Increased proto‐oncogene expression in peripheral blood lymphocytes from patients with systemic lupus erythematosus and other autoimmune diseases

Boumpas, Dimitrios T.; Tsokos, George C.; Mann, Dean L.; Eleftheriades, Elias G.; Harris, C. C.; Mark, George E.

doi:10.1002/art.1780290608

Cited by 46 publications

(12 citation statements)

References 33 publications

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“…Sustained calcium transients such as plateaus and oscillations are necessary to initiate protein synthesis in T cells, whereas shorter signals do not suffice (56 -58). Not surprisingly, altered gene transcription in lupus T cells has been described for calcium-dependent genes such as CD40L, Fas ligand, and c-myc (20,21,59,60).…”

Section: Discussionmentioning

confidence: 99%

Naive CD4+ T Cells from Lupus-Prone Fas-Intact MRL Mice Display TCR-Mediated Hyperproliferation Due to Intrinsic Threshold Defects in Activation

Zielinski

Jacob

Bouzahzah

et al. 2005

The Journal of Immunology

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Autoreactive T cell activation is a consistent feature of murine lupus; however, the mechanism of such activation remains unclear. We hypothesized that naive CD4+ T cells in lupus have a lower threshold of activation through their TCR-CD3 complex that renders them more susceptible to stimulation with self-Ags. To test this hypothesis, we compared proliferation, IL-2 production, and single cell calcium signaling of naive CD4+ T cells isolated from Fas-intact MRL/+Fas-lpr mice with H-2k-matched B10.BR and CBA/CaJ controls, following anti-CD3 stimulation in the presence or absence of anti-CD28. We also assessed the responsiveness of naive CD4+ T cells isolated from Fas-intact MRL and control mice bearing a rearranged TCR specific for amino acids 88–104 of pigeon cytochrome c to cognate and low affinity peptide Ags presented by bone marrow-matured dendritic cells. TCR transgenic and wild-type CD4+ T cells from MRL mice displayed a lower threshold of activation than control cells, a response that was class II MHC dependent. The rise in intracellular calcium in MRL vs controls was enhanced and prolonged following anti-CD3 triggering, suggestive of proximal defects in TCR-engendered signaling as the mechanism for the observed hyperactivity. These findings were observed as early as 1–2 mo postweaning and, based on analysis of F1 T cells, appeared to be dominantly expressed. This genetically altered threshold for activation of MRL T cells, a consequence of a proximal defect in CD3-mediated signal transduction, may contribute to the abrogation of T cell tolerance to self-Ags in lupus.

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Section: Discussionmentioning

confidence: 99%

Naive CD4+ T Cells from Lupus-Prone Fas-Intact MRL Mice Display TCR-Mediated Hyperproliferation Due to Intrinsic Threshold Defects in Activation

Zielinski

Jacob

Bouzahzah

et al. 2005

The Journal of Immunology

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“…Bcf-2 family genes are considered important in regulation of lymphocytic PCD (12). The proto-oncogene c-myc plays a role in activation-induced T cell death in T cell hybridomas (31,32), and expression of c-myc is shown to be abnormal in SS lymphocytes (33)(34)(35). Therefore, we chose to study bcl-2 bcf-xL, bcl-xS, bar, and c-myc gene expression in SS T and B cells.…”

Section: Discussionmentioning

confidence: 99%

Lymphocyte apoptosis and apoptosis‐associated gene expression in Sjögren's syndrome

Ogawa

Dang

Kong

et al. 1996

Arthritis & Rheumatism

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Objective. To study the mechanism and regulation of apoptosis in peripheral blood T and B lymphocytes from patients with Sjögren's syndrome (SS). Methods. The mode of in vitro lymphocyte death in the peripheral blood of patients with SS was determined by fluorescence microscopic analysis, terminal deoxynucleotidyl transferase assay, and DNA fragmentation analysis. Apoptotic cell death of T and B cells was determined at 48 hours of culture by fluorescence‐activated cell sorter analysis of propidium iodidestained cells. Messenger RNA (mRNA) expression of bcl‐2, bcl‐x, bax, and c‐myc in T and B cells was determined by enzyme‐linked immunosorbent assaypolymerase chain reaction (ELISA‐PCR). Expression of bcl‐xL and bcl‐xS was determined by Southern blot analysis of PCR products. Gene expression was calculated as the ratio of each gene message to the message of the GAPDH gene. Bcl‐2 protein levels in SS T cells were determined by ELISA. Results. SS T cells showed increased in vitro apoptosis compared with normal T cells (mean ± SD 12.3 ± 4.5% versus 7.3 ± 2.0%; P < 0.01). Freshly isolated SS T cells showed increased expression of bcl‐2 mRNA compared with normal controls (mean ± SD 1.50 ± 0.65 versus 0.88 ± 0.23; P < 0.05). There was no significant difference in levels of bax or c‐myc mRNA in T cells and B cells between SS patients and normal controls. When SS T lymphocytes were cultured in vitro for 72 hours, Bcl‐2 protein levels decreased with time. Conclusion. SS T cells showed accelerated apoptosis in vitro. Freshly isolated SS T cells had increased expression of bcl‐2. An increase in death‐promoter signals and decrease in death‐suppressor signals in vitro may have been responsible, in part, for the apoptosis in SS T lymphocytes.

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“…However, secondary immune defects have also been reported in human NHL (33). In conformity with NHL in dogs, several immune-mediated diseases have been linked to an increased incidence of NHL in humans (34,35), and it has been stated that overexpression of certain oncogenes in the lymphocytes of patients with various autoimmune diseases may occur and eventually lead to development of NHL (36).…”

Section: Descriptive Epidemiologymentioning

confidence: 99%

Canine malignant lymphoma: A review and comparison with human non‐hodgkin's lymphoma

Teske

1994

Veterinary Quarterly

144

142

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Increased proto‐oncogene expression in peripheral blood lymphocytes from patients with systemic lupus erythematosus and other autoimmune diseases

Cited by 46 publications

References 33 publications

Naive CD4+ T Cells from Lupus-Prone Fas-Intact MRL Mice Display TCR-Mediated Hyperproliferation Due to Intrinsic Threshold Defects in Activation

Naive CD4+ T Cells from Lupus-Prone Fas-Intact MRL Mice Display TCR-Mediated Hyperproliferation Due to Intrinsic Threshold Defects in Activation

Lymphocyte apoptosis and apoptosis‐associated gene expression in Sjögren's syndrome

Canine malignant lymphoma: A review and comparison with human non‐hodgkin's lymphoma

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