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PubMed1990

Characterization of murine complement receptor type 2 and its immunological cross-reactivity with type 1 receptor.

We have previously demonstrated that some mAbs prepared against mouse complement receptor type 1 (CR1) bind a 150,000 Mr protein in addition to the 190,000 Mr CR1 protein. We now identify the 150,000 Mr murine protein as complement receptor type 2 (CR2), since: (i) one of the monoclonal antibodies that bind this protein inhibits rosette formation between mouse B cells and C3d-bearing sheep erythrocytes; (ii) as is known for human CR2, this protein is present on B lymphocytes but not T lymphocytes; and (iii) this protein must have affinity for C3b, since it has weak factor I cofactor activity. In addition, this protein resembles the 145,000 Mr human CR2 molecule in size. Since four of the five mAbs that were produced by immunization with CR1 also bound CR2, and they bind to different CR1 epitopes, it seems that murine CR1 and CR2 share multiple epitopes. Injection of mice with one of the CR1-CR2 cross-reactive mAbs almost eliminated both CR1 and CR2 expression, but did not decrease B cell numbers or the expression of B cell IgM, Ia, or B220 antigens. In contrast, injection of mice with a non-cross-reactive anti-CR1 antibody only modulated CR1 expression. These antibodies should thus provide useful tools for the study of the in vivo roles of B cell complement receptors.

Animals↗
PubMed1992

Two modes of homologous C3 deposition on Ramos Burkitt's lymphoma cell substrains co-expressing DAF (CD55), CD59, and CR2 (CD21), and on cells lacking them.

We established decay-accelerating factor (DAF)/CD59-positive and -negative substrains of a human B cell line, Ramos, R(DAF+/CD59+) and R(DAF-/CD59-) respectively. Unexpectedly, treatment of R(DAF+/CD59+) cells with Mg2(+)-EGTA-serum resulted in efficient C3 deposition, while treatment of R(DAF-/CD59-) cells did not. All six substrains of R(DAF-/CD59-) cells were CR2-negative, and treatment of the cells with M177 [a membrane cofactor protein (MCP) cofactor-blocking antibody] and/or acidic buffer only minimally affected the extent of C3 deposition. However, when R(DAF-/CD59-) cells were pretreated with M177 followed by incubation with low conductivity (3 mS) Mg(2+)-EGTA-serum, C3 deposition leading to effective cytolysis was provoked. On the other hand, all seven R(DAF+/CD59+) substrains were CR2-positive and could potentially induce C3 autoactivation without cytolysis under physiological conditions. Both M177 and pH again minimally affected the extent of C3 deposition. However, conductivity altered the sensitivity to C3: at under 3.0 mS, R(DAF+/CD59+) cells became almost insensitive to alternative pathway-mediated C3 deposition. Anti-CR2 partially inhibited C3 deposition on R(DAF+/CD59+) cells and C3 deposition was abrogated on the CR2-lacking R(DAF-/CD59-) cells, suggesting that CR2 was associated with the deposition of C3. These results, together with the finding that fluid phase activation of complement did not enhance C3 deposition, suggest that there are two distinct modes of spontaneous homologous C3 deposition on human lymphoma cells. In one case, CR2 or its related molecules participates in C3 deposition overcoming the protective function of DAF/MCP and this type of C3 deposition is maximized under physiological conditions. In the other case, C3 deposition is induced by another homologous C3 activator that becomes functional under low conductivity conditions and the absence of DAF/MCP. These two modes of homologous alternative pathway activation would explain the reported instances of spontaneous C3 deposition on human B lymphoid cell lines (under physiological conditions in the presence of DAF/MCP) and on paroxysmal nocturnal hemoglobinuria erythrocytes (under low conductivity conditions in the absence of DAF/MCP).

Antigens, CD↗
PubMed1993

Ligand specificities of mouse complement receptor types 1 (CR1) and 2 (CR2) purified from spleen cells.

Murine complement receptor type 2 (MCR2) is homologous to human CR2, whereas murine CR1 (MCR1) is structurally and evolutionary different from human CR1. Since ligand specificities of MCR1 and MCR2 are not completely clarified, we analyzed their functional characteristics to correlate them with structural information obtained in molecular biological studies. MCR1 and MCR2 purified from spleen cells were incubated with thiol-Sepharose bearing murine C3b, iC3b, or C3d in the presence or absence of various anti-MCR1 or -MCR1/MCR2 mAbs. Bound and free MCR1 and MCR2 were quantitated by Western blotting or two-site immunoradiometric assay. MCR2 bound to C3d and iC3b similarly efficiently, and 5-fold less efficiently to C3b. These bindings were completely inhibited by MCR1/MCR2-crossreactive antibodies 7G6 and 4E3. MCR1 bound to C3b efficiently and this was partially inhibited by MCR1-monospecific antibody 8C12, but not by 7G6 and 4E3. Combinations of 8C12 and 7G6 or 4E3 completely inhibited MCR1 binding to C3b. Therefore, two binding sites, one unique to MCR1 and the other shared with MCR2, are involved in MCR1 binding to C3b. MCR1 bound also to C3d and this was completely inhibited by 7G6 and 4E3. The binding of this solubilized MCR1 to C3d was as efficient as that of MCR2 to C3d. It seems, therefore, that the site shared by MCR1 and MCR2 that is recognized by both 7G6 and 4E3 binds to C3d and less efficiently to C3b. These results clarify the ligand specificities of MCR1 and MCR2.

Animals↗
PubMed1993

The CR2/CD19 complex on human B cells contains the src-family kinase Lyn.

The complement receptor 2 (CR2 or CD21) can be found in non-covalent association with the B lymphocyte specific CD19 complex at the surface of mature human B cells. Upon ligation of the B cell antigen receptor complex (BCR), members of the CR2-CD19 complex may associate with membrane immunoglobulin (mlg). Moreover, CD19 and CD21 ligands, either murine mAb, C3d fragments or Epstein-Barr virus, are known to have profound effects on B cell activation. We here show that CD19 is tightly linked to the non-receptor src kinase Lyn and that the CD19 glycoprotein itself serves as a substrate for a yet undefined serine/threonine kinase present within the complex. In the process of antigen recognition, mlg and the CR2-CD19 complex may bind different sites of a complement-opsonized antigenic particle. We hypothesize that in this process, approximation to the BCR allows CD19-associated Lyn kinase to phosphorylate potential substrates within the antigen-receptor complex, thereby effecting its coupling to the intracellular compartment.

Antigens, CD↗
PubMed2004

Antigen localization within the splenic marginal zone restores humoral immune response and IgG class switch in complement C4-deficient mice.

Defects of early complement components (C1, C4 and C2) are associated with the development of systemic lupus erythematosus (SLE). The availability of complement knockout mice has increased our knowledge on the role of complement in the regulation of adaptive immunity. An impaired removal of apoptotic bodies, a disturbed clearance of IgG immune complexes (ICs) and an insufficient B-cell regulation via complement receptors CD21/CD35 have been discussed as explanations for the induction of autoimmunity; however, a unifying hypothesis for the loss of B-cell tolerance in the absence of C1 or C4 is still lacking. Using IgM-containing ICs, we observed a significant accumulation of antigen within the splenic marginal zone (MZ) of C4-deficient mice but not in C3-deficient or complement receptors CD21/CD35-deficient mice. The targeting of antigen toward the MZ restored adaptive immunity (antibody response and class switch) in C4-deficient animals. A new explanation for the association of SLE and complement C4 deficiency would be that in the absence of C4, natural antibodies (IgM type) localize more self-antigen toward the MZ so that the auto-antibody response is increased and autoimmune disease ensues. As such, an inadequate localization of self-antigens might be responsible for the annulment of peripheral B-cell tolerance in the absence of C4.

Animals↗
PubMed2005

Distribution of the chromatin protein DEK distinguishes active and inactive CD21/CR2 gene in pre- and mature B lymphocytes.

DEK is an abundant and ubiquitous chromatin protein that has only recently attracted attention. DEK preferentially binds to cruciform and superhelical DNA and induces positive supercoils into closed circular DNA. It is quite likely therefore that DEK performs an important architectural function in chromatin. However, it is not known how DEK is distributed in chromatin. As the first study of its kind, we investigate the distribution of DEK at the CD21/complement receptor 2 gene regulatory regions in two B lymphocyte lines, namely Ramos, which expresses the CD21 gene, and Nalm-6, which does not. We use a chromatin immunoprecipitation approach and show that DEK appears to be distributed over various regions of the expressed and silent genes, but occurs in 2- to 3-fold higher amounts at a promoter-proximal site of the expressed gene. Moreover, induction of CD21 expression in Nalm-6 cells leads to accumulation of DEK at this site. We propose that the accumulation of DEK is functionally linked to gene expression.

Azacitidine↗
PubMed2005

Targeting antigen to CD19 on B cells efficiently activates T cells.

CD19 is a B cell-surface molecule that participates as an important regulatory signaling complex for antigen bound at the surface by Ig. Triggering of CD19 through its linkage with CD21 amplifies signals transduced through the Src family kinases and modulates B cell differentiation in response to antigen. This study examines the kinetics of antigen uptake and processing of antigen directly targeted to the CD19 protein on purified B cells. We have demonstrated that the antigen internalized within minutes through CD19 forms a cap at the B cell surface and can be found within lysosomes in the cytoplasm in 90 min. B cells acquiring antigen via CD19 express elevated levels of B7-1 and B7-2 co-stimulatory molecules. Moreover, antigen-anti-CD19 complexes administered intravenously bind B cells in vivo and activate antigen-specific T cells more efficiently than non-specific uptake and in a manner similar to antigen taken up through surface IgM on B cells. This work illustrates an important and previously unrecognized mechanism for targeting proteins to B lymphocytes for antigen presentation and activation of CD4 T cells.

Animals↗
PubMed2005

Lack of induced co-stimulation as a result of complement receptor 2 (CR2) ligation on mouse splenic B cells.

B cells act as efficient antigen-presenting cells if they acquire antigen via membrane-bound Ig [termed the B cell receptor (BCR)]. Ligation of the BCR leads to antigen internalization, processing and presentation to CD4+ T cells in association with MHC class II molecules. Ligation of the BCR also leads to the generation of activation signals. One short-term consequence of this is the up-regulation of co-stimulatory molecule expression by the B cell, allowing full T cell activation. Other antigen receptors expressed by B cells can also mediate efficient antigen presentation to CD4+ T cells. Ligating one such receptor, complement receptor 2 (CR2), has also been described to induce co-stimulatory molecule expression. If correct, this may have serious consequences for ensuring the specificity of the resultant B cell response. We have therefore investigated the effects of ligating both the BCR and CR2 independently of each other, as well as with reagents to cross-link the two receptors, in order to clarify these findings. In contrast to the effects seen upon BCR ligation, we find no evidence for co-stimulatory molecule up-regulation following CR2 ligation. As antigen presentation in the absence of co-stimulation may lead to the induction of tolerogenic or regulatory signals being delivered to T cell populations, these findings imply that the role of CR2 in B cell-mediated antigen presentation is different from that of the BCR.

Animals↗
PubMed1996

Complement-binding proteins are strongly expressed by human preimplantation blastocysts and cumulus cells as well as gametes.

Human preimplantation embryos, gametes and cumulus cells were studied for expression of the complement-binding proteins CD46 (membrane cofactor protein), CD55 (decay accelerating factor) and CD59 (membrane attack complex inhibitory factor) as well as complement receptors type 1 (CRI), type 2 (CR2) and type 3 (CR3). Both the CD55 and CD59 glycosyl phosphatidylinositol (GPI)-anchored proteins were expressed by the plasma membrane and zona pellucida of oocytes, early embryos and expanded preimplantation blastocysts; in contrast, CD46 was expressed only on the plasma membrane. Cumulus cells consistently expressed CD46 and, most strongly, CD59 whereas CD55 expression was variable. Monoclonal antibodies (mAbs) to CRI, CR2 and CR3 epitopes gave only occasional reactivity on oocytes and were unreactive with blastocysts, spermatozoa and cumulus cells. CD46 is expressed only on the spermatozoal inner acrosomal membrane, and CD59 on the plasma membrane; CD55 expression was confirmed on the plasma membrane as well as the inner acrosomal membrane. Control mAbs specific for factor H were usually unreactive with gametes, blastocysts and cumulus cells. These data support the concept that gametes and early embryonic cells are protected from complement-mediated attack by expression of CD46, CD55 and CD59, although these complement-binding proteins may have additional roles in reproductive events.

Acrosome↗
PubMed2003

Decreased levels of serum soluble complement receptor-II (CR2/CD21) in patients with rheumatoid arthritis.

OBJECTIVE: The soluble cluster of differentiation 21 (sCD21) represents the extracellular portion of the CD21 glycoprotein and is released by shedding from cell surfaces into plasma. Soluble CD21 binds complement fragments and activates monocytes through binding to membrane CD23. Elevated levels of sCD21 are found during Epstein-Barr virus EBV infections, B-cell lymphoma and other lymphoblastoid tumours. The present study was undertaken to investigate levels of sCD21 in rheumatoid arthritis. METHODS: A specific enzyme-linked immunoassay was developed using sCD21, biochemically purified to homogeneity from human plasma as a standard for the determination of sCD21 concentration in patient sera. Peripheral blood B and T lymphocytes were isolated from healthy donors and rheumatoid arthritis patients and cultured, and supernatants were analysed for CD21 shedding. RESULTS: The normal values of serum sCD21 in healthy individuals between 20 and 40 yr of age ranged from 100 to 477 ng/ml (median 292 ng/ml), decreasing with age but not differing with gender. In rheumatoid arthritis patients, sCD21 levels ranged from 50 to 300 ng/ml (median 182 ng/ml), did not differ with age and were independent of rheumatoid factor. CONCLUSIONS: In contrast to healthy donors, patients with rheumatoid arthritis have significantly lower sCD21 levels (P < 0.0001), independently of the age of the patients. Sorted B cells from rheumatoid arthritis patients released amounts of CD21 comparable with those of normal controls. Possible causes and consequences of the findings are discussed.

Adolescent↗
PubMed2006

Lymphoid neogenesis in juvenile idiopathic arthritis correlates with ANA positivity and plasma cells infiltration.

OBJECTIVE: The aim of the study was to evaluate the pattern of the lymphoid organization in the synovial tissue of patients affected with juvenile idiopathic arthritis (JIA). METHODS: A total of 40 JIA patients who underwent synoviectomy or synovial biopsies were enrolled. The mean age at surgery was 15.1 yrs (range 6-30 yrs) and the mean disease duration was 6.7 yrs (range 3 months to 22.2 yrs). Tissue specimens were grouped according to the following criteria: (i) diffuse perivascular infiltrate without lymphoid organization, (ii) T cell-B cell aggregates with or without germinal centre reaction. RESULTS: Synovial tissues from 12 JIA patients did not show any sign of lymphoid organization, whereas 28 patients displayed a variable number of T-B cell aggregates. Typical features consistent with a germinal centre reaction were present in two JIA patients only. Lymphoid organization in JIA patients did not correlate with the duration and severity of the disease or with the degree of synovial inflammation, but did positively correlate with the presence of anti-nuclear antibodies. Moreover, a diffuse lymphocyte infiltration was significantly related to the presence of an acute phase of inflammation and the presence of lymphoid aggregates correlated with the degree of plasma cells infiltration. CONCLUSIONS: Lymphoid neogenesis in JIA represents a phase in the immunopathological process that characterize the development of inflammatory synovitis. It is not related to disease activity or severity, but appears to be more frequent in patients with circulating anti-nuclear antibodies.

Acute Disease↗
PubMed1999

Epstein-Barr virus envelope glycoprotein gp350 induces NF-kappaB activation and IL-1beta synthesis in human monocytes-macrophages involving PKC and PI3-K.

Epstein-Barr virus (EBV) is a highly immunotropic human herpesvirus with oncogenic potential and is involved in numerous pathologies. EBV utilizes its major envelope glycoprotein gp350 to bind to its receptor CR2/CD21 on target cells for initiating the infection. We have previously shown that EBV is able to modulate transcription and translation of a number of cytokine genes via its gp350-mediated binding to this receptor. However, the effects of the binding of purified gp350 to CR2/CD21 on plastic-adherent monocyte-macrophages (AMM) have not been investigated. These cells are a rich source of potent proinflammatory and immune-modulating cytokines, and express low levels of CR2/CD21. We show here for the first time that recombinant gp350 (rgp350) causes production of the potent proinflammatory cytokine IL-1beta in human AMM. Surprisingly, rgp350 is comparable in this capacity to the phorbol ester 12-0-tetradecanoylphorbol 13-acetate. This induction of IL-1beta production was accompanied by increased steady-state levels of its mRNA in gp350-treated AMM, and was dependent on the specific binding of rgp350 to the EBV receptor CR2/CD21. We also show that the signaling pathways resulting in the induction of IL-1beta synthesis by rgp350 required protein kinase C and phosphatidylinositol 3,4,5 triphosphate kinase activities and occurred via activation of the NF-kappaB family of transcription factors.-D'Addario, M., Ahmad, A., Xu, J. W., Menezes, J. Epstein-Barr virus envelope glycoprotein gp350 induces NF-kappaB activation and IL-1beta synthesis in human monocytes-macrophages involving PKC and PI3-K.

Antibodies, Monoclonal↗
PubMed1996

Inflammatory pseudotumor of the liver. Evidence for follicular dendritic reticulum cell proliferation associated with clonal Epstein-Barr virus.

We describe an "inflammatory pseudotumor" of the liver that, which on detailed investigation, proved that the spindle-cell component of this lesion is derived from follicular dendritic reticulum cells (FDRC). This contention is supported by morphologic observations and by immunophenotype. The FDRC population contain Epstein-Barr virus (EBV). It is known that FDRC express the EBV receptor CD21. In this particular case, the FDRC contained clonal EBV genomes, EBV RNA (EBER) transcripts, and expressed EBV latent membrane protein (LMP1). DNA sequencing of PCR products showed three point mutations compared with the standard LMP1 sequence of the EBV strain B95-8. The findings in this case corroborate those of other investigators concerning the possible role of EBV in the development of some inflammatory pseudotumors, including the recent production of functionally active EBV-transformed FDRC-like cell lines. This association could prove instructive in delineating the histogenesis of these tumors and further assist in making prognostic and therapeutic decisions.

Aged↗
PubMed1997

Lymph node involvement by splenic marginal zone lymphoma: morphological and immunohistochemical features.

Splenic marginal zone lymphoma (SMZL) has recently been proposed as a distinctive type of low-grade B-cell lymphoma. Although there is general agreement that this entity exists, its precise definition is blurred by uncertainty in differential diagnosis from other low-grade B-cell lymphomas. There is even more uncertainty as to the histology of splenic hilar and peripheral lymph nodes involved by SMZL. We therefore reviewed the histological and immunohistochemical features of 19 of these lymph nodes (14 hilar and five peripheral) from 14 cases of classical SMZL and compared them with the features of lymph nodes involved by other B-cell lymphomas. The morphology and immunohistology of the lymph nodes resemble those found in the white pulp of the spleen, showing a distinctive pattern, different from that which is observed in other B-cell lymphomas. In these cases, the overall architecture of the lymph nodes is effaced and replaced by a nodular infiltrate, although the sinuses are preserved in most hilar lymph nodes. Some of the nodules contain a central reactive follicular center, around which there is a broad zone of small lymphocytes. In other cases, the central area is partially infiltrated or, more commonly, totally replaced by these small lymphocytes, which in the periphery of the nodules showed a pale, slightly larger cytoplasm. Scattered nucleolated blasts are present, largely confined to the periphery of the nodules. The tumoral cells express immunoglobulin (Ig)D, IgM, and Ig light chain restriction and show a low proliferation fraction. These findings confirm that SMZL is a real entity, and not merely a morphological pattern of splenic infiltration by different types of low-grade B-cell lymphoma.

Adult↗
PubMed1997

Angiomyoid and follicular dendritic cell proliferative lesions in Castleman's disease of hyaline-vascular type: a study of 10 cases.

Castleman's disease of hyaline-vascular type (HV CD) may rarely be associated with a confusing variety of stromal cell overgrowths and neoplasms. We report here on the pathologic and clinical findings of 10 such cases. In addition to the usual complex histoimmunophenotype of the stroma of HV CD and some unusual features that mimicked neoplasms, we observed focal proliferations of angiomyoid (five cases) and follicular dendritic cell type (five cases). The former were nonneoplastic growths featuring compact tangles of spindle cells, exhibiting immunoreactivity for smooth muscle actin and interpreted as vessel-related pericytes and myoid cells. The latter were neoplastic growths of oval to spindle cells intermixed with lymphocytes; the tumor cells grew in long, intersecting bundles, featured various degree of atypia, and expressed the markers of follicular dendritic cells (CD21, CD35, KiM4p). The two types were clinically distinct. Four of five patients with angiomyoid proliferations were young women, who presented with an abdominal mass and were cured by surgery; that is, they had a clinical profile similar to that of patients with the stroma-rich variant of HV CD. The follicular dendritic cell proliferations were in older patients of either gender presenting with masses at various sites, recapitulating the profile of follicular dendritic cell tumors arising independently from HV CD; in three patients with long-term follow-up, recurrences or metastases developed at various intervals from the initial diagnosis (1 1/6, 3 1/2, and 11 years), and one patient died as a result. This study confirms the potential for, and the variety of, stromal cell proliferations in HV CD. Because their biologic behavior differs, correct identification of these various proliferative lesions is clinically important.

Actins↗
PubMed1998

Angioimmunoblastic lymphoma (AILD-type T-cell lymphoma) with hyperplastic germinal centers.

Angioimmunoblastic T-cell lymphoma (or angioimmunoblastic lymphadenopathy with dysgammaglobulinemia [AILD]) was originally considered to be an abnormal immune reaction in which reactive follicles with germinal centers (GCs) are usually absent. When hyperplastic GCs are present along with an angioimmunoblastic reaction, the lesion has been interpreted as a benign hyperimmune reaction. We report seven patients with angioimmunoblastic T-cell lymphoma (AITL) who initially had hyperplastic GCs, shown to be malignant lymphoma by further studies and clinical follow-up. Clonal T-cell populations were observed in all specimens evaluated, and sequential biopsies showed histologic progression to typical AITL in two patients. Clinical presentation was characterized by generalized lymphadenopathy of acute onset, constitutional symptoms, hepatosplenomegaly, skin rash, and polyclonal hypergammaglobulinemia in five patients; regional adenopathy preceded generalized adenopathy in two patients. Five patients had rapid progression of disease, and three patients whose treatment was delayed due to inadequate evidence to diagnose lymphoma died of infection. The initial biopsy findings of each patient were similar and showed angioimmunoblastic proliferation, hyperplastic GCs with ill-defined borders, and interfollicular tingible-body macrophages. These GCs differed from occasional residual follicles of typical AITL in that the GCs were enlarged and hyperplasia of follicular dendritic cells was not seen. Diagnostic clear cells were not observed. Apoptotic bodies were markedly increased and bcl-2+ lymphocytes were sparse compared with typical AITL. Results of in situ hybridization for Epstein-Barr virus were positive in each case. We conclude that hyperplastic germinal centers with ill-defined borders and frequent interfollicular tingible-body macrophages occur in a histologic variant of AITL that is necessary to recognize for early diagnosis and treatment.

Adult↗
PubMed1998

Multiple leiomyosarcomas of both donor and recipient origin arising in a heart-lung transplant patient.

The occurrence of Epstein-Barr virus-associated smooth-muscle tumors in immunocompromised patients has been reported, particularly in the pediatric population. In posttransplantation tumors, the tissue of origin has been either donor or recipient. Mixed-genotype sarcomas within the same patient have not yet been reported. We describe the occurrence of multiple leiomyosarcomas of both donor (arising in the lung allograft) and recipient (arising in the host liver) origin in a 15-year-old boy 3 years after heart-lung transplantation. Analysis of premortem lung tumors demonstrated the presence of Epstein-Barr virus DNA. Despite decreasing immunosuppression and commencing acyclovir, the patient died of systemic Pseudomonas infection. Immunohistochemical analysis revealed that both lung and liver tumors were negative for the Epstein-Barr virus receptor (CD21), and suggests that Epstein-Barr virus entry into the cells was not via this receptor but via an alternate mechanism such as cell fusion.

Adolescent↗