Novel B-cell maturation factor from spontaneously autoimmune viable motheaten mice.

Sidman, Charles L.; Marshall, Jan D.; Masiello, Nicholas C.; Roths, John B.; Shultz, Leonard D.

doi:10.1073/pnas.81.22.7199

Cited by 33 publications

(20 citation statements)

References 19 publications

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“…Our results show that the induction of the Bax mRNA in spleen cells of control B6-ϩ/ϩ mice was an early stress response (3 h) after the exposure. This was followed by the induction of the loss of mitochondrial membrane potential; as detected by the failure of the mitochondria to take up DiOC 6 , a dye that stains the outer membrane. This was not evident at 3 h, but became evident at 6 h after the irradiation.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, there was a marked decrease in DiOC 6 staining in irradiated cells from B6-ϩ/ϩ mice (32%) compared with unirradiated cells (61%) at 6 h. At 24 h after ␥-irradiation, most of the spleen cells from B6-me/me mice exhibited high DiOC 6 staining after irradiation (66%) compared with unirradiated (76%) cells. By 24 h after irradiation of cells from B6-ϩ/ϩ mice, most irradiated cells and unirradiated cells lost DiOC 6 uptake (8 and 33% of DiOC 6 ϩ for irradiated and unirradiated cells, respectively) (Fig. 5A, bottom).…”

Section: Spleen Cells From B6-me/me Mice Exhibited Defective ␥-Irradimentioning

confidence: 99%

“…A single-cell suspension (1 ϫ 10 6 cells/ml) was stained with 2 M DiOC 6 and Hoechst-33342 dye (50 ng/ml) at 37°C for 15 min. The stained cells were resuspended in FACS buffer for FACS analysis to quantitate the disruption of mitochondrial membrane potential according to the reduction of cells stained positive with DiOC 6 . Some stained cells were washed once with PBS, resuspended in a minimum amount of PBS, and analyzed microscopically (Nikon, Melville, NY) using a DM510 filter (Nikon) to visualize DiOC 6 staining of living cells and a UV-1A filter (Nikon) to visualize Hoechst-33342 staining of dead cells.…”

Section: Measurement Of Mitochondrial Transmembrane Potential Dissipamentioning

confidence: 99%

“…5A, top). Six hours after ␥-irradiation, most of the irradiated (60%) and unirradiated (62%) spleen cells from B6-me/me mice exhibited high staining of DiOC 6 (Fig. 5A, middle left).…”

Section: Spleen Cells From B6-me/me Mice Exhibited Defective ␥-Irradimentioning

confidence: 99%

“…These point mutations result in alternative splicing of the transcripts of the gene, which encodes Src homology protein tyrosine phosphatase (SHP-1) 3 (3,4). The deficiency of functional SHP-1 in homozygous moth-eaten (me/me) and viable motheaten (me v /me v ) mice affects hematopoiesis resulting in severe immunodeficiency, autoimmune symptoms, including immune complex deposition and autoantibody production, with early mortality due to pneumonitis and other inflammatory lesions (5,6). Interestingly, heterozygous Hcph me/ϩ mice live longer and exhibit an increased incidence of lymphoma development with minimal symptoms of autoimmune disease (1,7), which suggests that these mice may harbor a defect in their ability to mount an effective response to genotoxic stress.…”

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confidence: 99%

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Mutation of the Hematopoietic Cell Phosphatase (Hcph) Gene Is Associated with Resistance to γ-Irradiation-Induced Apoptosis in Src Homology Protein Tyrosine Phosphatase (SHP)-1-Deficient “Motheaten” Mutant Mice

Hsu

Shultz

et al. 2001

The Journal of Immunology

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To determine the role of Src homology protein tyrosine phosphatase (SHP-1) in the ionizing radiation-induced stress response, we analyzed the apoptotic response and cell cycle function in irradiated spleen cells of motheaten (me/me) mice. The defect in me/me mice has been attributed to mutations of the Hcph gene, which encodes SHP-1. Homozygotes develop severe systemic autoimmune and inflammatory disease, whereas heterozygotes live longer and develop hematopoietic and lymphoid malignance. Spleen cells from C57BL/6 (B6)-me/me and B6-+/+ controls were analyzed after γ-irradiation from a 137Cs source. B6-me/me cells were significantly more resistant than B6-+/+ cells to γ-irradiation-induced apoptosis exhibiting a higher LD50. The defective apoptosis response of the B6-me/me cells was exhibited by T and B cells and macrophages. Of the Bcl-2 family members analyzed, a significant difference was observed in the transcription of Bax mRNA, which was up-regulated early after irradiation in B6-+/+ cells, but not B6-me/me cells. Analysis of 3,3′-dihexyloxacarbocyanine iodide revealed resistance to the γ-irradiation-induced mitochondrial transmembrane permeability transition in the B6-me/me cells. The blocking of the cell cycle in the G0/G1 phase characteristic of the irradiated B6-+/+ cells was not observed in the B6-me/me cells. There was decreased phosphorylation of p38 mitogen-activated protein kinase and increased phosphorylation of p53 from spleen cell lysates of irradiated B6-me/me mice compared with wild-type mice. These data suggest that SHP-1 plays an important role in regulation of apoptosis and cell cycle arrest after a γ-irradiation-induced stress response.

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Section: Discussionmentioning

confidence: 99%

Section: Spleen Cells From B6-me/me Mice Exhibited Defective ␥-Irradimentioning

confidence: 99%

Section: Measurement Of Mitochondrial Transmembrane Potential Dissipamentioning

confidence: 99%

“…5A, top). Six hours after ␥-irradiation, most of the irradiated (60%) and unirradiated (62%) spleen cells from B6-me/me mice exhibited high staining of DiOC 6 (Fig. 5A, middle left).…”

Section: Spleen Cells From B6-me/me Mice Exhibited Defective ␥-Irradimentioning

confidence: 99%

mentioning

confidence: 99%

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Mutation of the Hematopoietic Cell Phosphatase (Hcph) Gene Is Associated with Resistance to γ-Irradiation-Induced Apoptosis in Src Homology Protein Tyrosine Phosphatase (SHP)-1-Deficient “Motheaten” Mutant Mice

Hsu

Shultz

et al. 2001

The Journal of Immunology

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Giant lymph node hyperplasia (castleman's disease) with spontaneous production of high levels of b-cell differentiation factor activity

Yabuhara

Yanagisawa

Murata

et al. 1989

Cancer

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A 13-year-old girl presented with general fatigue, back pain, anemia, hyperimmunoglobulinemia, and a mediastinal mass on chest radiograph. A mass was surgically removed, and its histologic examination determined the diagnosis of giant lymph node hyperplasia (Castleman's disease). With removal of the hyperplastic lymph node, the clinical symptoms soon disappeared and the abnormal laboratory findings were markedly improved within 1 month: serum IgG levels decreased from 4350 mg/dl to 1829 mg/dl. Immunostaining on the lymph node sections revealed polyclonal B-lymphocyte and T-lymphocyte populations. The patient's lymph node cells were cultured without any mitogenic stimulation, and the culture supernatants were assayed for their B-cell differentiation factor (BCDF) activity to induce IgG production by our Epstein-Barr virus-transformed cell line. The patient's lymph node cells produced high levels of BCDF activity: the supernatants could increase the IgG production from 140 ng/ml to 410 ng/ml when the values became from 140 ng/ml to 142 ng/ml or 148 ng/ml with those of the control lymph node cells. These results suggest that the hyperimmunoglobulinemia and its prompt improvement with removal of the hyperplastic lymph node may have been related to the spontaneous production of high levels of BCDF activity by the lymph node cells in the patient.

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Excessive production of interleukin 6/B cell stimulatory factor‐2 in rheumatoid arthritis

et al. 1988

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High levels of interleukin 6 (IL 6/B cell stimulatory factor-2) were detected in synovial fluids from the joints of patients with active rheumatoid arthritis (RA). The cells found in freshly isolated synovial fluid constitutively expressed IL 6 mRNA. The synovial tissues obtained by joint biopsy were also found to produce IL 6 in vitro. Immunohistochemical analysis demonstrated that CD2+ T cells as well as CD20+ blastoid B cells in the synovial tissues produce IL 6. The data indicate that IL 6 is generated constitutively in RA and its overproduction may explain the local as well as the generalized symptoms of RA, since IL 6 can function as B cell growth and differentiation factor as well as hepatocyte-stimulating factor.

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Novel B-cell maturation factor from spontaneously autoimmune viable motheaten mice.

Abstract: Both in vivo and in vitro, mice homozygous for the viable motheaten mutation show severe immunodeficiency, polyclonal B-cell activation and Ig secretion, and spon-

Cited by 33 publications

References 19 publications

Mutation of the Hematopoietic Cell Phosphatase (Hcph) Gene Is Associated with Resistance to γ-Irradiation-Induced Apoptosis in Src Homology Protein Tyrosine Phosphatase (SHP)-1-Deficient “Motheaten” Mutant Mice

Mutation of the Hematopoietic Cell Phosphatase (Hcph) Gene Is Associated with Resistance to γ-Irradiation-Induced Apoptosis in Src Homology Protein Tyrosine Phosphatase (SHP)-1-Deficient “Motheaten” Mutant Mice

Giant lymph node hyperplasia (castleman's disease) with spontaneous production of high levels of b-cell differentiation factor activity

Excessive production of interleukin 6/B cell stimulatory factor‐2 in rheumatoid arthritis

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