Impaired primary immune response in type-1 diabetes. Functional impairment at the level of APCs and T-cells

Spatz, Martin; Eibl, N; Hink, S; Wolf, Hermann M.; Fischer, Gottfried; Mayr, Wolfgang R.; Schernthaner, Guntram; Eibl, Martha M.

doi:10.1016/s0008-8749(03)00043-1

Cited by 68 publications

(63 citation statements)

References 50 publications

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“…The ICs should load on FDCs and bypass limitations imposed by MHC and T cells. Similarly, specific IgM responses should be inducible in animals or people with congenital and/or acquired T cell insufficiencies (62,63), including HIV infected (64), aged (65), diabetic (66), uremic (67), and neonates (68,69). We look forward to experiments designed to test these postulates.…”

Section: Discussionmentioning

confidence: 99%

T-Independent Antibody Responses to T-Dependent Antigens: A Novel Follicular Dendritic Cell-Dependent Activity

Shikh

Sayed²,

Szakal³

et al. 2009

The Journal of Immunology

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Follicular dendritic cells (FDCs) periodically arrange membrane-bound immune complexes (ICs) of T-dependent Ags 200–500Å apart, and in addition to Ag, they provide B cells with costimulatory signals. This prompted the hypothesis that Ag in FDC-ICs can simultaneously cross-link multiple BCRs and induce T cell-independent (TI) B cell activation. TI responses are characterized by rapid IgM production. OVA-IC-bearing FDCs induced OVA-specific IgM in anti-Thy-1-pretreated nude mice and by purified murine and human B cells in vitro within just 48 h. Moreover, nude mice immunized with OVA-ICs exhibited well-developed GL-7+ germinal centers with IC-retaining FDC-reticula and Blimp-1+ plasmablasts within 48 h. In contrast, FDCs with unbound-OVA, which would have free access to BCRs, induced no germinal centers, plasmablasts, or IgM. Engagement of BCRs with rat-anti-mouse IgD (clone 11–26) does not activate B cells even when cross-linked. However, B cells were activated when anti-IgD-ICs, formed with Fc-specific rabbit anti-rat IgG, were loaded on FDCs. B cell activation was indicated by high phosphotyrosine levels in caps and patches, expression of GL-7 and Blimp-1, and B cell proliferation within 48 h after stimulation with IC-bearing FDCs. Moreover, anti-IgD-IC-loaded FDCs induced strong polyclonal IgM responses within 48 h. Blockade of FDC-FcγRIIB inhibited the ability of FDC-ICs to induce T-independent IgM responses. Similarly, neutralizing FDC-C4BP or -BAFF, to minimize these FDC-costimulatory signals, also inhibited this FDC-dependent IgM response. This is the first report of FDC-dependent but TI responses to T cell-dependent Ags.

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Section: Discussionmentioning

confidence: 99%

T-Independent Antibody Responses to T-Dependent Antigens: A Novel Follicular Dendritic Cell-Dependent Activity

Shikh

Sayed²,

Szakal³

et al. 2009

The Journal of Immunology

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“…However, in a recent in vitro study involving type 1 patients, all with a HbA 1c <8.0% [31], there were impaired proliferative CD4+ cell responses to primary protein antigens, perhaps due to altered expression of cellular adhesion molecules and/or reduced cytokine release independent of glycaemia [32]. By contrast, another study involving patients with relatively good metabolic control showed a robust secondary immune response to standard antigens, suggesting normal T memory cell and CD4+ lymphocyte function [33]. Thus, although tight blood glucose control may help to normalize CMI in diabetic patients, other factors may be important.…”

Section: Adaptive Immunitymentioning

confidence: 99%

Common infections in diabetes: pathogenesis, management and relationship to glycaemic control

Peleg

Weerarathna

McCarthy

et al. 2006

Diabetes Metabolism Res

498

406

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SummarySpecific defects in innate and adaptive immune function have been identified in diabetic patients in a range of in vitro studies. However, the relevance of these findings to the integrated response to infection in vivo remains unclear, especially in patients with good glycaemic control. Vaccine efficacy seems adequate in most diabetic patients, but those with type 1 diabetes and high glycosylated haemoglobin levels are most likely to exhibit hyporesponsiveness. While particular infections are closely associated with diabetes, this is usually in the context of extreme metabolic disturbances such as ketoacidosis. The link between glycaemic control and the risk of common community-acquired infections is less well established but could be clarified if infection data from large community-based observational or intervention studies were available. The relationship between hospital-acquired infections and diabetes is well recognized, particularly among post-operative cardiac and critically ill surgical patients in whom intensive insulin therapy improves clinical outcome independent of glycaemia. Nevertheless, further research is needed to improve our understanding of the role of diabetes and glycaemic control in the pathogenesis and management of community-and hospitalacquired infections.

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“…toreactive T cells in NOD mice. The first event of the autoagressive immune response is initiated by immature dendritic cells that take up beta-cell antigens and migrate into pancreatic lymph nodes for antigenic presentation to naïve T cells (26). To determine whether expression of TGF-␤ influences antigen presentation by antigenpresenting cells, CFSE-labeled naïve BDC2.5 T cells were adoptively transferred into transgenic mice.…”

Section: Transient Expression Of Tgf-␤ In the Islets Is Sufficient Tomentioning

confidence: 99%

TGF-β regulatesin vivoexpansion of Foxp3-expressing CD4⁺CD25⁺regulatory T cells responsible for protection against diabetes

Peng

Laouar

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

381

273

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CD4 ؉ CD25 ؉ regulatory T cells are essential in the protection from organ-specific autoimmune diseases. In the pancreas, they inhibit actions of autoreactive T cells and thereby prevent diabetes progression. The signals that control the generation, the maintenance, or the expansion of regulatory T cell pool in vivo remain poorly understood. Here we show that a transient pulse of transforming growth factor ␤ (TGF-␤) in the islets during the priming phase of diabetes is sufficient to inhibit disease onset by promoting the expansion of intraislet CD4 ؉ CD25 ؉ T cell pool. Approximately 40 -50% of intraislet CD4 ؉ T cells expressed the CD25 marker and exhibited characteristics of regulatory T cells including small size, high level of intracellular CTLA-4, expression of Foxp3, and transfer of protection against diabetes. Results from in vivo incorporation of BrdUrd revealed that the generation of a high frequency of regulatory T cells in the islets is due to in situ expansion upon TGF-␤ expression. Thus, these findings demonstrate a previously uncharacterized mechanism by which TGF-␤ inhibits autoimmune diseases via regulation of the size of the CD4 ؉ CD25 ؉ regulatory T cell pool in vivo.T ype I diabetes is an autoimmune disease that results from the failure of tolerance to beta-cell antigens (1). The mechanisms that have evolved to ensure discrimination between self and nonself are highly complex and not foolproof. Models of passive tolerance, such as thymic deletion of autoreactive T cells or nonreponsiveness in the periphery because of anergy or ignorance, cannot account for the presence of autoreactive T cells in healthy individuals despite the absence of the development of organ-specific autoimmune diseases. T cells endowed with suppressive function to control actions of autoreactive T cells were described decades ago and were thought originally to be a specialized T cell population the effect of which would be mediated by secreted antigen-specific factors (2). Nowadays, suppressor T cells (also referred to as regulatory T cells) are delineated into two cell subsets of natural regulatory (CD4 ϩ CD25 ϩ ) cells that emerge from the thymus (3, 4) and adaptive regulatory (CD4 ϩ CD25 Ϫ ) cells induced in the periphery to develop suppressive activity (5-7). However, this concept of dichotomous thymic CD25 ϩ versus adaptive CD25 Ϫ regulatory T cells has been challenged by several reports, supporting evidence for the peripheral generation of CD25 ϩ regulatory T cells in vivo and in vitro (8)(9)(10)(11)(12). The finding that suppressive functions are instructively programmed by the expression of Foxp3 finally provided the basis for integrating a unified model of regulatory T cell diversity (13-15). Forced expression of Foxp3 in CD4 ϩ CD25 Ϫ nonregulatory T cells, either by retroviral expression or in transgenic mice, showed acquisition of suppressive activity in vitro and inhibition of disease in vivo, inducing in a substantial proportion of Foxp3-bearing cells the expression of CD25 and GITR markers indicating that ex...

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Impaired primary immune response in type-1 diabetes. Functional impairment at the level of APCs and T-cells

Cited by 68 publications

References 50 publications

T-Independent Antibody Responses to T-Dependent Antigens: A Novel Follicular Dendritic Cell-Dependent Activity

T-Independent Antibody Responses to T-Dependent Antigens: A Novel Follicular Dendritic Cell-Dependent Activity

Common infections in diabetes: pathogenesis, management and relationship to glycaemic control

TGF-β regulatesin vivoexpansion of Foxp3-expressing CD4⁺CD25⁺regulatory T cells responsible for protection against diabetes

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Impaired primary immune response in type-1 diabetes. Functional impairment at the level of APCs and T-cells

Cited by 68 publications

References 50 publications

T-Independent Antibody Responses to T-Dependent Antigens: A Novel Follicular Dendritic Cell-Dependent Activity

T-Independent Antibody Responses to T-Dependent Antigens: A Novel Follicular Dendritic Cell-Dependent Activity

Common infections in diabetes: pathogenesis, management and relationship to glycaemic control

TGF-β regulatesin vivoexpansion of Foxp3-expressing CD4+CD25+regulatory T cells responsible for protection against diabetes

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TGF-β regulatesin vivoexpansion of Foxp3-expressing CD4⁺CD25⁺regulatory T cells responsible for protection against diabetes