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E S Raveche

Publications and source records attributed to E S Raveche.

At least 19 recordsLinked to original sources
PubMed2001

The role of B-cell-specific activator protein in the response of malignant B-1 cells to LPS.

Chronic lymphocytic leukemia (CLL) results from the uncontrolled proliferation and accumulation of B-1 cells, many of which demonstrate self-reactivity. The response of B-1 cells to mitogen after undergoing malignant transformation is still unclear. Using our established malignant B-1 cell lines derived from the NZB murine model of human CLL, we investigated the response of malignant B-1 cells to the mitogen LPS. Interestingly, these malignant B-1 cells proliferated initially, but the proliferation rate decreased after a 48-h transition. Prolonged LPS treatment induced apoptosis and pathological differentiation. We studied possible underlying molecular mechanisms and found that the level of the DNA binding protein BSAP (B-cell-specific activator protein) was upregulated by LPS at the initial activation stage, followed by an increase in the apoptotic factor caspase-3 (CPP32) at 48 h and a subsequent decrease of BSAP at 72 h. The pathological differentiation induced by LPS was partially prevented by treatment with antisense BSAP. This study indicates that malignant B-1 cells could be driven to apoptosis and pathological differentiation when activated by the mitogen LPS, and BSAP may be an important factor in regulating these responses.

Animals↗
PubMed2001

The growth-regulatory role of B-cell-specific activator protein in NZB malignant B-1 cells.

The transcription factor B-cell-specific activator protein (BSAP) plays an important role in B-cell development. We explored the involvement of BSAP in the growth regulation of malignant B-1 cells derived from the NZB murine model of human chronic lymphocytic leukemia. BSAP protein was found in normal B-2 cells, elevated in normal B-1 cells, and highest in NZB malignant B-1 cells. When these malignant B-1 cells were treated with antisense oligonucleotides for BSAP, their growth was inhibited with a G2/M phase arrest. In contrast, B cell lines that did not appear to be of B-1 origin (IgG+/B220+/BSAPlow) were unaffected by treatment with antisense BSAP oligonucleotides. Centrifugal elutriation experiments showed that BSAP mRNA was expressed at the highest levels in the G2/M phases in malignant B-1 cells. Treatment with demecolcine (Colcemid), a known mitotic blocker, resulted in a decrease in the level of BSAP gene expression in malignant B-1 cells, further demonstrating links between BSAP expression and successful G2/M transition in the cell cycle. These data suggest a correlation between BSAP and the development of B-1 malignancy, perhaps through the regulation of cell-cycle progression.

Animals↗
PubMed1998

The correlation of telomerase and IL-10 with leukemia transformation in a mouse model of chronic lymphocytic leukemia (CLL).

Telomerase activity is upregulated in activated and malignant lymphocytes. We studied the correlation of telomerase and IL-10 to leukemia transformation in the NZB mouse model of human chronic lymphocytic leukemia (CLL). Telomerase levels increased from early to late leukemic stages, likewise IL-10 gene expression levels increased with the leukemic progression. The inverse relationship of telomerase and IL-10 levels to the survival of NZB mice was also established. Our data suggested that telomerase and IL-10 were involved in transformation in the murine model of CLL and the detection of telomerase activities might be of value in the prediction of CLL progression.

Age Factors↗
PubMed1996

Altered CD45 expression in malignant B-1 cells.

CD45 is an important surface glycoprotein which has an intrinsic tyrosine phosphatase activity and has been implicated in cell proliferation, signaling, and differentiation and is associated with the B cell receptor during signaling. In this manuscript, the role of CD45 expression in the development of B-1 malignancies in NZB mice, which serve as a model for human diseases such as chronic lymphocytic leukemia, was investigated. B-1 cells spontaneously hyperproliferate and form a clonal hyperdiploid malignant population in aging NZB mice. Phenotypic analysis indicates that the NZB malignant B-1 cells are bright for IgM, but have reduced levels of CD45 relative to normal, nonmalignant B cells (both B-1 and B-2) and are characterized by dull or negative expression of the CD45 isoform B220/6B2 normally found on all B cells. Malignant B-1 cells demonstrated decreased RNA levels of CD45 relative to IgM expression, while nonmalignant B-2 cells showed similar levels of RNA expression for both CD45 and IgM. As CD45 exists in several isoforms and B cells express the highest molecular weight isoform (B220), malignant B-1 cells were further analyzed with respect to their isoform usage. Although, at the RNA level malignant B-1 cells showed the presence of the of the B220 form of CD45, western blot analysis of B220 protein suggested a posttranslational glycosylation defect in the CD45/B220 expression recognized by the mAb 6B2. F1 recipients of premalignant NZB B-1 cells which had been sorted for IgMhi, B220/6B2negative cells developed hyperdiploid malignant donor B-1 clones earlier than did recipients of NZB B-1 cells which were bright for B220/6B2. However, all the malignant B-1 clones of NZB origin which developed in recipients of both transfer populations were B220/6B2 negative. This indicated that abnormal expression of CD45 may be prerequisite for long-term growth and malignant transformation. Thus alterations in CD45 may result in abnormal functioning of the malignant B-1 cells which may further affect the proliferation of, or signaling within, these cells.

Animals↗
PubMed1991

Influence of host environment on growth of clonal CD5+B (Lyl+B) cells.

Autoimmune NZB mice have increased percentages of CD5+B (Lyl+B) cells in both the spleen and peritoneum. We have previously reported that as NZB mice age they develop a clonal population of hyperdiploid CD5+B cells in the spleen. These cells can readily be transplanted into unirradiated recipients. The growth characteristics of such transplanted hyperdiploid NZB spleen cells were examined in different recipient strains to determine if the immunological status of the host environments affected the growth of the clonal CD5+B cells. Young NZB and NZB.xid recipients (lacking hyperdiploid CD5+B cells) allowed growth and expansion of unpassaged CD5+B cells derived from primary NZB mice. Similarly, (NZBxDBA/2) and (NZBxBALB/c) F1 recipients allowed for expansion of CD5+B cell clones from primary sources. In a separate experiment, T cell-depleted NZB spleen cells containing a hyperdiploid CD5+B cell clone were transferred to SCID mice. The SCID environment supported the growth of the primary clone. None of these recipients normally have elevated CD5+B cells, yet these recipients allowed growth of primary transferred hyperdiploid cells. However, a difference in the ability of these recipient strains in their ability to expand multiply passaged CD5+B cell clones was observed. These results indicate that while hyperdiploid CD5+B cells are difficult to be maintained in culture, they can readily be passaged in vivo. The host environment may provide growth factors or signals for endogenous growth factors. Although the CD5+B clones arise initially in a hyperactive autoimmune environment, a hyperimmune environment is not necessary to support their growth. Transferred CD5+B cells affect the recipient environment and reduce the percentages of normal B cells.

Animals↗
PubMed1991

Hyperdiploid-CD5-positive B cells in mouse.

Hyperdiploid B cells have been found in autoimmune NZB mice as they age. The hyperdiploid cells were found to be clonal both on the basis of cytogenetic analysis and studies of immunoglobulin gene rearrangements at the DNA level. Studies of the inheritance of the hyperdiploid traits in both F1 and backcrosses, as well as NZB recombinant inbred strains, revealed that the presence of hyperdiploid B cells was an inherited recessive trait linked to autoimmune hyperactivity. In addition, hyperdiploid B cells were found to possess a unique chromosome pair which lacked terminal C-bands. This observation allowed analysis of the fate of transferred NZB hyperdiploid B cells into unirradiated recipients. The hyperdiploid B cells were found to expand in recipients and become the dominant population in several lymphoid organs. Spontaneously occurring hyperdiploid B cells were not observed in NZB-xid mice possessing the CBA/N X chromosome, which confers abnormal B cell maturation and results in decreased autoimmunity in NZB-xid mice. Following the discovery that CD5+ B cells were elevated in certain autoimmune states, hyperdiploid B cells were examined and found to be CD5+ B cells as well. The malignant cell in chronic lymphocytic leukemia is also a CD5+ B cell. The hyperdiploid B cells of NZB mice appear to have many of the features of autoimmune B cells, as well as malignant cells.

Animals↗
PubMed1990

Possible immunoregulatory role for CD5 + B cells.

CD5 + B cells represent a subpopulation of B cells which have the characteristic of employing unmutated immunoglobulin variable region genes. These cells are found to be increased early in ontogeny. The percentage of CD5 + B cells is highest in the fetus and decreases after birth. The antibodies produced by CD5 + B cells are polyreactive and are the natural autoantibodies. These autoantibodies may not be pathogenic. CD5 + B cells are elevated in certain autoimmune disease states and are the malignant cell type in B-CLL, with a strong genetic component involved in determining elevated CD5 + B cell states. Elevated CD5 + B cells are found in immunodeficient states (young, aged, and autoimmune). CD5 + B cells may normally act as a first-line defense against invading foreign pathogens but are not involved in the specific immune response. There is some evidence, at least in newborns, that CD5 + B cells may affect the emerging B cell repertoire of conventional B cells via idiotype cascade. However, the action of CD5 + B cells in the newborn may be quite different than their activity in the adult. Nonimmunoglobulin-producing CD5 + B cells may be immunosuppressors. In this report, a unique subpopulation of CD5 + B cells was investigated. These cells were found only in the spleens of aged NZB mice. The CD5 + B cells were clonal and possessed extra chromosomes and did not appear to be producing antibodies. These cells were capable of rapid proliferation in unirradiated recipients. By taking advantage of this proliferative capability, the effect of exogenous clonal CD5 + B cells on recipient immune system was evaluated. Clonal CD5 + B cells from NZB mice were immunosuppressive and decreased the numbers of conventional B cells as well as the level of "natural antibodies." In summary, CD5 + B cells may play different roles in the immune system depending upon environment, age, and their differentiation state (i.e., proliferation versus antibody secretion). The natural antibody produced by CD5 + B cells may be involved in maintenance functions such as removal of dead cells and first-line defense mechanisms. In addition, CD5 + B cells may themselves regulate the immune system and produce a factor which is immunosuppressive. An understanding of the various functions of CD5 + B cells may elucidate fundamental immunoregulatory circuits.

Animals↗
PubMed1990

Effects of induced anemia in normal and autoimmune mice.

Normal and autoimmune mice were studied with regard to signals eliciting differentiation and division of bone marrow stem cells. The erythropoiesis induced by anemia following serial bleedings was analyzed in young autoimmune New Zealand Black (NZB) mice and non-autoimmune strains. No difference in the response to the stimulus created by anemia was noted between the strains. After serial bleedings as a stimulus to stem cell proliferation, a five-fold increase in numbers of proliferating spleen cells occurred in both NZB and DBA/2 strains; the increased proliferating spleen cells in both strains were non-lymphoid. The bled animals had decreased percentages of B cells. The production of autoantibodies was not significantly altered by the experimentally induced anemia. In contrast, anti-immunoglobulin activation of resting B cells was increased in response to anemia. Young mice which had experimentally induced anemia had several characteristics in common with old autoimmune NZB mice. Both old NZB mice and young anemic animals had splenomegaly, increased numbers of proliferating spleen cells, decrease in splenic Ly 5+ cells and an increase in splenic colony forming units (CFUs). The anemic normal strains of animals lacked other characteristics of old NZB mice such as hyperimmunoglobulinemia or autoantibody production or elevated CD5+B cell numbers. This work supports the concept that the increase in spleen cell number, proliferating spleen cells, CFUs and the increased percentages of non-Ly-5 cells (which include erythroid precursors) found in the spleens of old NZB mice may in part result from their autoimmune hemolytic anemia.

Anemia↗
PubMed1988

In vivo effects of hyperdiploid Ly-1+ B cells of NZB origin.

Cells with increased chromosome number and DNA content have been found in the spleens of old NZB mice. These hyperdiploid cells are of clonal origin and demonstrate discrete IgH chain gene rearrangements by Southern blot analysis. In this report, hyperdiploid cells were analyzed by three-color flow cytometric techniques and found to be Ly-1+ B cells which were dull for Ly-1 and bright for surface IgM. These cells, unlike typical diploid Ly-1+ B cells, were negative for B220/6B2 and surface IgD. Hyperdiploid Ly-1+ B cells were found to be the predominant splenic subpopulation in animals receiving a spleen cell transfer from donors which possessed hyperdiploid Ly-1+ B cells. (NZB x DBA/2)F1 recipients of NZB spleen cells demonstrated a 10- to 1000-fold increase in Ly-1+ B cells in the spleen but showed no increased levels of Ly-1+ B cells in the peritoneum. Nearly all the splenic Ly-1+ B cells were hyperdiploid with the phenotype of the NZB parent. Cytogenetic analysis revealed that all the hyperdiploid cells were NZB donor cells. These findings suggest that the increase in splenic Ly-1+ B cells in the F1 recipients was due to expansion of injected splenic hyperdiploid Ly-1+ B cells of NZB origin. All of the F1 recipients of NZB hyperdiploid Ly-1+ B cells demonstrated a significant decrease in endogenous B cells as well as decreased serum IgM and anti-ssDNA autoantibodies. These studies suggest that hyperdiploid Ly-1+ B cells are different from typical peritoneal Ly-1+ B cells both in the lymphoid organs to which they home and in their proliferative capacity. NZB hyperdiploid Ly-1+ B cells, which may arise as a natural consequence of hyperactive Ly-1+ B cells, may play an immunoregulatory role in the spleen.

Animals↗
PubMed1987

Clonal expansion of abnormal B cells in old NZB mice.

The spleens of old NZB mice have an abnormal population of B cells with extra chromosomes. These hyperdiploid B cells manifest increased proliferative capacity; they grow in (NZB X DBA/2)F1 spleens after intravenous injections. Molecular analysis of individual old NZB and F1 passaged spleens demonstrate that hyperdiploid cells represent a clonal or oligoclonal expansion of B cells. All spleens with at least 10% hyperdiploid cells demonstrated both heavy and kappa light chain immunoglobulin gene rearrangements by Southern blot hybridization. None of the hyperdiploid spleens from old NZB mice had lambda rearrangements and only one of five showed evidence of clonal rearrangement of the TCR-beta gene. One also had a VK10 clonal rearrangement. Elevated p53 oncogene protein was observed in NZB hyperdiploid spleen cells; however, no p53 or other oncogene rearrangements or amplifications were seen. Hyperdiploid cells were IgM-bright, IgD-dull, Ia+, dull B220, Thy-1-, and Ly-1-dull. Spleens with hyperdiploid B cells had increased percentages of Ly-1 B cells. The data suggest that hyperdiploid cells in old NZB mice represent clonal expansion of B cells and that they may represent an intermediate stage between autoimmunity and malignancy.

Aging↗
PubMed1987

Dietary copper deficiency and autoimmunity in the NZB mouse.

NZB mice were exposed from birth to a diet either adequate or deficient in copper. By age 6 wk the mice exposed to the copper-deficient diet showed symptoms characteristic of copper deficiency (anemia, hypoceruloplasminemia, and achromatrichia). The splenic lymphocytes from the copper-deficient group had reduced numbers of cells expressing the following surface markers: Ly-5, Ly-1, B-220, and sIg. Less than 10% of the splenic lymphocytes in this group were cycling, as determined by flow cytometry analysis. The spontaneous 96-h anti-ss-DNA levels in the copper-deficient group were lower than those in the control group. The exogenous colony-forming units (CFUs) were significantly enhanced in the copper-deficient mice. The decreased splenic lymphoid populations, decreased anti-ss-DNA titers, and increased exogenous CFUs in the copper-deficient mice appear to be due to an increase in erythropoiesis at the expense of lymphopoiesis.

Animals↗
PubMed1986

Oncogene expression in autoimmune and normal peripheral blood mononuclear cells.

PBMC from patients with autoimmune diseases and from normal controls were studied for the expression of several cellular oncogenes. Gene expression was assessed by Northern blot analysis of poly(A)+ RNA obtained from leukapheresis samples. Patients with SLE expressed significantly more c-myc protooncogene RNA than did normal controls. Increased expression of the N-ras protooncogene was found in that subset of patients whose autoimmune disease was very active. Cells from individuals with SLE, but not from those with other autoimmune illnesses, showed significantly decreased levels of the c-myb and c-fos protooncogenes. To examine the implications of these findings, B and T cells were purified from apheresis samples donated by normal volunteers. When mitogen was used to activate the B cells in vitro, their pattern of protooncogene expression changed to resemble that found in freshly isolated cells from lupus patients. These results suggest that the differences detected in the expression of protooncogenes by patients with SLE may be due to the abnormal activation of their B cells in vivo. The pattern of protooncogene expression found in patients with other autoimmune illnesses is consistent with the activation of additional cell types in those diseases.

Autoimmune Diseases↗
PubMed1986

Effect of anti-Ia treatment on the production of anti-DNA antibody by NZB mice.

A cell transfer system was used to study the effect of anti-Ia antibodies on anti-DNA-producing B cells. B cells from autoimmune New Zealand Black (NZB) mice were necessary and sufficient to transfer anti-DNA antibody production to congenic NZB. xid recipients. Anti-Ia treatment of either donors or recipients led to a significant reduction in the number of B cells secreting anti-DNA antibody. This effect was detectable after as little as 3 days of treatment and persisted for at least 1 month after the cessation of therapy. In this system, we could find no evidence of suppressor cell induction. These data suggest that anti-Ia antibodies directly suppress autoantibody-producing B lymphocytes.

Animals↗
PubMed1986

Differential proliferative responses of B cells from BALB/c and autoimmune NZB mice to B-cell growth factor(s).

Highly purified B cells from NZB mice have altered responses to various stimuli which require additional costimulatory signals supplied by factors present in EL-4 supernatants when compared to age-matched control nonautoimmune strains. Both crude preparations of EL-4 supernatants as well as partially purified BSF-p1 induced peak proliferation in B cells from normal strains of mice only in the presence of another stimulatory signal, anti-mu. In contrast, B cells from autoimmune-prone NZB mice proliferated in response to B-cell growth factors, with an age-dependent variation. Splenic B cells from 16- to 22-week-old NZB mice, an age where pronounced autoimmune disease is not observed, demonstrated a near maximum proliferative response with B-cell growth factors alone. While normal B cells responded maximally to BSF-p1 in the presence of anti-mu, B cells from young adult NZB mice (16-22 weeks of age) were not further stimulated to proliferate upon the addition of anti-mu. Such NZB B cells appeared to lack the requirement for a stimulation signal delivered by anti-mu in order to respond to B-cell growth factors. These results suggested that NZB cells were partially activated in vivo in the preautoimmune state so that subliminal triggers lead to full activation.

Animals↗
PubMed1985

Analysis of B-cell subpopulations. I. Relationships among splenic xid, Ly 1+, and Lyb 5+ B cells.

The phenotypic and functional relationships among the various B-cell subsets is of importance for better understanding studies of the immune system. In this report, the realm of B cells encompassed by Lyb 5, Ly 1, and xid has been examined through the use of the alloantiserum anti-Lyb 5, the unique functional properties of Ly 1+ B cells, and the spontaneous autoantibody producing congenic xid mice, NZB.xid. By functional and phenotypic analysis, we have shown that (i) Lyb 5- B cells and B cells of xid mice are largely, but not completely, overlapping; (ii) xid spleen cells contain a population which is Lyb 5+; (iii) Ly 1+ B cells fall largely in the Lyb 5+ compartment; and (iv) the autoantibody-producing Ly 1+ B cells are predominantly Lyb 5+.

Animals↗
PubMed1985

Immune abnormalities in the diabetic New Zealand obese (NZO) mouse: insulin treatment partially suppresses splenic hyperactivity measured by flow cytometric analysis.

Immune abnormalities in both the humoral and cell-mediated immune systems were found in New Zealand obese (NZO) mice, a model of diabetes associated with autoimmune disease. Both the formation of anti-sheep red blood cell plaques and mitogen stimulation of NZO spleen cells were significantly decreased compared to normal strains of mice. In addition to perturbations of splenic lymphocyte function, the enlarged spleens of NZO mice demonstrated increased cycling cells as measured by flow cytometric analysis of the DNA content of individual cells. These abnormalities are similar but less pronounced than those found in another autoimmune model, the New Zealand black (NZB) strain. The pancreases of diabetic NZO mice contained a higher fraction of nuclei with greater than 2c amount of DNA. Chronic insulin administration decreased the percentages of splenic proliferating cells and polyploid pancreas cells in NZO mice. In addition, insulin treatment of NZO mice decreased spleen weights and serum glucose levels. Chronic insulin treatment did not alter these parameters in either nondiabetic Balb/c or autoimmune NZB mice. Thus, the features of the NZO strain which serve as both an autoimmunity model and a diabetes model can be dissociated. Insulin treatment had a unique effect on NZO traits but not on NZB traits even through many of these traits were present in both strains. In conclusion, although autoimmunity may underlie the diseases of both the NZO and the NZB strains, the amelioration of some of the features of the NZO strain by insulin may represent the beneficial effects of insulin on the metabolic control of cellular function in NZO mice.

Animals↗
PubMed1985

Separate control of B lymphocyte early activation and proliferation in response to anti-IgM antibodies.

Resting B cells enter and progress through the G1 phase of the cell cycle in response to low concentrations (1 to 5 micrograms/ml) of anti-IgM antibodies. Commitment to enter S phase requires the presence of a fivefold to 50-fold higher concentration of anti-IgM. These and other results strongly suggest that two separately controlled events are involved in B cell activation. The current studies demonstrate that B cells incubated with high concentrations of anti-IgM from the initiation of culture become independent of additional anti-IgM approximately 10 hr before entry into S phase. We have designated this anti-IgM independent portion of the G1 phase of the cell cycle as G1 beta, whereas the earlier phase is referred to as G1 alpha. Furthermore, low concentrations of anti-IgM are sufficient for progress through early portions of G1 alpha, but high concentrations are required for the last 4 to 8 hr (G1 alpha') if the cells are to go through the rest of the cell cycle. Removal of anti-IgM at any time during G1 alpha causes prompt cessation of the size enlargement that accompanies progress through G1. Such cells retain their size and their relative place in G1 for periods of at least 17 hr and recommence movement through G1 alpha phase when anti-IgM is readded. Thus, B cells may exist in states of partial activation and must possess a mechanism to integrate the amount of stimulatory signal they have received; they enter a commitment period for S phase only when that signal passes some threshold value.

Animals↗