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At least 667 records · Page 37Linked to original sources
PubMed1999

Epstein-Barr virus infection of renal proximal tubule cells: possible role in chronic interstitial nephritis.

Chronic interstitial nephritis frequently accompanies renal diseases of different etiologies. Far less common is the entity of primary interstitial nephritis wherein the glomerular and vascular structures of the kidney are not the primary focus of the disease process. Using in situ hybridization and the polymerase chain reaction, we detected DNA from the Epstein-Barr Virus (EBV) exclusively in renal tissue of patients with the idiopathic variety of chronic interstitial nephritis. The EBV genome, but not that of cytomegalovirus or adenovirus, was detected primarily in renal proximal tubule cells. Furthermore, the CD21 antigen, which serves as the receptor for EBV in B lymphocytes, was detected by immunocytochemistry primarily on proximal tubule cells and was markedly upregulated in the EBV-infected tissue. Western blot analysis of primary cultures of normal proximal tubule cells identified a 140-kDa protein, confirming the expression of the CD21 antigen. Colocalization experiments using proximal and distal tubule markers confirmed that EBV DNA and the CD21 antigen are found primarily in proximal tubule cells. EBV infection of renal proximal tubular cells may participate in evoking a cellular immune response that results in a damaged renal interstitium.

Adult↗
PubMed1995

Immunohistological detection of gap junctions in human lymphoid tissue: connexin43 in follicular dendritic and lymphoendothelial cells.

We investigated the expression of gap junction connexins26, -32, and -43 in normal, reactive, and diseased human lymphoid tissue with single and double immunolabeling and confocal laser scanning microscopy. In all tissues, connexin43 positivity was detected in follicular dendritic cells positive for CD21 and CD35 antigens, around lymphoendothelial cells moderately positive for Factor VIII, CD31 and cathepsin-D antigens; and somewhat in vascular endothelia including high endothelial venules strongly positive for Factor VIII and CD31 antigens. The ultrastructural hallmark of gap junctions, pentalaminar structures with appropriate spacing, was found in follicular dendritic cell processes. Connexin43 was also detected between smooth muscle and stromal cells of the gut, in capsular fibroblasts, and in tonsil epithelium. Neither connexin32 nor -26 was revealed, except for connexin26 in the tonsil epithelium. In follicular dendritic cells, connexin43 co-localized closely with the desmosomal proteins desmoplakin and desmoglein, suggesting that cell adherence has a role in gap junction formation. Most connexin43 was observed in sinus lining cells of lymph nodes involved in malignancies and in follicular dendritic cells in the light zone of germinal centers where maturing but still proliferating lymphocytes are situated. In the light of their distribution, gap junctions may play a part in regulating the growth of germinal centers and in integrating activating or controlling signals in follicular dendritic and sinus lining cell networks. Because connexin43 is the connexin of stromal cells, finding it in follicular dendritic cells in consistent with the proposal that these cells originate from resident stromal cells.

Animals↗
PubMed2006

B-cell extrinsic CR1/CR2 promotes natural antibody production and tolerance induction of anti-alphaGAL-producing B-1 cells.

B-1b cells produce IgM natural antibodies against alpha1-3Galbeta1-4GlcNAc (alphaGal). These can be tolerized by nonmyeloablative induction of mixed chimerism using alphaGal-positive (alphaGal+) donor marrow. We assessed the role of CR1/2 in this model for induction of tolerance of B-1b cells. Mixed hematopoietic chimerism was induced in alpha1-3galactosyltransferase (GalT-/-) and GalT-/-Cr2-/- mice with alphaGal+ BALB/c marrow donors. Anti-alphaGal Ab and anti-alphaGal Ab-producing B cells became undetectable in GalT-/- chimeras, whereas they persisted in chimeric GalT-/-Cr2-/- mice. To determine whether CR1/2 expression on stromal cells and/or hematopoietic cells was critical for B-1-cell tolerance, we generated GalT-/- radiation chimeras in which CR1/CR2 was expressed on either stromal cells, hematopoietic cells, neither, or both. After induction of mixed chimerism from alphaGal+ allogeneic bone marrow (BM) donors, anti-alphaGal-producing B cells were rendered tolerant in reconstituted recipients expressing only stromal CR1/CR2. Our results suggest a possible role for follicular dendritic cells that pick up immune complexes via CR1/CR2 receptors in the tolerization of B-1b cells.

Animals↗
PubMed2002

Tyrosine phosphorylation of B-cell adaptor for phosphoinositide 3-kinase is required for Akt activation in response to CD19 engagement.

CD19 is a coreceptor that amplifies signaling initiated by antigen cross-linking of the B-cell antigen receptor (BCR). CD19 can also signal independently of BCR coligation. This study shows that B-cell adaptor for phosphoinositide 3-kinase (BCAP), previously characterized as a substrate of the tyrosine kinases upon BCR engagement, is phosphorylated by cross-linking of CD19. Tyrosine phosphorylation of BCAP, mediated by Lyn, provides binding site(s) for phosphoinositide 3-kinase (PI3K), thereby participating in Akt activation. Thus, these results provide evidence that BCAP serves as an adaptor molecule for CD19 to activate the PI3K pathway in B cells.

Amino Acid Motifs↗
PubMed2002

Engagement of complement receptor 2 on the surface of B cells from patients with systemic lupus erythematosus contributes to the increased responsiveness to antigen stimulation.

B cells from patients with systemic lupus erythematosus (SLE) display increased responses following cross-linking of the surface antigen receptor. We explored the possibility that the increased responses are at least partially due to simultaneous cross-linking of the complement receptor 2 (CR2). To this end, we stimulated fresh B cells from SLE patients with an anti-IgD antibody conjugated to the Epstein-Barr virus gp350 protein, which binds to CR2, and recorded the free intracytoplasmic calcium response during the first 10 min. Despite the fact that SLE B cells were found to express half as many surface CR2 as normal B cells, both peak responses and the percentage of responding cells were significantly increased in the former. These observations suggest that regulatory molecules such as CR2 are involved in the increased B cell responses in SLE patients. We propose that certain immune complexes that circulate in the sera of SLE patients that have anti-surface immunoglobulin specificities and are decorated with natural ligands of CR2, such as C3d, elicit and promote B cell overactivity.

Adult↗
PubMed2006

Prognostic impact of germinal center-associated proteins and chromosomal breakpoints in poor-risk diffuse large B-cell lymphoma.

PURPOSE: Outcome of diffuse large B-cell lymphoma (DLBCL) with a germinal center B-cell (GCB) expression profile is superior to that of non-GCB DLBCL. This conclusion is mainly derived from patients with mixed international prognostic index (IPI) risk profiles treated with CHOP-like therapy (cyclophosphamide, doxorubicin, vincristine, and prednisone). We wondered whether the prognostic impact of the expression profile would hold out in a homogeneous cohort of poor-risk DLBCL patients treated with high-dose sequential therapy (HDT) and autologous stem-cell transplantation (ASCT) as first-line therapy. PATIENTS AND METHODS: DLBCL from 66 newly diagnosed poor-risk patients, treated in two sequential prospective Dutch Hemato-Oncology Association (HOVON) trials, were studied retrospectively for expression of CD10, bcl6, MUM1/IRF4, bcl2, Ki67, and CD21+ follicular dendritic cells (FDC) by immunohistochemistry, and for the breakpoints of BCL2, BCL6, and MYC by fluorescent in situ hybridization (FISH). Lymphomas with any follicular component were excluded. RESULTS: A GCB immunophenotype profile was found in 58% and non-GCB immunophenotype profile in 42% of the tumors. Clinical characteristics of both groups were similar. Complete response (CR) rate was higher in patients with CD10+ tumors (58% v 30%; P = .03). A GCB immunophenotype profile, its constituting markers CD10 more than 30% and MUM1 less than 70%, and bcl2 less than 10% were each associated with a better overall survival (OS). FDC networks, equally present in GCB and non-GCB tumors, had superior CR (73% v 31%; P = .01), but disease-free survival rates were lower and there was no difference in OS rates. None of the breakpoints had a prognostic impact on outcome. CONCLUSION: Also in patients with poor-risk DLBCL treated with HDT and ASCT, the GCB immunophenotype and bcl2 expression retained a major impact on survival.

Adolescent↗
PubMed2004

EBV attachment stimulates FHOS/FHOD1 redistribution and co-aggregation with CD21: formin interactions with the cytoplasmic domain of human CD21.

CD21 is a multifunctional receptor for Epstein-Barr virus (EBV), for C3dg and for CD23. Upon engagement of immune complexes CD21 modulates immunoreceptor signaling, linking innate and adaptive immune responses. The mechanisms enabling CD21 to independently relay information between the exterior and interior of the cell, however, remain unresolved. We show that formin homologue overexpressed in spleen (FHOS/FHOD1) binds the cytoplasmic domain of human CD21 through its C terminus. When expressed in cells, EGFP-FHOS localizes to the cytoplasm and accumulates with actin in membrane protrusions. Plasma membrane aggregation, redistribution and co-localization of both proteins are stimulated when EBV (ligand) binds CD21. Though widely expressed, FHOS RNA is most abundant in the littoral cell, a major constituent of the red pulp of human spleen believed to function in antigen filtration. Formins are molecular scaffolds that nucleate actin by a pathway distinct from Arp2/3 complex, linking signal transduction to actin reorganization and gene transcription. Thus, ligand stimulation of FHOS-CD21 interaction may transmit signals through promotion of cytoskeletal rearrangement. Moreover, formin recruitment to sites of actin assembly initiated by immunoreceptors could be a general mechanism whereby co-receptors such as CD21 modulate intracellular signaling.

3T3 Cells↗
PubMed2006

Redox regulation of CD21 shedding involves signaling via PKC and indicates the formation of a juxtamembrane stalk.

Soluble CD21 (sCD21), released from the plasma membrane by proteolytic cleavage (shedding) of its extracellular domain (ectodomain) blocks B cell/follicular dendritic cell interaction and activates monocytes. We show here that both serine- and metalloproteases are involved in CD21 shedding. Using the oxidant pervanadate to mimic B cell receptor activation and thiol antioxidants such as N-acetylcysteine (NAC) and glutathione (GSH) we show that CD21 shedding is a redox-regulated process inducible by oxidation presumably through activation of a tyrosine kinase-mediated signal pathway involving protein kinase C (PKC), and by reducing agents that either directly activate the metalloprotease and/or modify intramolecular disulfide bridges within CD21 and thereby facilitate access to the cleavage site. Lack of short consensus repeat 16 (SCR16) abolishes CD21 shedding, and opening of the disulfide bridge between cys-2 (Cys941) and cys-4 (Cys968) of SCR16 is a prerequisite for CD21 shedding. Replacing these cysteines with selenocysteines (thereby changing the redox potential from -180 to -381 mV) results in a loss of inducible CD21 shedding, and removing this bridge by exchanging these cysteines with methionines increases CD21 shedding.

Amino Acid Sequence↗
PubMed2001

Ontogeny of pig discrete Peyer's patches: expression of surface antigens.

Leukocyte populations present in the discrete Peyer's patches (PP) of the pig were characterized from birth (Day 0) to day 35 after birth by immunohistochemistry and image analysis. Immediately after birth, cell membrane expression of CD2 and CD3, major histocompatibilty complex (MHC) class 11 (both SLA (swine leukocyte antigen) -DQ+ and SLA-DR+), CD21, 74-22-15 and surface immunoglobulin (sIg) were all demonstrable. Computer assisted morphometric techniques were used to confirm the significant expansion of these cell populations from birth onwards. The distribution of the cell types was not random but suggested a preferential retention of cells at specific sites. This implies a degree of organization of immunological cells within the discrete PP, enhancing the potential to mount immune responses in the most efficient manner.

Animals↗
PubMed2001

Inhibiting the complement system does not reduce injury in renal ischemia reperfusion.

The complex pathogenesis of ischemia reperfusion injury (IRI) includes endothelial expression of adhesion molecules, leukocyte recruitment and activation, reactive oxygen species production, and apoptotic and necrotic cell death. A role for complement in IRI of different organs, including kidney, has been proposed on the basis of results of experiments that used pharmacologic inhibitors as well as animals that were deficient in individual complement proteins. Here, renal IRI in mice was examined. Animals that were deficient in C3 had partial protection from IRI induced by 27.5 min of bilateral renal ischemia, followed by 20 h of reperfusion (blood urea nitrogen [BUN] values, 46.6 +/- 6.9 and 68.4 +/- 7.9 mg/dl in C3 -/- and C3 +/+ mice; n = 7 and 8, respectively; P = 0.033). Given the reduction in IRI in C3 -/- mice, it was investigated, by use of the rodent C3 convertase inhibitor CR1-related gene/protein y-Ig (Crry-Ig), whether exogenous administration of a complement inhibitor could lessen renal injury. Despite the use of Crry-Ig in high doses, there was no significant reduction of injury induced by 20 to 30 min of ischemia followed by up to 30 h of reperfusion. Histologic examination revealed acute tubular necrosis and neutrophilic infiltration, both of which correlated significantly with BUN values (P < 0.001). Of interest, C3 deposition around renal tubules was significantly less in animals with IRI, compared with that in unmanipulated controls (P < 0.001). In Crry-Ig-treated animals, C3 deposition was inversely proportional to BUN values (r = -0.63; P < 0.001), which presumably indicates that severe vascular IRI allowed access of the 160 kD Crry-Ig to the interstitium. Thus, renal IRI in mice may have a partial complement dependence, yet pharmacologic inhibition of the complement system does not seem to be effective, likely because of the presence of other mediator systems that operate in parallel.

Animals↗
PubMed2005

Immunological effects of refolded human soluble BAFF synthesized in Escherichia coli on murine B lymphocytes in vitro and in vivo.

The B cell activating factor of the TNF family (BAFF, also known as BLyS, TALL-1, THANK, and zTNF4) is an important survival factor for B lymphocytes. Our previous study has demonstrated that the final purified material of human soluble BAFF (refolded hsBAFF) synthesized in Escherichia coli is biologically active in a validated induced human B lymphocyte proliferation bioassay. In this study, the administration of refolded hsBAFF to isolated mouse B lymphocytes and mice was carried out to study the immunological effects of hsBAFF on in vitro and in vivo B lymphocytes. The results showed that splenic B lymphocyte proliferation significantly increased after hsBAFF administration (in vitro 1, 2, 3, 5 microg/ml and in vivo 0.01, 0.5, 1.0 mg/kg body mass). An oppositely elevated immune response of B lymphocyte to LPS stimulation after hsBAFF administration (1, 2.5, 5 microg/ml) and a significantly elevated change after treatment with hsBAFF and costimulation with anti-IgM (2.5 microg/ml) was observed in vitro, respectively. A similar change existed also in hsBAFF-treated mice on the 8th postexperiment day, but the value with anti-IgM alone didn't increase compared to normal control in vitro. We found that the treatment of mice with hsBAFF resulted in a developmental maturation of T1 B lymphocytes to T2 and mature B lymphocytes by detecting distributions of splenic CD21(lo) with CD45R/B220(+) and CD21(hi) with CD45R/B220(+) subsets. These results suggest that the refolded hsBAFF synthesized in Escherichia coli may enhance immune responses in the body by regulating the proliferation, differentiation, and immune response of B lymphocytes.

Animals↗
PubMed2003

Regulation of B-cell activation by complement receptors CD21 and CD35.

The role of complement in the development and regulation of antibody responses under both healthy and pathological conditions is known for long. Unraveling the elements involved and the molecular mechanisms underlying the events however is still in progress. This review focuses on the role of complement receptors CR1 (CD35) and CR2 (CD21) expressed on B lymphocytes, which interact with ligands generated upon activation of component C3, the major protein of the complement cascade. The binding and possible effects of immune complexes comprising antigen, antibody and complement on B-cell activation are discussed. Results of clinical studies of autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis and conclusions drawn from animal models used to investigate various aspects of human diseases are also debated. We discuss similarities regarding the overall structure and certain functions of complement and complement receptors in mice and men however, call the attention to major differences regarding tissue distribution and their role in B-cell functions.

Animals↗
PubMed2002

Complement receptors in HIV infection.

Similar to other pathogens, HIV can directly activate the complement pathway even in the absence of antibodies. During and after seroconversion, HIV-specific antibodies enhance the activation of complement and increase deposition of complement fragments on virions dramatically. However, even in the presence of HIV-specific antibodies, no or only poor lysis occurs. HIV has adapted different protection mechanisms to keep complement activation under the threshold necessary to induce virolysis. In addition to its own envelope proteins, the viral envelope contains membrane-anchored host molecules. Among those are complement regulatory proteins that remain functionally active on the surface of HIV and turn down the complement cascade. In addition, serum proteins with complement regulatory activities become secondarily attached onto the virus, thereby enhancing the protection of HIV against complement-mediated damage. Therefore, opsonised virions accumulate in HIV-infected individuals, which subsequently interact with complement receptor (CR) expressing cells. This review is mainly focused on these interactions, which result either in infection of CR-positive cells with high efficiency, or retention of viral particles on their surface via CRs, thereby promoting transmission of virus to other permissive cells.

Animals↗
PubMed1997

Evolution of AIDS and AIDS related malignancies in pediatric patients in the United States.

The pediatric AIDS epidemic began in the U.S.A. between 1983 and 1985. Hemophilia patients were among the first victims of this disease with the majority of these patients infected prior to 1984. At the South Texas Hemophilia Center 69 of 108 patients less than 21 years of age demonstrated serologic evidence of infection. Of these patients, 6 subsequently developed malignancies between 1987 and 1994. Between 1992 and 1996 data was subsequently accumulated on the development of malignancy in HIV positive patients through the Pediatric Oncology Group, which to date has enrolled 24 HIV positive children with malignancy. In these studies the majority of patients had B cell, non-Hodgkin's lymphomas, however approximately 20% of the patients were identified with leiomyosarcomas. Histologic studies of tumors of 6 children with AIDS and leiomyosarcomas or leiomyoma identified the EBV receptor or CD 21 in the tumor using immunoperoxidase techniques, whereas similar staining was not seen in smooth muscle tumors from HIV negative children. In situ hybridization techniques identified EBV-EBER probe in the tumors from HIV positive patients. In 2 patients with adequate tumor tissue EBV genome was present in high concentration using PCR techniques and Southern blot studies showed a monoclonal and biclonal proliferation. Other laboratories have reported similar EBV findings in lymphomas from AIDS patients. Thus EBV appears to be an important cofactor in development of malignancy in pediatric AIDS patients.

AIDS-Related Opportunistic Infections↗
PubMed1991

Expression of functional human Epstein-Barr virus/C3d receptor ([CR2] CD21) on insulinoma cell line. Induction of tumor rejection but not diabetes in syngeneic rats.

We stably expressed human complement receptor 2 ([CR2] CD21 C3d/Epstein-Barr virus [EBV] receptor) on the rat insulinoma cell line RINm5F with a recombinant retroviral vector. CR2-expressing RINm5F cells secreted 78-33% less insulin than parental cells or cells transduced with an antisense vector and could be infected with high-titer EBV. We tested whether human CR2 expression on RINm5F cells would affect tumorigenesis after transplantation to syngeneic New England Deaconess Hospital rats. Non-CR2-expressing antisense-transduced RINm5F cells rapidly grew tumors and caused hypoglycemia, hyperinsulinemia, and the death of the animals after 15.7 +/- 0.7 days. CR2-expressing RINm5F cells were infiltrated by mononuclear cells at an early stage and eventually caused noninfiltrated tumors and the death of the animals after 33.0 +/- 0.4 days. These tumors were CR2- and are believed to have arisen from a minor CR2- population of tumor cells. The pancreatic islets were histologically normal at all time points. We conclude that expression of a xenoantigen on a rat insulinoma cell line induces an immune response in syngeneic rats but does not result in breakage of tolerance to parental or revertant cells.

Animals↗
PubMed1997

Rejection of islets differing by a single antigen is dependent on donor MHC.

To study the effect of expression of a single foreign antigen on the outcome of otherwise compatible mouse islet grafts, we have used transgenic mice expressing the human complement receptor 2 (CR2, CD21, C3d/EBV receptor) on their pancreatic beta-cells (RIP-CR2 mice). Donors were RIP-CR2 mice, typed at the major histocompatibility complex (MHC) as H-2(k), H-2(b), or H-2(bxk), and recipients were streptozotocin-treated nontransgenic B6 x CBA F1 mice (H-2(bxk)). H-2(b) or H-2(bxk) CR2-expressing islets were not rejected (mean survival time [MST] >100 days) but induced a peri-insulitis and an antibody response to CR2. In contrast, H-2(k) CR2-expressing islets were rejected in 80% of the cases with a MST of 65 +/- 23 days and were massively infiltrated by a destructive insulitis. In both cases, the infiltrate was mainly made of CD4+ cells, with few CD8+ cells. The isotype of IgG antibody response to CR2 was studied: recipients of H-2(k) grafts had a predominantly IgG1 response, while recipients of H-2(b) grafts had a balanced IgG2a and IgG1 response. To further evaluate the mechanism of differential rejection of the two types of grafts, recipients were immunized with CR2-expressing rat insulinoma cells before transplantation. Preimmunization with CR2 did not affect the outcome of H-2(b) grafts but greatly accelerated the rejection of H-2(k) grafts. These experiments indicate that expression of a single foreign antigen on beta-cells triggers an immune response leading to rejection or to peri-insulitis, depending on the MHC of donor islets.

Animals↗
PubMed2006

Complement plays an important role in spinal cord injury and represents a therapeutic target for improving recovery following trauma.

Initiation of an inflammatory cascade following traumatic spinal cord injury (SCI) is thought to cause secondary injury and to adversely impact functional recovery, although the mechanisms involved are not well defined. We report on the dynamics of complement activation and deposition in the mouse spinal cord following traumatic injury, the role of complement in the development of SCI, and the characterization of a novel targeted complement inhibitor. Following traumatic injury, mice deficient in C3 had a significantly improved locomotor score when compared with wild-type controls, and analysis of their spinal cords revealed significantly more tissue sparing, with significantly less necrosis, demyelination, and neutrophil infiltration. Wild-type mice were also treated with CR2-Crry, a novel inhibitor of complement activation that targets to sites of C3 deposition. A single intravenous injection of CR2-Crry 1 hour after traumatic injury improved functional outcome and pathology to an extent similar to that seen in C3-deficient animals. CR2-Crry specifically targeted to the injured spinal cord in a distribution pattern corresponding to that seen for deposited C3. As immunosuppression is undesirable in patients following SCI, targeted CR2-Crry may provide appropriate bioavailability to treat SCI at a dose that does not significantly affect systemic levels of serum complement activity.

Animals↗
PubMed1987

Induction of differentiation of African Burkitt's lymphoma cells by phorbol ester: possible relation with early B cells.

The phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA) was used to examine the phenotypic changes in three African Burkitt's lymphoma cell lines, P3HR1, Daudi, and Raji. Cells were cultured with a nanogram concentration of TPA for up to seven days and then analyzed by flow cytometry and an immunoperoxidase staining method. The cells were stained with a panel of monoclonal antibodies reactive with B lymphocytes or B cell leukemia/lymphomas, and an antibody to the enzyme terminal deoxynucleotidyl transferase (Tdt). All three cell lines were found to express more HLA-linked DC/DS (Leu 10) antigen, while demonstrating a concomitant decrease in the expression of common acute lymphoblastic leukemia antigen (CALLA) and terminal deoxynucleotidyl transferase after TPA induction. The other antigens including Ig, BA1, BA2, Tac, Leu 8, Leu 1, C3bR, Leu 12, and Leu M5 showed no significant changes. The marker expression and differentiation pattern of these African Burkitt's lymphoma lines are very similar to those of pre-B cells except for the surface IgM expression observed in Daudi cells. The expression of CALLA and Tdt in African Burkitt's lymphoma is probably not the result of an Epstein-Barr virus infection, but may in fact reflect the true nature or origin of tumor cells. We conclude that African Burkitt's lymphoma cells are derived from an early stage of B-cell differentiation closely related to, but more mature than pre-B cells.

Antigens, Neoplasm↗