UMLS:C0011854 - FACTA Search

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Query: UMLS:C0011854 (type 1 diabetes)
20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Serum levels of recently discovered circulating forms of adhesion molecules, ICAM-1 and L-selectin, were found to be elevated in IDDM patients and in subjects at risk for developing IDDM compared with 100 normal, nondiabetic blood donors. Both adhesion molecules were determined by sandwich ELISA. Serum concentrations of either clCAM-1 or cL-selectin were > 2SD of normal mean in 10 of 14 recent-onset IDDM patients (P < 0.05). Serum levels of clCAM-1 and cL-selectin did not correlate. In first-degree relatives, elevated adhesion molecule levels were observed in the 6 ICA+ individuals and in the ICA- individuals all (n = 14) with a genetic risk of IDDM (sharing HLA-DR3 and/or-DR4 with the diabetic relative) but not in the HLA-DR3- and/or -DR4- relatives (n = 13). We conclude that elevated clCAM-1 and cL-selectin levels occur independently of ICA status and probably reflect ongoing immune processes in recent-onset IDDM patients and first-degree relatives at risk for IDDM.
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PMID:Elevated levels of circulating adhesion molecules in IDDM patients and in subjects at risk for IDDM. 128 Feb 39

Insulin dependent diabetes mellitus (IDDM) in the non-obese diabetic (NOD) mouse is the result of a cellular mediated autoimmune event that destroys pancreatic islet beta cells. This destruction is characterized by a progressive lymphocytic infiltration into the islets as well as circulating autoantibodies and T cells reactive with islet antigens. To gain a better understanding of the cells responsible for islet destruction we isolated lymphocytes from the islets of prediabetic NOD mice and conducted a comparative phenotypic analysis with the analogous subpopulations of lymphocytes isolated from peripheral blood and lymph node (LN) of the same mice. CD3+ cells were analysed for T cell receptor (TcR); cell bearing gamma delta TcR were consistently observed at a higher frequency in the infiltrating T cells than in the periphery. Lymphocytes were also characterized for the expression of CD4 and CD8 T cell markers and, within each population, for the expression of activation markers (CD25, CD69) and adhesion markers (CD51, CD54, CD11b, CD49e, L-selectin). Significantly increased levels of CD4+CD8+ double-positive and CD4-CD8- double-negative T cell populations were observed in the infiltrating lymphocytes as compared with peripheral lymphocytes. In addition, within both CD4 and CD8 subpopulations isolated from islet infiltrates, CD11b+ and CD49e+ cells were increased with respect to the same subset of cells isolated from the periphery. In contrast, the level of cells that expressed L-selectin was significantly higher in the periphery for both CD4+ and CD8+ cells than for infiltrating cells. These data describe the phenotype of islet reactive T cells in the NOD mouse and identify possible targets for therapeutic intervention.
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PMID:Differences in adhesion markers, activation markers, and TcR in islet infiltrating vs. peripheral lymphocytes in the NOD mouse. 761 49

In IDDM, mononuclear cells accumulate in the islets of Langerhans and destroy insulin-producing beta-cells. To study the mechanisms that control extravasation of circulating mononuclear cells into the pancreas, we examined the phenotype of vascular endothelium of the pancreas, propagated a T-cell line from pancreatic islets at the onset of the disease and compared endothelial binding of this cell line in vitro to vascular endothelium in different body regions. The adhesion molecules expressed on the resulting T-cell line and the functional binding capacity of these cells to the endothelium of the normal and diabetic pancreas, mucosa-associated lymphatic tissues, and regional and peripheral lymph nodes were studied. We present evidence of pancreatic endothelial activation in diabetes, leading to endothelial morphology typical for HEVs and accompanying local increase in extravasation of mononuclear cells into the pancreas. Endothelial-cell binding experiments with the T-cell line showed strong adherence of the cells to the endothelium of diabetic pancreas and mucosal lymphoid tissue. The cell line was uniformly CD4-positive, TCR V beta 5.1-positive, LFA-1-positive (CD 11a/CD18), VLA-4 alpha-positive (CD 49d), and CD 44-positive but negative for L-selectin (peripheral lymph node homing receptor). The pancreatic or control cell lines showed no binding to vessels of normal pancreas, and the binding of the pancreatic cell line to the endothelium of peripheral lymph node was weak. Our results suggest that lymphocyte-endothelial cell interactions are important for the accumulation of inflammatory mononuclear cells into the pancreas and imply that lymphocytes derived from the mucosal lymphoid tissue may be involved in the pathogenesis of IDDM.
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PMID:Endothelial cell-binding properties of lymphocytes infiltrated into human diabetic pancreas. Implications for pathogenesis of IDDM. 840 9

Non-obese diabetic mice spontaneously develop a type 1 diabetes. The entry of leukocytes in the islets of Langerhans was studied in untreated and in irradiated mice. FITC-labeled cells from spleen, lymph nodes or bone marrow of healthy or diabetic donors did home to the inflamed islets of unmanipulated recipients. B and T cells migrated equally well, whereas rare neutrophils entered the islets. Lymphocyte homing was blocked by anti-L-selectin and anti-alpha 4 integrin antibodies. Insulitis transfer experiments using mice congenic at the Thy-1 locus showed that anti-alpha 4 integrin treatment totally inhibited the migration of donor type T cells in the islets, whereas anti-L-selectin only had an early and transient effect. The expression of vascular addressins in the islets was linked to the presence of mononuclear cells. Thus, in the developing islet infiltrate, the entry of cells appears continuous and restricted to lymphocytes, whether autoreactive or not, and involves the L-selectin. This mechanism rather promotes the migration of naive-type cells. Conversely, during the adoptive transfer of insulitis the entry of L-selectin- diabetogenic T cells is highly favored, to the detriment of L-selectin+ naive type cells.
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PMID:Homing of lymphocytes into islets of Langerhans in prediabetic non-obese diabetic mice is not restricted to autoreactive T cells. 874 60

The infiltration of pancreatic islets by mononuclear cells is the hallmark of the development of insulin dependent diabetes mellitus (IDDM) in the NOD mouse, an animal model for human IDDM. The aim, of this study was to correlate adhesion molecule expression with the degree of islet infiltration and to compare Th1- and Th2-driven islet inflammation. Cryostat sections of NOD mouse pancreata before and after diabetes development were analysed by semiquantitative immunohistochemistry. NOD mouse islets did not show the expression of ICAM-1, LFA-1, L-selectin and VCAM-1 prior to infiltration by mononuclear cells. Furthermore, islets with early stage insulitis (grade 1, periinsular location of small infiltrates) still were devoid of adhesion molecule expression. ICAM-1 and LFA-1 were first demonstrable in islets with strong periinsular infiltrates (insulitis grade 2) while L-selectin and VCAM-1 were only seen in islets with mild or strong intraislet infiltration (grade 3-4). Adhesion molecules were demonstrable in areas of macrophage and T-lymphocyte infiltrates but not in adjacent endocrine islet tissue. Islets of all infiltration stages contained Th2 lymphocytes (positive for IL-4). Substantial numbers of Th1 cells (positive for IFN-gamma, TNF-alpha, IL-2 and/or IL-2 receptor) were observed only after acceleration of diabetes development by a single injection of cyclophosphamide (250 mg/kg i.p.). Interestingly, the adhesion molecule expression pattern in islets with "Th1' versus "Th2 insulitis' was not different. In conclusion, the expression of adhesion molecules in islets during the development of autoimmune diabetes does not precede mononuclear infiltration but probably occurs in response to the activation of initial small infiltrates. ICAM-1 and LFA-1 expression is seen prior to L-selectin and VCAM-1. However, adhesion molecule expression during Th1 versus Th2 cell infiltration is very similar, suggesting similar adhesion molecule requirements of the two Th subsets.
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PMID:Differential expression of ICAM-1 and LFA-1 versus L-selectin and VCAM-1 in autoimmune insulitis of NOD mice and association with both Th1- and Th2-type infiltrates. 893 79

To clarify conflicting claims of altered serum concentrations of soluble L-selectin (sCD62L) in recent-onset IDDM, sCD62L was measured in 89 children and adolescents with IDDM (35 recent-onset, 12 during the first year of insulin treatment, and 42 with long-standing (> 1 yr) treatment) alongside 124 controls. Children < 14 yr of age both with and without IDDM (n = 160) had grossly elevated sCD62L concentrations (20.2 +/- 4.9 nmol/l), as compared with adolescents (14-18 yr, n = 23; 15.9 +/- 3.9 nmol/l) and adults (> 18 yr, n = 30; 11.2 +/- 2.3 nmol/l) (p < 0.0001). Multivariate analysis confirmed the strong inverse association between age and sCD62L (p < 0.001) while revealing that sCD62L concentrations were slightly elevated in recent-onset IDDM, as compared with insulin-treated IDDM patients or nondiabetic controls (p = 0.028). Actual sCD62L concentrations in the 35 recent-onset IDDM patients were 22.2 +/- 4.9 nmol/L vs 19.6 +/- 3.6 nmol/l in 35 non-diabetic controls matched for age (p = 0.022). While this significant but small rise of systemic sCD62L reflects leukocyte activation, it is obscured by the inverse association between sCD62L and chronological age in children and adolescents. Therefore, determining sCD62L serum concentrations appears to be of limited value for clinical investigators caring for children and adolescents with IDDM.
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PMID:Circulating L-selectin concentrations in children with recent-onset IDDM. 1068 42

There is increasing evidence that the alterations of function and/or level of adhesion molecules play a key role in the pathogenesis of autoimmune diseases, such as Graves' disease or type 1 diabetes. The aim of the present study was to evaluate the expression of lymphocyte function-associated antigen 1 alpha (LFA-1 alpha, CD11a) and L-selectin (CD62L) molecules on peripheral mononuclear cells in Graves disease and type 1 diabetes in comparison to healthy controls, since they were shown to play an important role in lymphocytes and/or monocytes migration into the organs affected by immune process and are suggested to contribute to the pathogenesis of Graves disease and type 1 diabetes. The percentages of monocytes/lymphocytes expressing LFA-1 alpha antigen and lymphocytes expressing L-selectin antigen and the fluorescence intensity of the studied molecules were measured by flow cytometry. At the onset of both autoimmune diseases the percentage of highly CD11a positive lymphocytes and the mean fluorescence intensity were statistically higher than in the healthy controls and patients with Graves' disease after thyreostatic therapy. The fluorescence intensity of LFA-1 alpha on monocytes was also increased in type 1 diabetic patients, but not in Graves' disease. The analysis of CD62L antigen expression on peripheral blood lymphocytes revealed decreased percentages of L-selectin positive cells in patients with Graves' disease (before and after treatment) and insulin-dependent diabetes in comparison to the controls. Our study suggests that the alterations of the expression of CD11a and/or CD62L molecules on peripheral blood lymphocytes could be the markers of ongoing autoimmune process in Graves disease and type 1 diabetes.
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PMID:The alterations of CD11A expression on peripheral blood lymphocytes/monocytes and CD62L expression on peripheral blood lymphocytes in Graves' disease and type 1 diabetes. 1069 30

There have been some studies published recently which have suggested that L-selectin and/or other adhesion molecules could be the new markers for diabetes type 1 risk development in humans and animal models of the disease. The alterations of soluble L-selectin have been found not only in overt but also in the preclinical stage of disease development and were independent from the presence of ICA - a marker of ongoing autoimmunity, but associated with HLA related genetic predisposition to insulin-dependent diabetes mellitus (IDDM). The aim of our study was to evaluate the frequency of the L-selectin gene T668C mutation (from thymine to cytosine at position 668) resulted in F206L an amino acid substitution in patients with overt diabetes and their unaffected first degree relatives in comparison to the unselected control population. In the unaffected siblings of IDDM subjects we have observed a significantly higher frequency of the L-selectin gene T668C mutation in comparison to their relatives with type 1 diabetes and healthy controls. It was also shown that there is an association between T668C mutation and low HLA related risk of IDDM development, the highest frequency of F206L mutation in the EGF domain of L-selectin was observed in relatives with 'protective' HLA DQB1*0602 allele and nonDRB1*03-nonDRB1*04 haplotype, while in subjects with highest risk of IDDM haplotype the frequency of T668C mutation was similar to the controls. We would like to hypothesise that the T668C L-selectin gene mutation could have a (protective?) role in the development of IDDM, but further studies concerning their role in type 1 diabetes are needed.
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PMID:L-selectin gene T668C mutation in type 1 diabetes patients and their first degree relatives. 1106 6

We measured the concentrations of the soluble forms of the intercellular adhesion molecule-1 (sICAM-1) and L-selectin in 95 autoantibody-positive siblings of children with type 1 diabetes and 95 sex- and age-matched siblings testing negative for diabetes-associated autoantibodies to assess the possible role of soluble adhesion molecules as markers of progressive ss-cell destruction in preclinical diabetes and their ability to discriminate between those siblings who progress to clinical disease and those who remain nondiabetic. We observed an inverse correlation between age and the levels of both sICAM-1 (r = -0.31, p < 0.001) and sL-selectin (r = -0.27, p < 0.001) in the control siblings but no association with HLA-DR phenotypes. There was no difference in the circulating levels of soluble adhesion molecules between the antibody-positive and negative siblings. Among the antibody-positive siblings, those with at least three autoantibodies had higher sICAM-1 levels (p < 0.01) than those testing positive for only one, and siblings with three autoantibodies or more had higher concentrations of sL-selectin (p < 0.01) than those with two autoantibodies. Siblings with an islet cell antibody level of 20 Juvenile Diabetes Foundation units or more had higher sICAM-1 concentrations than those with a level below 20 (p < 0.001), and those testing positive for antibodies to the protein tyrosine phosphatase-related IA-2 antigen had increased levels of both sICAM-1 (p = 0.03) and sL-selectin (p = 0.02) compared with siblings who tested negative. The antibody-positive siblings who progressed to clinical type 1 diabetes were significantly younger than the nonprogressors (p < 0.001) and had higher levels of sICAM-1 initially (p < 0.001). The difference in sICAM-1 concentrations remained significant (p = 0.03) after age adjustment. Our results indicate that concentrations of soluble adhesion molecules are increased in the autoantibody-positive siblings who have the highest risk of developing clinical diabetes, suggesting that ss-cell destruction is reflected in increased circulating levels of these molecules. This is supported by the observation of elevated sICAM-1 concentrations in the 29 siblings who actually progressed to clinical type 1 diabetes. Peripheral levels of soluble adhesion molecules are not able to discriminate between progressors and nonprogressors, however, due to substantial overlapping between these two groups.
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PMID:Soluble adhesion molecules in preclinical type 1 diabetes. The Childhood Diabetes in Finland Study Group. 1113 83

Administration of anti-L-selectin (CD62L) mAb to neonatal nonobese diabetic (NOD) mice mediates long term protection against the development of insulitis and overt diabetes. These results suggested that CD62L has a key role in the general function of beta cell-specific T cells. To further examine the role of CD62L in the development of type 1 diabetes, NOD mice lacking CD62L were established. The onset and frequency of overt diabetes were equivalent among CD62L(+/+), CD62L(+/-), and CD62L(-/-) NOD littermates. Furthermore, patterns of T cell activation, migration, and beta cell-specific reactivity were similar in NOD mice of all three genotypes. Adoptive transfer experiments with CD62L(-/-) CD4(+) T cells prepared from BDC2.5 TCR transgenic mice revealed no apparent defects in migration to pancreatic lymph nodes, proliferation in response to beta cell Ag, or induction of diabetes in NOD.scid recipients. In conclusion, CD62L expression is not essential for the development of type 1 diabetes in NOD mice.
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PMID:L-selectin is not required for T cell-mediated autoimmune diabetes. 1188 30

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