Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0011849 (diabetes)
277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

T lymphocytes recognise peptide antigens through the T cell antigen receptor, which is composed of variable alpha and beta chains. There are forty-six functional variable regions on the beta chain. In this study the expression of the T cell receptor beta-chain variable regions 2S1 and 3S1, in a large cohort of multiplex insulin-dependent diabetes mellitus families, have been determined by use of monoclonal antibodies and flow cytometry. Peripheral blood was collected from these multiplex families and three control groups, healthy individuals, sporadic insulin-dependent diabetes mellitus patients and non-insulin-dependent diabetes mellitus patients. The level of TCRBV2S1 expression in the multiplex families was significantly higher than all the control groups for both the CD4+ and CD8+ T lymphocyte subsets. Detailed analysis of the family data showed that this increased expression was not associated with age, sex, HLA type or the diabetic phenotype. The TCRBV3S1 expression in all the diabetic cohorts was significantly lower than the healthy controls, in the CD4 subset only. Detailed analysis of the family data showed only the fathers TCRBV3S1 expression was lower than the healthy controls. This study gives further insight into TCRBV usage which could reflect the mechanism of the autoimmune response in IDDM multiplex families.
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PMID:Individuals from multiplex insulin-dependent diabetes mellitus (IDDM) families express higher levels of TCRBV2S1 than controls. 954 38

Viral induction of autoimmunity is thought to occur by either bystander T-cell activation or molecular mimicry. Coxsackie B4 virus is strongly associated with the development of insulin-dependent diabetes mellitus in humans and shares sequence similarity with the islet autoantigen glutamic acid decarboxylase. We infected different strains of mice with Coxsackie B4 virus to discriminate between the two possible induction mechanisms, and found that mice with susceptible MHC alleles had no viral acceleration of diabetes, but mice with a T cell receptor transgene specific for a different islet autoantigen rapidly developed diabetes. These results show that diabetes induced by Coxsackie virus infection is a direct result of local infection leading to inflammation, tissue damage, and the release of sequestered islet antigen resulting in the re-stimulation of resting autoreactive T cells, further indicating that the islet antigen sensitization is an indirect consequence of the viral infection.
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PMID:Diabetes induced by Coxsackie virus: initiation by bystander damage and not molecular mimicry. 966 63

Nonobese diabetic (NOD) mice develop insulin-dependent diabetes mellitus due to autoimmune T lymphocyte-mediated destruction of pancreatic beta cells. Although both major histocompatibility complex class I-restricted CD8(+) and class II-restricted CD4(+) T cell subsets are required, the specific role each subset plays in the pathogenic process is still unclear. Here we show that class I-dependent T cells are required for all but the terminal stages of autoimmune diabetes development. To characterize the diabetogenic CD8(+) T cells responsible, we isolated and propagated in vitro CD8(+) T cells from the earliest insulitic lesions of NOD mice. They were cytotoxic to NOD islet cells, restricted to H-2Kd, and showed a diverse T cell receptor beta chain repertoire. In contrast, their alpha chain repertoire was more restricted, with a recurrent amino acid sequence motif in the complementarity-determining region 3 loop and a prevalence of Valpha17 family members frequently joined to the Jalpha42 gene segment. These results suggest that a number of the CD8(+) T cells participating in the initial phase of autoimmune beta cell destruction recognize a common structural component of Kd/peptide complexes on pancreatic beta cells, possibly a single peptide.
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PMID:Major histocompatibility complex class I-restricted T cells are required for all but the end stages of diabetes development in nonobese diabetic mice and use a prevalent T cell receptor alpha chain gene rearrangement. 977 May 21

We report the onset of pure red cell aplasia (PRCA) in a patient with a history of polyglandular syndrome including Addison's disease, malabsorption syndrome, diabetes type I and gastric hyperplastic polyposis. An autoimmune origin for this complex disorder was not supported by the presence of organ specific antibodies, but T cells were found to be of polyclonal origin, as demonstrated by molecular analysis of T cell receptor (TCR) gene rearrangement. The pathophysiology of this case, based on laboratory findings and response to therapy, is discussed.
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PMID:Pure red cell aplasia in autoimmune polyglandular syndrome with T lymphocytosis. 986 28

Little is known about the events triggering lymphocyte invasion of the pancreatic islets in prelude to autoimmune diabetes. For example, where islet-reactive T cells first encounter antigen has not been identified. We addressed this issue using BDC2.5 T cell receptor transgenic mice, which express a receptor recognizing a natural islet beta cell antigen. In BDC2.5 animals, activated T cells were found only in the islets and the lymph nodes draining them, and there was a close temporal correlation between lymph node T cell activation and islet infiltration. When naive BDC2.5 T cells were transferred into nontransgenic recipients, proliferating cells were observed only in pancreatic lymph nodes, and this occurred significantly before insulitis was detectable. Surprisingly, proliferation was not seen in 10-day-old recipients. This age-dependent dichotomy was reproduced in a second transfer system based on an unrelated antigen artificially expressed on beta cells. We conclude that beta cell antigens are transported specifically to pancreatic lymph nodes, where they trigger reactive T cells to invade the islets. Systemic or extrapancreatic T cell priming, indicative of activation via molecular mimicry or superantigens, was not seen. Compromised presentation of beta cell antigens in the pancreatic lymph nodes of juvenile animals may be the root of a first "checkpoint" in diabetes progression.
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PMID:Initiation of autoimmune diabetes by developmentally regulated presentation of islet cell antigens in the pancreatic lymph nodes. 989 15

The roles of enteric viruses and food antigens as possible triggers in human insulin-dependent diabetes mellitus and the evidence that mucosal-associated homing receptors are important in both human and experimental diabetes prompted us to undertake an immunohistochemical study of intestinal specimens from patients with IDDM. We studied jejunal morphology and immunohistochemistry in 26 patients with IDDM, 13 of whom had the HLA-DQB1*0201 gene and therefore a higher risk of coeliac disease. The findings were compared with those in specimens from age-matched controls. Villous structure and the density of the intraepithelial lymphocytes were normal in every biopsy specimen. The extent of positivity with anti-DR and -DP antibodies in the villous epithelium was significantly greater in the specimens from patients than in those from controls (P = 0.0002 in both comparisons). The crypts were also more positive: for DR P = 0.0001, and for DP P = 0.002. The densities of T cells, CD4+, CD8+, and T cell receptor alpha/beta+ and gamma/delta+ cells in the epithelium and lamina propria were similar in patients and controls, but the patients had significantly more alpha 4/beta 7 integrin+ cells in the lamina propria (P = 0.006). No difference was seen between HLA-DQB1*0201-positive and -negative patients. These findings reflect a stage of inflammation in the structurally normal intestines of patients with IDDM and suggest secretion of inflammatory Th1-type cytokines in the intestine.
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PMID:Jejuna of patients with insulin-dependent diabetes mellitus (IDDM) show signs of immune activation. 1020 7

T cell fate following antigen encounter is determined by several intracellular signals generated by the interaction of the T cell with an antigen-presenting cell. In the periphery activation requires T cell receptor signaling (signal one) in combination with costimulatory signals (signal two), usually provided through the cognate interaction of CD28 and B7 molecules. Provision of signal one alone to purified murine peripheral T cells in vitro induces apoptosis or anergy rather than promoting activation. These T cells can be rescued from apoptosis if they are provided with costimulation supplied, for example, by engaging the CD28 co-receptor with an anti-CD28 monoclonal antibody or by adding an exogenous source of interleukin-2. However, a majority of peripheral T cells from autoimmune, diabetes-prone Biobreeding (BB) rats exhibited different responses to these stimuli. T cells from these rats could not be rescued from apoptosis by costimulation. This was not due to the inability of BB-DP T cells to upregulate CD28 and the IL-2 receptor in response to TCR crosslinking. The failure of these costimulatory interactions to rescue BB-DP T cells segregated with the diabetes-susceptibility gene iddm1. Iddm1 in the rat causes peripheral T cell lymphopenia, which is associated with a dramatically shortened peripheral T cell life span. Our results indicate that a diabetogenic gene may contribute to autoimmunity by negating costimulatory signals important for the survival of long-lived peripheral T cells.
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PMID:A diabetogenic gene prevents T cells from receiving costimulatory signals. 1035 84

Spontaneous autoimmune diabetes in nonobese diabetic (NOD) mice is the result of a CD4(+) and CD8(+) T cell-dependent autoimmune process directed against the pancreatic beta cells. CD8(+) T cells play a critical role in the initiation and progression of diabetes, but the specificity and diversity of their antigenic repertoire remain unknown. Here, we define the structure of a peptide mimotope that elicits the proliferation, cytokine secretion, differentiation, and cytotoxicity of a diabetogenic H-2K(d)-restricted CD8(+) T cell specificity (NY8.3) that uses a T cell receptor alpha (TCRalpha) rearrangement frequently expressed by CD8(+) T cells propagated from the earliest insulitic lesions of NOD mice (Valpha17-Jalpha42 elements, often joined by the N-region sequence M-R-D/E). Stimulation of splenic CD8(+) T cells from single-chain 8. 3-TCRbeta-transgenic NOD mice with this mimotope leads to preferential expansion of T cells bearing an endogenously derived TCRalpha chain identical to the one used by their islet-associated CD8(+) T cells, which is also identical to the 8.3-TCRalpha sequence. Cytotoxicity assays using islet-derived CD8(+) T cell clones from nontransgenic NOD mice as effectors and peptide-pulsed H-2K(d)-transfected RMA-S cells as targets indicate that nearly half of the CD8(+) T cells recruited to islets in NOD mice specifically recognize the same peptide/H-2K(d) complex. This work demonstrates that beta cell-reactive CD8(+) T cells mount a prevalent response against a single peptide/MHC complex and provides one peptide ligand for CD8(+) T cells in autoimmune diabetes.
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PMID:Prevalent CD8(+) T cell response against one peptide/MHC complex in autoimmune diabetes. 1043 Sep 39

A minor subset of murine MHC class I-restricted T cells which express both the alphabeta form of the T cell receptor and a NK lineage marker, termed NKT cells, is capable of secreting significant amounts of Interleukin-4 and Interferon-y upon activation. As such NKT cells may play a role in development of Th1 and Th2 cells during T cell ontogeny or expansion of T cells expressing a dominant cytokine pattern in the effector phase. We have studied the role of NKT cells in a murine model of disease multidose streptozotocin induced diabetes mellitus (MDSDM). In MDSDM thymic and splenic NKT cells are present at normal levels but have greatly reduced capacity to secrete Interleukin-4 upon stimulation with anti-TCR antibody compared to control mice; conversely, Interferon-y secretion is maintained. By analysis of cytokine RNA production we found that treatment of several strains of mice with streptozotocin changes the peripheral helper T cell phenotype elicited after immunization with Keyhole Limpet Hemocyanin from a mixed Th1- and Th2-type cytokine pattern (characterized by IFN-gamma and IL-4 and IL-5 expressions, respectively) to predominately Th1-type. Furthermore, susceptibility to MDSDM is significantly enhanced when NKT cells are selectively eliminated in vivo by administration of depleting anti-CD122 antibody TMbeta-1. In addition, antibody depletion of NKT cells from non-obese diabetic mice significantly accelerates onset of disease. Collectively these data support a model for development of murine diabetes mellitus in which NKT cell cytokine expression influences the development of Th1-type diabetogenic T cells.
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PMID:NKT cell cytokine imbalance in murine diabetes mellitus. 1043

In this paper, we test the hypothesis that triggering of a second T cell receptor (TCR) expressed on diabetogenic T cells might initiate the onset of diabetes. A cross between two TCR-transgenic strains, the BDC2.5 strain that carries diabetogenic TCRs and the A18 strain that carries receptors specific for C5, was set up to monitor development of diabetes after activation through the C5 TCR. F1 BDC2. 5 x A18 mice developed diabetes spontaneously beyond 3-4 mo of age. Although their T cells express both TCRs constitutively, the A18 receptor is expressed at extremely low levels. In vitro activation of dual TCR T cells followed by adoptive transfer into neonatal or adult F1 mice resulted in diabetes onset and death within 10 d after transfer. In contrast, in vivo immunization of F1 mice with different forms of C5 antigen not only failed to induce diabetes but protected mice from the spontaneous onset of diabetes. We propose that antigenic stimulation of cells with low levels of TCR produces signals inadequate for full activation, resulting instead in anergy.
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PMID:Triggering a second T cell receptor on diabetogenic T cells can prevent induction of diabetes. 1044 28


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