Death Pathways in T Cell Homeostasis and Their Role in Autoimmune Diabetes

Gronski, Matthew A; Weinem, Michael

doi:10.1900/rds.2006.3.88

Cited by 22 publications

(23 citation statements)

References 89 publications

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“…Our current study confirmed these findings. The decreased expression of perforin and FasL in patients with long-term type 1 DM might affect the capacity to regulate immune responses and to maintain normal levels of peripheral tolerance, which are essential for protection from autoimmune disease [24; 48; 49]. This may contribute to higher frequency of other autoimmune diseases in type 1 DM.…”

Section: Discussionmentioning

confidence: 99%

Immune profiling by multiple gene expression analysis in patients at-risk and with type 1 diabetes

Han

Leyva

Matheson

et al. 2011

Clinical Immunology

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There is a need for biomarkers to monitor the development and progression of type 1 DM. We analyzed mRNA expression levels for granzyme B, perforin, fas ligand, TNF-α, IFN-γ, Foxp3, IL-10, TGF-β, IL-4, IL-6, IL-17, Activation-induced cytidine deaminase (AID) and Immunoglobulin G gamma chain (IgG) genes in peripheral blood of at-risk, new-onset and long-term type 1 DM, and healthy controls. The majority of the genes were suppressed in long-term type 1 DM compared to controls and new-onset patients. IFN-γ, IL-4 and IL-10 mRNA levels were significantly higher in new-onset compared to at-risk and long-term groups. There was decreased mRNA expression for AID and IgG and up-regulation of IFN-γ with age in controls. Data suggest an overall depressed immunity in long-term type 1 DM. Increased gene expression levels for IFN-γ, IL-4 and IL-10 in new-onset patients from at-risk patients might be used as potential markers for progression of the disease.

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Section: Discussionmentioning

confidence: 99%

Immune profiling by multiple gene expression analysis in patients at-risk and with type 1 diabetes

Han

Leyva

Matheson

et al. 2011

Clinical Immunology

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“…However, mitochondrial membrane depolarization initiates apoptosis, and ROS vitiate NF-kB 's ability to inhibit it [37], resulting in T-cell destruction and a weakened proliferative capacity. This provides direct evidence linking the depressed MMP and increased ROS levels in the GK rat thymocytes and splenocytes with their decreased proliferative capacity.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial nutrients improve immune dysfunction in the type 2 diabetic Goto‐Kakizaki rats

Hao

Shen

Tian

et al. 2009

J Cellular Molecular Medi

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The development of type 2 diabetes is accompanied by decreased immune function and the mechanisms are unclear. We hypothesize that oxidative damage and mitochondrial dysfunction may play an important role in the immune dysfunction in diabetes. In the present study, we investigated this hypothesis in diabetic Goto-Kakizaki rats by treatment with a combination of four mitochondrial-targeting nutrients, namely, R-α-lipoic acid, acetyl-L-carnitine, nicotinamide and biotin. We first studied the effects of the combination of these four nutrients on immune function by examining cell proliferation in immune organs (spleen and thymus) and immunomodulating factors in the plasma. We then examined, in the plasma and thymus, oxidative damage biomarkers, including lipid peroxidation, protein oxidation, reactive oxygen species, calcium and antioxidant defence systems, mitochondrial potential and apoptosis-inducing factors (caspase 3, p53 and p21). We found that immune dysfunction in these animals is associated with increased oxidative damage and mitochondrial dysfunction and that the nutrient treatment effectively elevated immune function, decreased oxidative damage, enhanced mitochondrial function and inhibited the elevation of apoptosis factors. These effects are comparable to, or greater than, those of the anti-diabetic drug pioglitazone. These data suggest that a rational combination of mitochondrial-targeting nutrients may be effective in improving immune function in type 2 diabetes through enhancement of mitochondrial function, decreased oxidative damage, and delayed cell death in the immune organs and blood.

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“…25 An increasing accumulation of protein BimEL early after SB application prompts speculations that the BimEL heterodimerization with one or more anti-apoptotic proteins from Bcl-2 family 26 or direct activation interactions of BimEL with apoptotic mediators Bak and Bax 27 probably participate in the cytochrome c release. The role of Bim in lymphoid cells, specifically in the development and function of the immune system, 28 in maintaining lymphocyte homeostasis, 29 in apoptosis during the termination of an immune response 30 and in protecting against autoimmune disease 31 is well documented. Other literature data report the induction of Bim in various cancerous cells following the application of SB-related drugs functionally based on HDAC inhibition; in pancreatic adenocarcinoma cells, 32 in leukemia cells 33 and in breast cancer cells.…”

Section: Discussionmentioning

confidence: 99%

BimEL‐dependent apoptosis induced in peripheral blood lymphocytes with n‐butyric acid is moderated by variation in expression of c‐myc and p21(WAF1)

Kalousek

Brodská

Otevřelová

et al. 2008

Cell Biochemistry & Function

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We have examined the effect of sodium butyrate (SB) on the viability of normal peripheral blood lymphocytes (PBLs) in vitro and the effect of this agent on the expression of 20 apoptosis-related genes. Data suggest that PBL treated with 2 mmol L(-1) SB resisted for at least 8 h the destructive activity of the agent, but eventually 30% of cells died within 72 h. As documented by flow cytometry and cytochrome c release study, cells underwent mitochondrial-derived apoptosis. While the expression of the majority of genes examined by RT-PCR and Western blots remained indifferent to 2 mmol L(-1) SB, the cellular levels of BimEL, c-myc, p53, and p21(WAF1) varied profoundly with the time of SB treatment. The Bax activator BimEL increased rapidly, driving cells toward apoptosis likely controlled by c-myc and p21(WAF1) activities. The c-myc, exercising the role of mediator of the function of BimEL and inhibitor of p21(WAF1) expression, decreased significantly for several hours after adding SB but within 48 h it returned to close to its original value. An apoptosis inhibitor and executive caspase substrate p21(WAF1) increased early at the beginning of treatment but subsequently, within a time frame of 72 h, profoundly dropped in terms of both a caspase-dependent and caspase-independent way. We suggest that variations in c-myc and p21(WAF1) expression delay apoptosis making PBL resistant to SB for several hours, and together with fast catabolism of SB in vivo protect PBL against the destructive activity of this anti-cancerous metabolite of colonic bacteria.

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Death Pathways in T Cell Homeostasis and Their Role in Autoimmune Diabetes

Cited by 22 publications

References 89 publications

Immune profiling by multiple gene expression analysis in patients at-risk and with type 1 diabetes

Immune profiling by multiple gene expression analysis in patients at-risk and with type 1 diabetes

Mitochondrial nutrients improve immune dysfunction in the type 2 diabetic Goto‐Kakizaki rats

BimEL‐dependent apoptosis induced in peripheral blood lymphocytes with n‐butyric acid is moderated by variation in expression of c‐myc and p21(WAF1)

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