Expression of transporter associated with antigen processing-1 in the endocrine cells of human pancreatic islets: effect of cytokines and evidence of hyperexpression in IDDM

Vives-Pi, M.; Armengol, M. P.; Alcalde, L.; Costa, M.; Somoza, N.; Vargas, F.; Jaraquemada, D.; Pujol-Borrell, Ricardo

doi:10.2337/diabetes.45.6.779

Cited by 9 publications

(7 citation statements)

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“…This regulation of TAP-1 gene expression is unusual (structurally but not functionally): in spite of being located within the HLA class II region, TAP-1 genes are expressed co-ordinately with HLA class I, and yet their expression is not strictly parallel. These results are in agreement with initial reports describing TAP, in which it is mentioned that these genes are constitutively expressed in epithelial cells at low level but that they can be induced by IFN-g [22], and are concordant with results recently obtained by ourselves in human islets [23] and by Epperson et al in endothelial cells [24a].…”

Section: Discussionsupporting

confidence: 93%

Hyperexpression of transporter in antigen processing-1 (TAP-1) in thyroid glands affected by autoimmunity: a contributory factor to the breach of tolerance to thyroid antigens?

Sospedra

Armengol

Ashhab

et al. 1997

Clinical and Experimental Immunology

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SUMMARYAccording to the 'aberrant HLA expression' hypothesis, endocrine autoimmunity is driven by presentation of self antigens by target cells over-expressing HLA molecules. In autoimmune thyroid diseases (AITD), thyroid follicular cells (thyrocytes) over-express HLA class I and HLA class II molecules. Since efficient presentation of endogenous peptides via class I requires transporters that translocate endogenous peptides from the cytoplasm to the endoplasmic reticulum, i.e. transporters associated with antigen processing (TAP) -1 and -2, the capability of thyrocytes to express TAP and whether TAP is hyperexpressed in AITD glands are issues relevant to the above hypothesis. Results from immunofluorescence and Northern blotting studies on primary thyrocyte cultures and on a thyroid cell line demonstrate that thyrocytes express constitutively TAP-1 at a low level, and that this expression is readily induced by interferon-gamma (IFN-g) and to a lesser extent by IFN-a. In AITD, but not in non-autoimmune glands, thyrocytes hyperexpress TAP-1, as demonstrated by both immunohistopathology and flow cytometry. The cytokine pattern does not bear, as assessed by reverse transcriptase-polymerase chain reaction (RT-PCR), a clear relationship with TAP-1 expression. These results have broad implications and suggest that the core concept of the 'aberrant HLA expression' hypothesis of endocrine autoimmunity could be incorporated in the currently prevailing view of 'autoimmunity by breach of peripheral tolerance'.

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Section: Discussionsupporting

confidence: 93%

Hyperexpression of transporter in antigen processing-1 (TAP-1) in thyroid glands affected by autoimmunity: a contributory factor to the breach of tolerance to thyroid antigens?

Sospedra

Armengol

Ashhab

et al. 1997

Clinical and Experimental Immunology

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“…Numerous immune defects were found in IFN-␥-negative mice (13,19). In IDDM, IFN-␥ may potentially influence the development of autoimmune Th1 CD4 ϩ T cells (20,21), affect the sensitivity of ␤ cells to destruction (e.g., by up-regulation in concert with IL-1 of expression of the proapoptotic receptor Fas) (4), and influence autoantigen presentation by both MHC class I and class II molecules (22)(23)(24)(25).…”

Section: Nsulin-dependent Diabetes Mellitus (Iddm)mentioning

confidence: 99%

IFN-γ Affects Homing of Diabetogenic T Cells

Savinov

Wong

Chervonsky

2001

The Journal of Immunology

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IFN-γ is a cytokine with pleiotropic functions that participates in immune and autoimmune responses. The lack of IFN-γ is known to delay the development of autoimmune diabetes in nonobese diabetic (NOD) mice. Splenocytes from diabetic NOD and IFN-γ knockout (KO) NOD mice transfer diabetes into NOD recipients equally well. However, adoptive transfer of diabetogenic T cells from NOD mice into NOD.IFN-γ-KO or NOD mice lacking β-chain of IFN-γ receptor (NOD.IFN-γRβ-KO) appeared to be much less efficient. We found that IFN-γ influences the ability of diabetogenic cells to penetrate pancreatic islets. Tracing in vivo of insulin-specific CD8+ T cells has shown that homing of these cells to the islets of Langerhans was affected by the lack of IFN-γ. While adhesion of insulin-specific CD8+ cells to microvasculature was normal, the diapedesis was significantly impaired. This effect was reversible by treatment of the animals with rIFN-γ. Thus, IFN-γ may, among other effects, influence immune and autoimmune responses by supporting the homing of activated T cells.

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“…Such a mechanism of cell death would require that the cells exhibit the same proteasome defect as that of NOD mouse lymphocytes, characterized by loss of LMP2 expression, aberrant NF-B activation, increased sensitivity to the cytotoxic effect of TNF-, and reduced expression of peptide-filled MHC class I molecules on the cell surface. However, one of the early pathological features of autoimmune diabetes in both humans and rodent models is hyperexpression of correctly assembled MHC class I molecules on the surface of cells (Foulis 1987, Ono et al 1988, Weringer & Like 1988, Hanafusa et al 1990, Kay et al 1991, Vives-Pi et al 1996, Stephens et al 1997, a phenomenon that requires intact proteasome function. Studies of both humans and animals with diabetes or other autoimmune diseases suggest that discordance in the regulation of MHC-linked genes between tissues might confer target specificity for attack by cytotoxic T lymphocytes (Hayashi & Faustman 1999).…”

Section: Gender/age-related and Tissue-specific Proteasome Dysfunctiomentioning

confidence: 99%

Central role of defective apoptosis in autoimmunity

Kühtreiber

Hayashi²,

Dale

et al. 2003

Journal of Molecular Endocrinology

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Lymphocyte development, selection and education represent tightly controlled immune processes that normally prevent autoimmunity. Lymphocyte development likely induces cellular selection through apoptosis to remove potentially autoreactive cells. Dysregulated apoptosis, both interrupted as well as accelerated apoptosis, are now demonstrated as central defects in diverse murine autoimmune disease. In murine models of autoimmune lupus, mutations in cell death receptor Fas (CD95) and its ligand, FasL (CD95 L), have been identified. These errors create a lymphoid system resistant to apoptosis. In contrast, select lymphoid subpopulations of maturing autoimmune prone non-obese diabetic mice have identifiable and pathogenic T cells with both in vivo and in vitro heightened apoptosis after drug interventions. In part, these defects are due to faulty activation of transcription factors such as nuclear factor-B (NF-B) that normally protect against apoptotic death. The genetic basis of interrupted NF-B in pathogenic memory T cells in diabetes is attributable to a developmentally controlled gene defect in an essential subunit of the proteasome. No specific gene in most common forms of human autoimmune disease has yet been identified. Functional assays from diverse laboratories repeatedly demonstrate heightened apoptosis in multiple cellular signaling pathways for cell death, suggesting a common theme in disease causality.

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Expression of transporter associated with antigen processing-1 in the endocrine cells of human pancreatic islets: effect of cytokines and evidence of hyperexpression in IDDM

Cited by 9 publications

References 0 publications

Hyperexpression of transporter in antigen processing-1 (TAP-1) in thyroid glands affected by autoimmunity: a contributory factor to the breach of tolerance to thyroid antigens?

Hyperexpression of transporter in antigen processing-1 (TAP-1) in thyroid glands affected by autoimmunity: a contributory factor to the breach of tolerance to thyroid antigens?

IFN-γ Affects Homing of Diabetogenic T Cells

Central role of defective apoptosis in autoimmunity

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