Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P14784 (IL-2 receptor)
 3,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The DQw3.2 specificity has previously been recognized using genomic RFLP analysis and certain combinations of monoclonal antibodies. Here we report three CD4+ T lymphocyte clones (TLCs) generated from a DR3,4; DQw2,w3.1 responder stimulated with cells from a DR3,4; DQw2,w3.2 donor, and using a modified cloning procedure involving enrichment of IL-2 receptor-positive T cell during priming. The resulting TLCs were strongly inhibited by some monoclonal anti-DQ, but not anti-DR or -DP antibodies. In panel studies using HLA homozygous stimulating cells, it was found that the TLCs recognize an HLA epitope encoded by a DQ gene carried only by DR4,DQw3.2 haplotypes. By comparison with published DQ chain amino acid sequences of some stimulating cells able or not to induce a response in these clones, evidence was obtained that Ala at position 57 on the DQ beta chain is most probably involved in the epitope. The epitope is present on cells from 12 out of 12 DR4,DQw3 insulin dependent diabetes mellitus (IDDM) patients, but on cells only from 6 out of 12 healthy DR4,DQw3 controls. Thus, a DQ-encoded epitope involving residue 57 on the DQ beta chain, and which is strongly associated to IDDM, may be recognized by T cells.
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PMID:T lymphocyte clones recognizing an HLA-DQw3.2-associated epitope involving residue 57 on the DQ beta chain. 245 88

The IL-2 system which involves IL-2 production, IL-2 receptor expression, and response to IL-2, is associated with autoimmune phenomena. Immunological abnormalities including autoimmune phenomena are believed to contribute to the pathogenesis of IDDM. In this study, the production of IL-2, the responses to IL-2 and IL-2 receptor expression by peripheral blood T lymphocytes were compared in IDDM and normal non-diabetic children. The percentage of IL-2 receptor-positive circulating T cells was significantly increased in diabetic children, although IL-2 receptor expression induced by con A stimulation did not differ in the diabetic and control children. IL-2 production was significantly decreased in diabetic children compared with the control children. The response of stimulated T cells to IL-2 did not differ in IDDM and control children. In IDDM, IL-2 production by CD4-positive T lymphocytes within the IL-2 system is thought to be selectively defective. On the other hand, IL-4, which is also produced by CD4-positive T lymphocytes, was increased. Since IL-4 did not suppress IL-2 production, it would seem that the IL-2 producing subset in CD4+HLA-DR+ T cells is decreased in IDDM. These results suggest that in recent onset IDDM, IL-2 receptor-positive circulating T cells require an IL-2 supply.
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PMID:Imbalance of the interleukin 2 system in children with IDDM. 805 85

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

IDDM is a T cell-mediated autoimmune disease which is paradoxically associated with T cell functional deficiencies. The proliferative response of PBMC under CD3-, Vbeta2-, Vbeta8- and Vbeta7-stimulation was investigated in IDDM and NIDDM patients, non-diabetic first-degree relatives and control subjects. Despite normal surface expression of the TCR/CD3 complex, the TCR/CD3-mediated proliferation of PBMC from IDDM patients was significantly impaired compared to control subjects (P<0.05). This defect was specific for the autoimmune disease, constitutive and not linked to the class II MHC genotype, to metabolic disturbances or to presence of specific autoantibodies. Inefficient activation of T cells was not related to a lower capacity of CD28 to transduce co-stimulative signals because proliferative responses under CD2/CD28 stimulations were similar in IDDM and control groups. The IL-2/IL-2 receptor system was functional because unstimulated PBMC proliferated in response to increasing amounts of IL-2. Nevertheless, despite normal expression of CD25, addition of IL-2 did not normalize the proliferative defect linked to IDDM. In conclusion, excluding a faulty co-stimulation pathway, these results are in favour of a constitutive defect in the CD3/TCR transduction machinery, increasing sensitivity to apoptosis or anergy in T cells from IDDM patients.
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PMID:Constitutive impaired TCR/CD3-mediated activation of T cells in IDDM patients co-exist with normal co-stimulation pathways. 1047 93

Although it is well known that patients with type 1 diabetes mellitus are susceptible to other autoimmune diseases, the simultaneous occurrence of clustered distinct autoimmune diseases is uncommon. We report a 16-year-old girl, previously diagnosed as having coeliac disease and IgA deficiency, who at 13 years of age developed a clustering of distinct autoimmune diseases, including type 1 diabetes mellitus, rheumatoid arthritis (RA) and euthyroid autoimmune thyroiditis, eventually resulting in a simultaneous long-term remission. The clinical picture was associated with a functional immunodeficiency characterized by a defect in proliferative responses to T cell predominant mitogens and a normal response to the B cell predominant mitogen. In addition, the T cell activation markers HLA-DR, IL-2 receptor and transferrin receptor) were not upregulated. The clinical course of this immunodeficiency paralleled the outcome of the autoimmune diseases. After the abrupt onset, spontaneous clinical remission of both diabetes mellitus and RA was observed. Insulin was first reduced in dose and then discontinued completely at 15 months, in the presence of normal C peptide secretion and normal metabolic control (HbA1c 5.8%). Anti-glutamate decarboxylase (GAD65) and anti-IA-2 antibodies remained persistently high. During the remission phase a normalization of the functional immune defect was observed. The gradual resolution of the multisystemic diseases as well as the normalization of immune function in our patient is unusual. This case may be of considerable value in furthering our knowledge of the immunological mechanisms implicated in these rare multireactive syndromes.
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PMID:Simultaneous peripubertal onset of multireactive autoimmune diseases with an unusual long-lasting remission of type 1 diabetes mellitus. 1110 28

Regulatory T-cells are a subset of T cells that have beene extensively studied in modern immunology. They are important for the maintenance of peripheral tolerance, and have an important role in various clinical conditions such as allergy, autoimmune disorders, tumors, infections, and in transplant medicine. Basically, this population has a suppressive effect on the neighboring immune cells, thus contributing to the local modulation and control of immune response. There are two main populations of regulatory T cells - natural regulatory T cells, which form a distinct cellular lineage, develop in thymus and perform their modulatory action through direct intercellular contact, along with the secreted cytokines; and inducible regulatory T cells, which develop in the periphery after contact with the antigen that is presented on the antigen presenting cell, and their primary mode of action is through the interleukin 10 (IL-10) and transforming growth factor beta (TGF-alpha) cytokines. Natural regulatory T cells are activated through T cell receptor after contact with specific antigen and inhibit proliferation of other T cells in an antigen independent manner. One of the major difficulties in the research of regulatory T cells is the lack of specific molecular markers that would identify these cells. Natural regulatory T cells constitutively express surface molecule CD25, but many other surface and intracellular molecules (HLA-DR, CD122, CD45RO, CD62, CTLA-4, GITR, PD-1, Notch, FOXP3, etc.) are being investigated for further phenotypic characterization of these cells. Because regulatory T cells have an important role in establishing peripheral tolerance, their importance is manifested in a number of clinical conditions. In the IPEX syndrome (immunodysregulation, polyendocrinopathy and enteropathy, X-linked), which is caused by mutation in Foxp3 gene that influences the development and function of regulatory T cells, patients develop severe autoimmune reactions that involve autoimmune endocrine disorders (type 1 diabetes, thyroiditis), respiratory and nutritive allergy, eczema and severe infections. In different types of allergy (pollen allergy, dust mite, nutritive allergens, contact hypersensitivity, etc.) and autoimmune diseases (such as rheumatoid arthritis, multiple sclerosis and type 1 diabetes) a lower number or decreased functional capability of regulatory T cells have been described. In inflammatory conditions and infections, this cell population has an important task in restricting immune response and protecting the host from excessive damage. This ability of regulatory T cells can be used by some pathogens (Epstein Barr virus, Mycobacterium tuberculosis, Leishmania major, etc.) and tumor cells to avoid host response and therefore contribute to the development of some pathological conditions. The knowledge gained on the phenotype and function of regulatory T cells could be useful in many medical conditions. In allergy, autoimmune diseases and in transplant procedures in medicine it would be desirable to increase their function, thus to partially suppress the immune system activity. On the other hand, in some infections and tumors, it would be preferable to decrease the activity of regulatory T cells and boost the function of effector T cells. Regulatory T cells comprise a very active field of immunology, therefore monitoring and modulating of their activity is of great potential significance in a broad spectrum of clinical conditions. By developing and standardizing methods for their monitoring, it would be possible to follow additional parameters of certain clinical conditions and possibly utilize them in therapy.
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PMID:[Regulatory T cells]. 1721 1

An important limitation in T cell studies of human autoimmune (type 1) diabetes is lack of direct access to cells infiltrating the pancreas. We hypothesized that cells recently released from the pancreas into the blood might express a characteristic combination of markers of activation. We therefore examined the recently activated circulating T cell population [CD3+, human leucocyte antigen D-related (HLA-DR+)] using cytokine production and 10 additional subset markers [CD69, CD25, CD122, CD30, CD44v6, CD57, CD71, CCR3 (CD193), CCR5 (CD195) or CXCR3 (CD183)], comparing newly diagnosed adult (ND) (age 18-40 years) patients (n=19) to patients with diabetes for >10 years [long-standing (LS), n=19] and HLA-matched controls (C, n=16). CD3+ DR+ cells were enriched by two-step immunomagnetic separation. No differences in basal or stimulated production of interleukin (IL)-4, IL-10, IL-13 or interferon (IFN)-gamma by CD3+ DR+ enriched cells were observed between the different groups of subjects. However, among the CD3+ DR+ population, significant expansions appeared to be present in the very small CD30+, CD69+ and CD122+ subpopulations. A confirmatory study was then performed using new subjects (ND=26, LS=15), three-colour flow cytometry, unseparated cells and three additional subset markers (CD38, CD134, CD4/CD25). This confirmed the expansion of the CD3+ DR+ CD30+ subpopulation in ND subjects. We conclude that a relative expansion in the T cell subpopulation with the activated phenotype CD3+ DR+ CD30+ is seen in the peripheral blood of subjects with newly diagnosed type 1 diabetes. This subpopulation represents less than 0 x 7% of circulating T cells and may provide a rich source of disease-specific T cells that can be isolated from blood.
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PMID:Activated T cell subsets in human type 1 diabetes: evidence for expansion of the DR+ CD30+ subpopulation in new-onset disease. 1730 96

Interleukin-2 (IL-2) plays an established role in T-cell regulation through binding to the high-affinity IL-2 receptor (IL-2R). The alpha-chain encoded by the IL2RA (CD25) gene is a substantial component of the high-affinity receptor molecule highly expressed by activated T lymphocytes. Recently, a strong evidence was obtained for the involvement of IL-2RA in conferring susceptibility to type 1 diabetes (T1D). Significant association with T1D was also found in the region on chromosome 4q27 containing the IL2 gene and homologous to the susceptibility locus idd3 in non-obese diabetic (NOD) mice, an animal model for human T1D. Here we focus on the discussion of these new findings suggesting for a crucial role of IL-2/IL-2RA-mediated regulatory mechanisms in preventing T1D. The non-redundant role of IL-2 and its receptor in etiology of T1D could be particularly attributable to the regulation of CD4+ CD25+ regulatory T cells, whose function is critical in maintaining immune homeostasis.
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PMID:The crucial role of IL-2/IL-2RA-mediated immune regulation in the pathogenesis of type 1 diabetes, an evidence coming from genetic and animal model studies. 1841 24

Multiple sclerosis (MS) is an organ-specific autoimmune disorder that is in part genetically determined. The gene encoding the alpha-chain of the IL-2 receptor, IL2RA, harbors alleles associated with risk to MS and other autoimmune diseases. In addition, IL2RA genetic variants correlate with the levels of a soluble form of the IL-2 receptor in subjects with type 1 diabetes and multiple sclerosis. Here, we show that the IL2RA genotypes differentially affects soluble IL-2RA (sIL-2RA) levels in MS cases vs healthy controls; the two variants associated with MS (rs12722489 and rs2104286) account for 15 and 18% of the total variance in log(10)-transformed sIL-2RA concentration in control subjects but less so in subjects with MS (2 and 5%), suggesting that perturbations associated with disease or treatment may influence sIL-2RA levels in subjects with MS. Whereas analyses demonstrate that sIL-2RA serum concentrations are a remarkably stable phenotype in both healthy controls and untreated MS subjects, a difference is observed between benign and malignant MS. These data indicate that, in addition to specific allelic variants at IL2RA, immunological perturbations associated with aggressive forms of the disease can influence sIL-2RA levels in serum of MS subjects. We also demonstrate, functionally, that sIL-2RA can inhibit IL-2 signaling, yet enhance T cell proliferation and expansion. In summary, we propose that before disease onset, strong genetic factors associated with disease risk dictate sIL-2RA levels that may be further modulated with onset of chronic systemic inflammation associated with MS.
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PMID:Soluble IL-2RA levels in multiple sclerosis subjects and the effect of soluble IL-2RA on immune responses. 1915 2

Simultaneous pancreas-kidney transplantation (SPKT) is the treatment of choice for patients with end-stage renal failure due to type 1 diabetes mellitus. With advances in surgical techniques and immunosuppression management, outcomes have improved, with current 1- and 10-year pancreas graft survival rates of 86% and 53%, respectively. Induction therapy with either alemtuzumab or rabbit antithymocyte globulin (rATG) in combination with a calcineurin inhibitor (CNI) and mycophenolate mofetil (MMF) or sirolimus appears to be safe and effective in the setting of rapid steroid withdrawal (RSW), with excellent graft survival and low rejection rates. There are no large randomized trials between alemtuzumab and rATG to determine whether one is better than the other. Anti-interleukin (IL)-2 receptor antibody induction and no induction in combination with a CNI, MMF or sirolimus, and prednisone have demonstrated excellent graft survival rates but are associated with a higher incidence of acute rejection. The efficacy of anti-IL-2 receptor antibodies or no induction in the setting of RSW is unproven. Both of the CNIs, ciclosporin and tacrolimus, are effective in preventing acute rejection in SPKT recipients; however, pancreas allograft survival may be better with tacrolimus. MMF is more effective than azathioprine in preventing acute rejection. Sirolimus appears to be effective in preventing acute rejection, but the combination of sirolimus with a CNI may accentuate the nephrotoxicity of the CNI. RSW with induction therapy is safe and effective in SPKT recipients, but longer follow-up data on outcomes are needed. Recent analysis of registry data shows that most transplant centres are using an induction agent followed by a combination of tacrolimus, MMF and corticosteroids in SPKT recipients.
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PMID:Immunosuppression in simultaneous pancreas-kidney transplantation: progress to date. 2042 94


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