3 fragments were T blasts that carried the CD3 marker and expressed IL-2R (CD25). CD4 and CD8 cells were represented with equal frequency in the C3-fragment fixing and C3-fragment negative populations. Pre-exposure of the MLC-activated lymphocytes to human serum increased their cytotoxic capacity toward CR type 2-carrying targets. The enhanced lysis was abrogated by F(ab)2 rabbit anti-human C3d or rabbit anti-CR type 2 antibodies. The results suggest that the C3 fragments fixed on the lymphocytes bind to CR on the targets and elevate the avidity of binding between the two interacting cells. This was also indicated by an increase in the frequency of lymphocyte-target conjugates.

Antigens, Differentiation, B-Lymphocyte↗
PubMed1989

Polymeric C3dg primes human B lymphocytes for proliferation induced by anti-IgM.

Polymeric C3dg (pC3dg), having an average m.w. of approximately 400,000 and saturating complement receptor type 2 (CR2) on B lymphoblastoid cells at 1 micrograms/ml, was preincubated with tonsillar B cells for 24 h, after which anti-IgM was added and proliferation assessed by thymidine incorporation. Preculture of B cells with 0.01 to 1.0 micrograms/ml of polymerized C3dg (pC3dg) caused a dose-dependent enhancement of proliferation and accelerated entry into S phase after addition of anti-IgM. The continued presence of pC3dg during stimulation by anti-IgM was not required. pC3dg alone did not induce proliferation and preculture of B cells with C3dg monomer had no effect on the subsequent response to anti-IgM. The priming effect of pC3dg required at least 6 h and was greatest after 24 h of preculture. Preincubation with pC3dg did not lower the concentration of anti-IgM necessary for induction of proliferation, but did enhance proliferation at all concentrations above this threshold. Augmented proliferation occurred only in B cells of higher density in Percoll gradients, and neither T cells nor monocytes were required. Thus, independent interaction of CR2 with its natural ligand primes the B cell for subsequent stimulation through the Ag receptor, an effect that might synergize with the previously described CR2 function of lowering the threshold for B cell activation when crosslinked to membrane IgM.

Antibodies, Anti-Idiotypic↗
PubMed1989

Murine complement receptor gene family. II. Identification and characterization of the murine homolog (Cr2) to human CR2 and its molecular linkage to Crry.

CR2, a 145,000 to 150,000 Mr protein which binds specific breakdown products of C3, has been identified on the surface of both human and murine B cells. In order to understand the evolutionary relatedness of the human and murine proteins, we have used the coding sequences from the human CR2 gene to investigate those homologous sequences of murine Cr2. Human CR2 cDNA sequences were used as probes on a cDNA library derived from BALB/c spleen mRNA to identify cross-reacting cDNA sequences. A number of putative cDNA clones encoding murine Cr2 have been isolated and examined. DNA sequence analysis of these Cr2 cDNA clones indicates that they represent the murine homolog to human CR2. mRNA analysis with these Cr2 cDNA clones has revealed a transcription pattern similar to, but distinct from that seen for CR2. Whereas human CR2 coding sequences identify a single mRNA species of approximately 5 kb from human tonsillar mRNA, the murine counterpart identifies four transcripts from murine spleen of approximately 3, 5, 9 and 11 kb in size. The Cr2 cDNA clones which detect the four forms of spleen mRNA overlap in coding sequences and contain exons mapping to three colinear fragments as defined by EcoRI digestion. This suggests that the 3- 5-, 9-, and 11-kb mRNA forms arise by alternative splicing from a single gene. Use of these murine Cr2-specific cDNA clones to isolate their respective genomic sequences has allowed for the linkage of the 3' end of the Cr2 gene to the 5' end of the Crry gene, the evolutionary homolog to human CR1.

Amino Acid Sequence↗