Insulitis-caused redistribution of heat-shock protein HSP60 inside beta-cells correlates with induction of HSP60 autoantibodies

Brudzynski, K.

doi:10.2337/diabetes.42.6.908

Cited by 15 publications

(9 citation statements)

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“…p38 MAPK and HSP60 are believed to play important roles in T cell function, including the control of cytokine expression (Brudzynski, 1993;Schafer et al, 1999;Gregori et al, 2002;Rincon and Pedraza-Alva, 2003). In addition, p38 MAPK and/or HSP60 appear to be involved in antigen presentation and mediating the activation of T cells, thus increasing cellular immunity (Benagiano et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have shown that HSP60 is a diabetes-associated autoantigen and plays an important role in T cell responses in a variety of Th1-dependent inflammatory conditions such as insulitis and arthritis (Brudzynski, 1993;Birk et al, 1996;Cehn et al, 1999;Sheikh-Hamad et al, 1998). Blocking p38 MAPK has been shown to reduce HSP expression in different cells (Uehara et al, 1999;Bellmann et al, 2000), demonstrating that these two proteins are functionally linked.…”

Section: Significant Reduction In Cd5mentioning

confidence: 99%

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Preventive and Therapeutic Potential of p38α-Selective Mitogen-Activated Protein Kinase Inhibitor in Nonobese Diabetic Mice with Type 1 Diabetes

Medicherla¹,

Protter²,

Jing³

et al. 2006

J Pharmacol Exp Ther

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Mitogen-activated protein kinases (MAPKs) and heat shock proteins (HSPs) are ubiquitous proteins that function within T cells in both normal and stress-related pathophysiological states, including type 1 diabetes. The nonobese diabetic (NOD) mouse spontaneously develops T cell-mediated autoimmune pancreatic beta cell destruction that is similar to type 1 diabetes in humans. Because p38 MAPKs have been shown to modulate T cell function, we studied the effects of a p38␣ MAPK-selective inhibitor, indole-5-carboxamide (SD-169), on the development and progression of type 1 diabetes in the NOD mouse. In preventive treatment studies, SD-169 significantly reduced p38 and HSP60 expression in T cells of the pancreatic beta islets. Following treatment, the incidence of diabetes as determined by blood glucose levels was significantly lower, and immunohistochemistry of pancreatic beta islet tissue demonstrated significant reduction in CD5 ϩ T cell infiltration in the SD-169 treatment group as compared with untreated NOD mice. In therapeutic studies using mildly and moderately hyperglycemic NOD mice, SD-169 treatment lowered blood glucose and improved glucose homeostasis. Furthermore, following cessation of SD-169 treatment, NOD mice showed significant arrest of diabetes. In conclusion, we report that this p38␣-selective inhibitor prevents the development and progression of diabetes in NOD mice by inhibiting T cell infiltration and activation, thereby preserving beta cell mass via inhibition of the p38 MAPK signaling pathway. These results have bearing on current prophylactic and therapeutic protocols using p38␣-selective inhibitors in the prediabetic period for children at high risk of type 1 diabetes, in the honeymoon period, and for adults with latent autoimmune diabetes.Type 1 diabetes is a multifactorial disease in which autoimmunity plays a prime role. The disease becomes clinically manifest when the majority of endocrine beta cells have been destroyed in a T cell-mediated process (Yoshida and Kikutani, 2000). Methods that predict the development of type 1 diabetes may allow the evaluation of pharmacological treatment strategies that halt or even prevent beta cell destruction (Debussche et al., 1993;Keymeulen and Somer, 1993;Mahon et al., 1993;Ryu et al., 2001;Shapiro et al., 2002). Following the initiation of insulin therapy, 60 to 80% of patients with type 1 diabetes will experience a transient remission known as the honeymoon period (Keymeulen and Somer, 1993), and therapeutic strategies have been described to prolong this period by slowing the ongoing self-destruction of the insulin-producing beta cells (Hosker and Turner, 1982;Heinze and Thon, 1985;Crump, 1987;Palmer and McCulloch, 1990;Herold et al., 2002;Shapiro et al., 2002). Between 5 and 30% of adults presenting with mild hyperglycemia suggestive of type 2 diabetes may actually have a slowprogressive form of type 1 diabetes designated latent autoimmune diabetes of adults (Casteels et al., 1998). Immunosuppressive agents prevent the onset of type 1 diab...

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Section: Discussionmentioning

confidence: 99%

Section: Significant Reduction In Cd5mentioning

confidence: 99%

Preventive and Therapeutic Potential of p38α-Selective Mitogen-Activated Protein Kinase Inhibitor in Nonobese Diabetic Mice with Type 1 Diabetes

Medicherla¹,

Protter²,

Jing³

et al. 2006

J Pharmacol Exp Ther

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“…The fact that proteins like E2 and imogen 38 probably need to interact with cytosolic chaperonins of the HSP70 family to be directed to mitochondria (41), and that they possess potential or ancestral "signal peptide"-like structures within their mitochondrial targeting sequences, suggests a possible molecular mechanism by which a sequestered organellar protein may be redirected to the secretory pathway and gain access to the cell surface or compartments involved in antigen presentation. Such a phenomenon probably occurs with a number of different mitochondrial proteins (e.g., [50][51][52] and could account for the apparent tissue specificity of an autoimmune attack directed at otherwise widely distributed tissue antigens. There is no direct evidence, at the moment, for such a mechanism either in the case of E2 or imogen 38, which emphasizes the need to understand more of the cell biology of imogen 38 in both the normal and prediabetic islet and the mechanism by which it is presented to T cells in vivo.…”

Section: Discussionmentioning

confidence: 99%

Imogen 38: a novel 38-kD islet mitochondrial autoantigen recognized by T cells from a newly diagnosed type 1 diabetic patient.

Arden

Roep²,

Neophytou³

et al. 1996

J. Clin. Invest.

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Cell-mediated autoimmune attack directed against islet proteins of ‫ف‬ 38 kD in size has been associated with type 1 diabetes. A novel murine cDNA encoding an antigen of this size was cloned using a screening procedure based on the proliferative response of a human diabetic T cell clone (1C6) to a recombinant antigen epitope library. Membrane preparations from COS 7 cells transfected with the fulllength 1,267-bp cDNA elicited a proliferative response from the reporter T cells comparable to that of the defined peptide epitope and native insulinoma antigen. In vitro translation and transfection experiments suggested that the protein is initially synthesized as a 44-kD protein and then processed to the native 38-kD form through the proteolytic removal of a 54-aa NH 2 -terminal mitochondrial targeting sequence. Differential centrifugation, Percoll density gradient centrifugation, and immunofluorescence studies confirmed localization of the antigen to mitochondria. Northern blot, Western blot, and 1C6 T cell proliferation assays showed that, although imogen 38 was more highly expressed in ␤ cell than ␣ cell lines, it was also present in other tissues. It is concluded that imogen 38 may be a target for bystander autoimmune attack in diabetes rather than a primary autoantigen. ( J. Clin. Invest. 1996. 97:551-561.)

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“…The actions of Hsp60 could lead to the modification of those proteins, and in this manner it could have a role in many diseases, including carcinogenesis. Heart Heart failure; Coronary vascular disease [137][138][139][140] Kidney Glomerulonephritis [141] Large bowel Inflammatory bowel diseases [19,142,143] Lung Chonic obstructive pulmonary disease [20] Oral cavity Periodontitis [144,145] Pancreas Type 1 diabetes [146][147][148][149][150][151] Skin Scleroderma, pemphigoid; Psoriasis; Dermatomyositis [152,153] Synovial joints Rheumatoid arthritis; Juvenile idiopathic arthritis [154][155][156][157] Vessels Vasculitis; Atherosclerosis [158][159][160][161][162][163][164][165][166][167] Adapted from [2]. Hsp60 seems to contribute to tumor cell survival, but this is controversial.…”

Section: Hsp60 Chaperonopathies and Chaperonotherapy: Targets And Agentsmentioning

confidence: 99%

Hsp60 chaperonopathies and chaperonotherapy: targets and agents

Cappello

Gammazza

Piccionello

et al. 2013

Expert Opinion on Therapeutic Targets

132

133

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Insulitis-caused redistribution of heat-shock protein HSP60 inside beta-cells correlates with induction of HSP60 autoantibodies

Cited by 15 publications

References 0 publications

Preventive and Therapeutic Potential of p38α-Selective Mitogen-Activated Protein Kinase Inhibitor in Nonobese Diabetic Mice with Type 1 Diabetes

Preventive and Therapeutic Potential of p38α-Selective Mitogen-Activated Protein Kinase Inhibitor in Nonobese Diabetic Mice with Type 1 Diabetes

Imogen 38: a novel 38-kD islet mitochondrial autoantigen recognized by T cells from a newly diagnosed type 1 diabetic patient.

Hsp60 chaperonopathies and chaperonotherapy: targets and agents

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