A possible role of apoptosis for regulating autoreactive responses in                 systemic lupus erythematosus

Funauchi, Masanori; Sugiyama, Masafumi; SukYoo, B; Ikoma, Shinya; Ohno, Motoki; Kinoshita, Koji; Kanamaru, Akihisa

doi:10.1191/096120301680416977

Cited by 17 publications

(15 citation statements)

References 21 publications

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“…Similarly to various systemic autoimmune diseases, in which altered apoptosis capability of PBMCs is characteristic and may contribute to the maintenance of the autoimmune processes (Bijl et al, 2001;Funauchi et al, 2001;Papo et al, 1998;Stummvoll et al, 2000;Zeher et al, 1999), our findings revealed the presence of activated peripheral blood T lymphocytes with impaired apoptosis, resulting in long-lived T cells peripherally in RA. This may contribute to the recruitment of these cells to the site of tissue damage and the perpetuation of the autoimmune inflammatory process.…”

Section: Szodoray Et Almentioning

confidence: 85%

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Programmed Cell Death in Rheumatoid Arthritis Peripheral Blood T-Cell Subpopulations Determined by Laser Scanning Cytometry

Szodoray

Jellestad

Nakken

et al. 2003

Laboratory Investigation

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SUMMARY:Because peripheral blood mononuclear cells play an important role in the perpetuation of the autoimmune process in rheumatoid arthritis (RA) and because the maintenance of these cells might be caused by the dysregulation of apoptosis, we investigated the apoptosis susceptibility of peripheral blood mononuclear cells from patients with RA. Freshly separated peripheral blood lymphocytes were stained for apoptosis markers (CD95, Bax, Bcl-2, TNF receptor) and for an activation marker (CD45-RO), and the apoptosis frequency of cells bearing these markers were assessed by the terminal-deoxynucleotidyl transferase-mediated dUTP digoxigenin nick end labeling method and nuclear condensation analysis with laser scanning cytometry. Also, the ability of CD4 ϩ and CD8 ϩ T-cell populations to undergo apoptosis was investigated with 24-hour culture in medium alone or with different apoptosis inducers (anti-CD3, anti-CD95, anti-TNF receptor). Laser scanning cytometry analysis was used to enumerate the phenotype and apoptosis ratios of both freshly isolated and cultured lymphocytes. Quantitative ELISA was performed to detect plasma levels of TNF-␣ and soluble Fas ligand. Furthermore, we studied the relationship between marked apoptotic defects in patients with RA and the severity of clinical disease. CD4 ϩ T-cell counts in patients with RA were elevated compared with controls. A decreased rate of anti-CD95-mediated apoptosis was found within the CD4 ϩ and CD8 ϩ lymphocytic subpopulations. In patients with RA, decreased Bax expression and decreased apoptosis rate within the Bax-positive cells were found, whereas Bcl-2 expression was elevated. The CD45-RO expression was higher, whereas the apoptosis within CD45-RO ϩ cells were decreased in RA. Evaluation of plasma soluble Fas ligand revealed significantly decreased levels in patients compared with controls. The reduced susceptibility to CD95-mediated apoptosis may contribute to the expansion of an activated CD4 ϩ lymphocyte subpopulation and thus to the maintenance of peripheral autoreactive T-cell clones in RA. We also revealed a relationship between in vitro demonstrated lymphocyte apoptosis defects and clinical disease activity.

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Section: Szodoray Et Almentioning

confidence: 85%

“…Because PBMCs play an important role in the pathogenesis of various systemic autoimmune diseases, such as systemic lupus erythematosus (Bijl et al, 2001;Funauchi et al, 2001;Papo et al, 1998), Sjögren's syndrome (Zeher et al, 1999), and systemic sclerosis, (Stummvoll et al, 2000), we further investigated this phenomenon in RA.…”

mentioning

confidence: 99%

Programmed Cell Death in Rheumatoid Arthritis Peripheral Blood T-Cell Subpopulations Determined by Laser Scanning Cytometry

Szodoray

Jellestad

Nakken

et al. 2003

Laboratory Investigation

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“…Several intracellular mechanisms by which monocyte/macrophage/T-helper cell apoptosis rates are elevated in SLE have been proposed [147][148][149][150][151][152]. These include, persistent mitochondrial hyperpolarization via elevated mitochondrial transmembrane potential (i.e.δPsim) and ATP depletion [149], increased hypermutated memory B cells [147,150], elevated COX-2 production [151] and 7, 8 dihydroneopterin-resistance [152].…”

Section: Psoriatic Arthritismentioning

confidence: 97%

“…These include, persistent mitochondrial hyperpolarization via elevated mitochondrial transmembrane potential (i.e.δPsim) and ATP depletion [149], increased hypermutated memory B cells [147,150], elevated COX-2 production [151] and 7, 8 dihydroneopterin-resistance [152].…”

Section: Psoriatic Arthritismentioning

confidence: 99%

The Role of Apoptosis in Arthritis

Malemud¹,

Gillespie²

2005

CRR

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Programmed cell death (i.e. apoptosis) plays a critical role in the pathogenesis and progression of several arthritic conditions and autoimmune disorders. Apoptosis induction is dependent on the extent to which the initiating apoptotic signal occurs via a receptor-mediated event (i.e. extrinsic pathway) or by changes in mitochondrial membrane permeability (i.e. intrinsic pathway). In this regard, differential activation of downstream caspases that degrade chromatin-containing DNA resulting in internucleosomal DNA fragmentation occurs by one of these apoptosis pathways or by combinations of both. In degenerative joint diseases such as osteoarthritis, interleukin-1 (IL-1), tumor necrosis factor-α (TNF-α) as well as nitric oxide (NO) levels are significantly elevated in osteoarthritic joint synovial fluid. Thus, IL-1, TNF-α as well as NO induced human chondrocyte apoptosis in vitro and apoptosis frequency is often elevated in aging and osteoarthritic cartilage compared to young normal subjects or cartilage age-matched to the osteoarthritic specimens, respectively. A decrease in viable chondrocytes which could result from apoptosis induction in articular cartilage probably has significant implications for cartilage repair in osteoarthritis. Synovial hyperplasia with the resultant formation of pannus suggests that apoptosis-resistance pathways are active in rheumatoid arthritis. A resistance to apoptosis induction is pertinent to cartilage and bone destruction as well in rheumatoid arthritis as is the severity and progression of rheumatoid arthritis pathology. It is noteworthy that medical management of rheumatoid or psoriatic arthritis with anti-TNF-α monoclonal antibodies, while limiting lymphocyte infiltration into affected tissues does not induce apoptosis in synovial joint tissue. Systemic lupus erythematosus is an autoimmune disorder in which the failure to delete auto-reactive Tlymphocytes during immune development suggests that dysfunctional T-lymphocyte function may result from defective apoptosis. Defective T lymphocytes are responsible for abnormal B-cell function, autoantibody production as well as synovial joint arthropathy in lupus. In another view, lupus may be characterized by overly aggressive apoptosis leading to increased apoptotic cell load coupled to a deficiency in apoptotic cell clearance. Lymphocyte infiltration of salivary and lacrimal glands characteristic of Sjögren's syndrome causes gland destruction by apoptosis with resultant gland dysfunction.

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“…Defects in inducing apoptosis could lead to the persistence of autoreactive T-or B-cells. On the other hand, apoptosis generates altered self-antigens which can stimulate an autoimmune response in sensitive persons [19] .…”

Section: Discussionmentioning

confidence: 99%

Mycophenolic acid inhibits SLE-associated cytokine expression and promotes apoptosis of peripheral blood mononuclear cells from patients with systemic lupus erythematosus1

Wang

et al. 2006

Acta Pharmacologica Sinica

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Aim: To investigate the effect of the novel immunosuppressant mycophenolic acid (MPA) on cytokine production and apoptosis of the peripheral blood mono‐nuclear cells (PBMC) of patients with systemic lupus erythematosus (SLE). Methods: The levels of IL‐10, IL‐12, IFN‐γ, sFas and sFasL in the supernatants of cultured PBMC from 41 SLE patients was determined by the ABC‐ELISA method. The percentage of IFN‐γ+IL‐10−, IFN‐γ−IL‐10+, and IFN‐γ+IL‐10+ subsets in CD4+ cells were detected by three‐color flow cytometry. The percentage of apoptotic Th cells was detected by AV‐FITC/PI flow cytometry. Samples from 22 sex‐ and age‐comparable healthy people were used as normal controls. Results: The levels of IL‐10, IL‐12, and IFN‐γ were all significantly elevated in the supernatants of cultured PBMC from SLE samples, compared with normal controls. The enhanced productions of IL‐10, IL‐12, and IFN‐γ by PBMC from SLE both spontaneously and stimulated by phytohaemagglutinin (PHA) were significantly reduced by MPA. The percentages of CD4+IFN‐γ−IL‐10+ and CD4+IFN‐γ+IL‐10+ cell subsets in cultured PBMC from SLE were significantly increased, but decreased when MPA was added into the culture. After being cultured in vitro for 48 h, the PBMC of SLE patients showed a higher secretion of sFasL as well as a higher percentage of apoptosis. MPA significantly increased the apoptotic percentage of SLE PBMC, but reduced the secretion of sFasL and sFas. Conclusion: MPA reduces the abnormal production of SLE‐associated cytokines, such as IL‐10, IL‐12, and IFN‐γ; inhibits the increase of CD4+IFN‐γ+IL‐10, CD4+IFN‐γ−IL‐10+ and CD4+IFN‐γ+IL‐10+ subset; and promotes the apoptosis of PBMC in SLE patients, which may be associated with the therapeutic mechanism of MPA for SLE.

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A possible role of apoptosis for regulating autoreactive responses in systemic lupus erythematosus

Cited by 17 publications

References 21 publications

Programmed Cell Death in Rheumatoid Arthritis Peripheral Blood T-Cell Subpopulations Determined by Laser Scanning Cytometry

Programmed Cell Death in Rheumatoid Arthritis Peripheral Blood T-Cell Subpopulations Determined by Laser Scanning Cytometry

The Role of Apoptosis in Arthritis

Mycophenolic acid inhibits SLE-associated cytokine expression and promotes apoptosis of peripheral blood mononuclear cells from patients with systemic lupus erythematosus1

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