T-cell reactivity to 38 kD insulin-secretory granule protein in patients with recent onset type 1 diabetes

Roep, Bart O.; Kallan, A. A.; Hazenbos, Wouter L. W.; Bruining, Jan; Bailyes, E M; Arden, Susan D.; Hutton, John C.; Vries, R. R. P. De; Bonifacio, Ezio

doi:10.1007/bf03347750

Cited by 20 publications

(25 citation statements)

References 19 publications

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“…Specificity of an anti-jun-B T-cell response would require processing and presentation of islet (p-cell)-specific jun-B epitopes or the persistent effect of a p-cell cytotropic virus (30) or both, or chemotoxin (31) to induce aberrant expression of jun-B. Roep et al (12,13) generated T-cell lines from IDDM subjects to a 38,000-/W r fraction of insulin secretory granules. Although secretory granules would not be expected to contain jun-B, after isolation they appear to be contaminated by a multiplicity of proteins; moreover, the T-cell lines reacted not only with 38,000-M r granule fraction but also with the pellet fraction that contained endoplasmic reticulum (13).…”

Section: Discussionmentioning

confidence: 99%

“…Recently, T-cells in the peripheral blood of recent-onset IDDM subjects and at-risk ICA-positive first-degree relatives of IDDM subjects have been shown to proliferate'to islets (8,9) and specifically to insulin (8,9) and GAD (10,11). In addition, Roep et al (12,13) generated T-cell lines from peripheral blood of recent-onset IDDM subjects to an uncharacterized 38,000-M r fraction of insulin secretory granule membranes.…”

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confidence: 99%

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Transcription Factor jun-B is Target of Autoreactive T-Cells in IDDM

Honeyman

Cram²,

Harrison³

1993

Diabetes

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Target antigens defined by autoantibodies in IDDM include insulin, a putative glycolipid that reacts with islet cell antibodies, and a 64,000-/tf r protein recently identified as glutamic acid decarboxylase. In addition, some IDDM sera that contain antibodies to glutamic acid decarboxylase also coprecipitate a 38,000-M r protein from islets. This study used a high titer anti-38,000-M r serum to screen bacteriophage A. cDNA expression libraries and identified human islet and placental clones encoding jun-B, the nuclear transcription protein, of predicted 38,000 M r . Peripheral blood T-cells exhibited significant proliferation in response to a recombinant fragment of jun-B (amino acids 1-180) in 12 of 17 (71%) recent-onset IDDM subjects, 8 of 16 (50%) ICA-positive first-degree relatives of IDDM subjects who were at risk, 3 of 12 (25%) other autoimmune disease subjects, and 0 of 10 healthy control subjects. Proliferation to tetanus toxoid did not differ significantly between the groups. Responses to jun-B were not related to age, sex, or human leukocyte antigen status. Thus, autoreactive T-cells identify a novel antigen, p38 jun-B, in IDDM and appear to indicate subjects at risk for the development of clinical disease. Diabetes 42:626-30,1993

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Transcription Factor jun-B is Target of Autoreactive T-Cells in IDDM

Honeyman

Cram²,

Harrison³

1993

Diabetes

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“…Several autoantigens have been identified by autoantibodies in the sera of acutely diabetic and prediabetic subjects, including GAD, IA-2, and insulin (1)(2)(3)(4)(5). Recent studies have revealed that the cellular immune response is the major effector mechanism in the destruction of pancreatic ␤-cells in human subjects with type 1 diabetes (6)(7)(8). Among T-cells, T-helper type 1 (Th1) cells that secret interleukin (IL)-2 and interferon (IFN)-␥ are suspected to be the key effector cells responsible for the destruction of pancreatic ␤-cells (9).…”

Section: Suppression and Acceleration Of Autoimmune Diabetes By Neutrmentioning

confidence: 99%

Suppression and acceleration of autoimmune diabetes by neutralization of endogenous interleukin-12 in NOD mice.

et al. 2000

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A corpus of evidence suggests that T-helper type 1 (Th1)-dependent cellular immunity plays a pivotal role in the pathogenesis of autoimmune diabetes. This study was intended to find ways to prevent the development of NOD diabetes using a neutralizing anti-interleukin (IL)-12 antibody (C17.8) that inhibits Th1 cell differentiation. When C17.8 was administered from 5 to 30 weeks of age, NOD mice exhibited suppression of both insulitis and diabetes. However, when C17.8 administration ceased at 15 weeks of age, 8 of 13 recipients showed diabetes at 30 weeks of age. These results suggest that IL-12 plays an important role not only in the development of effector cells but also in their activation. In contrast, when C17.8 was injected into 2-week-old female NOD mice for 6 consecutive days, all 16 recipients showed diabetes at 30 weeks of age, whereas 12 of 20 control mice became diabetic. This result suggests that depletion of endogenous IL-12 at a young age results in the enhancement of diabetes. Flow cytometric analysis indicated that activated memory T-cells were present in higher numbers after C17.8 treatment. Transfer of spleen cells from 15-week-old C17.8-treated NOD mice to NOD-scid mice resulted in an earlier onset and a higher incidence of diabetes. Furthermore, administration of C17.8 to 2-week-old NOD mice also resulted in a much earlier onset of diabetes. These results suggest that short-term treatment with anti-IL-12 antibody prohibits IL-2 production at a young age, which may influence the expansion and apoptosis of pathogenic T-cells, resulting in the acceleration of autoimmune diabetes.

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“…[15]. The nature of the islet antigen recognized by diabetogenic T cells is unknown although T cells of diabetic patients have been shown to react to various antigens such as insulin, insulin secretory granules, 38 kDa granule membrane proteins, RINm5F insulinoma membranes, fetal pig proislets, human islets and GAD [16][17][18][19][20][21][22]. However, the relation of such responses with the autoimmune-mediated beta-cell destruction process in IDDM is still an open question.…”

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confidence: 99%

Altered immune response to insulin in newly diagnosed compared to insulin-treated diabetic patients and healthy control subjects

et al. 1997

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Insulin-dependent diabetes mellitus (IDDM) is the result of a genetically associated autoimmune mediated process in which the insulin-producing pancreatic beta-cells are thought to be destroyed by autoreactive T cells [1,2]. The disease process is accompanied by autoreactive T cells and autoantibodies to various islet antigens. Many IDDM patients develop humoral immune responses to insulin [3,4], islet cells [5], tyrosine phosphatase homologue islet cell antibody ((ICA)512/islet cell antigen (IA)-2, 37 K) [6-9] and glutamic acid decarboxylase (GAD)65 [10][11][12]. Even though autoantibodies may not be directly involved in the destructive process, 60 % of new-onset diabetic patients are positive for insulin autoantibodies (IAA) compared to only 0.5 % of healthy control subjects [2]. The involvement of T cells in the pathogenesis has been implicated by insulitis [13], the recurrence of insulitis and diabetes after pancreas transplantation [14] and the transfer of diabetes with non-T-cell-depleted bone marrow transplants

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T-cell reactivity to 38 kD insulin-secretory granule protein in patients with recent onset type 1 diabetes

Cited by 20 publications

References 19 publications

Transcription Factor jun-B is Target of Autoreactive T-Cells in IDDM

Transcription Factor jun-B is Target of Autoreactive T-Cells in IDDM

Suppression and acceleration of autoimmune diabetes by neutralization of endogenous interleukin-12 in NOD mice.

Altered immune response to insulin in newly diagnosed compared to insulin-treated diabetic patients and healthy control subjects

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