Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Invariant NK T (iNKT) cells regulate immune responses, express NK cell markers and an invariant TCR, and recognize lipid Ags in a CD1d-restricted manner. Previously, we reported that activation of iNKT cells by alpha-galactosylceramide (alpha-GalCer) protects against type 1 diabetes (T1D) in NOD mice via an IL-4-dependent mechanism. To further investigate how iNKT cells protect from T1D, we analyzed whether iNKT cells require the presence of another subset(s) of regulatory T cells (Treg), such as CD4+ CD25+ Treg, for this protection. We found that CD4+ CD25+ T cells from NOD.CD1d(-/-) mice deficient in iNKT cell function similarly in vitro to CD4+ CD25+ T cells from wild-type NOD mice and suppress the proliferation of NOD T responder cells upon alpha-GalCer stimulation. Cotransfer of NOD diabetogenic T cells with CD4+ CD25+ Tregs from NOD mice pretreated with alpha-GalCer demonstrated that activated iNKT cells do not influence the ability of T(regs) to inhibit the transfer of T1D. In contrast, protection from T1D mediated by transfer of activated iNKT cells requires the activity of CD4+ CD25+ T cells, because splenocytes pretreated with alpha-GalCer and then inactivated by anti-CD25 of CD25+ cells did not protect from T1D. Similarly, mice inactivated of CD4+ CD25+ T cells before alpha-GalCer treatment were also not protected from T1D. Our data suggest that CD4+ CD25+ T cells retain their function during iNKT cell activation, and that the activity of CD4+ CD25+ Tregs is required for iNKT cells to transfer protection from T1D.
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PMID:Protection from type 1 diabetes by invariant NK T cells requires the activity of CD4+CD25+ regulatory T cells. 1695 29

This paper presents a series of 10 hypotheses on the etiology of type 1 diabetes. We begin with the hypothesis that wheat gluten is one of the elusive environmental triggers in type 1 diabetes. Habitual consumption of wheat gluten increases the intestinal synthesis of dipeptidyl peptidase IV. This enzyme helps to shape the repertoire of peptides released into the small intestine following the ingestion of wheat gluten by catalyzing the release of X-Pro dipeptides from the N-terminus of the proline-rich glutenins and gliadins in wheat gluten. The release of gluten-derived peptides causes the tight junctions of the small intestine to open through a zonulin-dependent mechanism, which allows these peptides to enter the lamina propria where they get presented as antigens by HLA-DQ, -DR and CD1d molecules. Binding of one or more gluten peptides by CD1d leads to abrogation of oral tolerance, and a marked increase in peripheral immune responses to wheat proteins. Furthermore, it is our contention, that in response to beta cell apoptosis during normal remodeling of the pancreas and CCL19/CCL21 expression within the pancreatic lymph nodes (PLNs), gluten-loaded dendritic cells migrate from the small intestine to the PLNs. These dendritic cells present gluten-derived antigens on the surface of the PLNs, which leads to migration of CD4(-)CD8(-) gammadelta and CD4(-)CD8(+) alphabeta T cells to the pancreas where they mediate Fas and perforin dependent cytotoxicity. We also hypothesize that at least one of the type 1 diabetes associated HLA-DR molecules that bind and present wheat-derived peptide(s) also bind and present an islet cell antigen(s), activating plasma cell synthesis of islet cell autoantibodies and irrevocable, complement-dependent destruction of islet cells. Our final two hypotheses state that type 1 diabetes morbidity is reduced in those areas of globe where genetically susceptible individuals get adequate amounts of vitamin D, in the diet and/or through exposure to sunlight, and in areas where people are exposed to bacterial, viral, or parasitic infections in early childhood.
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PMID:Putting the pieces of the puzzle together - a series of hypotheses on the etiology and pathogenesis of type 1 diabetes. 1704 15

Type 1 interferon-beta (T1IFN-beta) is an innate cytokine and the first-choice therapy for multiple sclerosis (MS). It is still unclear how T1IFN-beta, whose main function is to promote innate immunity during infections, plays a beneficial role in autoimmune disease. Here we show that T1IFN-beta promoted the expansion and function of invariant natural killer (iNKT) cells, an innate T-cell subset with strong immune regulatory properties that is able to prevent autoimmune disease in pre-clinical models of MS and type 1 diabetes. Specifically, we observed that T1IFN-beta treatment significantly increased the percentages of Valpha24(+) NKT cells in peripheral blood mononuclear cells of MS patients. Furthermore, iNKT cells of T1IFN-beta-treated individuals showed a dramatically improved secretion of cytokines (interleukins 4 and 5 and interferon-gamma) in response to antigenic stimulation compared to iNKT cells isolated from the same patients before T1IFN-beta treatment. The effect of T1IFN-beta on iNKT cells was mediated through the modulation of myeloid dendritic cells (DCs). In fact, DCs modulated in vivo or in vitro by T1IFN-beta were more efficient antigen-presenting cells for iNKT cells. Such a modulatory effect of T1IFN-beta was associated with up-regulation on DCs of key costimulatory molecules for iNKT (i.e. CD80, CD40 and CD1d). Our data identified the iNKT cell/DC pathway as a new target for the immune regulatory effect of T1IFNs in autoimmune diseases and provide a possible mechanism to explain the clinical efficacy of T1IFN-beta in MS.
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PMID:Innate immunity modulates autoimmunity: type 1 interferon-beta treatment in multiple sclerosis promotes growth and function of regulatory invariant natural killer T cells through dendritic cell maturation. 1761 56

Reduced numbers and function of invariant NKT (iNKT) cells partially contribute to type 1 diabetes (T1D) development in NOD mice. Previous linkage analysis identified a genetic locus on chromosome 2 controlling numbers of thymic iNKT cells. Interestingly, this locus resides within the Idd13 region that distinguishes NOD mice from the closely genetically related, but strongly T1D-resistant NOR strain. Thus, we tested if a genetic variant that confers T1D resistance in NOR mice may do so by enhancing iNKT cell numbers. iNKT cells were enumerated by an alpha-GalCer analog loaded CD1d tetramer in NOD and NOR mice as well as in NOD stocks carrying NOR-derived congenic regions on chromosome 1, 2, or 4. Significantly, more thymic and splenic iNKT cells were present in NOR than NOD mice. The NOR-derived Idd13 region on chromosome 2 contributed the most significant effect on increasing iNKT cell numbers. Subcongenic analyses indicated that at least two genes within the Idd13 region regulate iNKT cell numbers. These results further define the genetic basis for numerical iNKT cell defects contributing to T1D development in NOD mice.
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PMID:Subcongenic analysis of genetic basis for impaired development of invariant NKT cells in NOD mice. 1761 75

Identification of human CD1d-restricted T-cell receptor (TCR)-invariant natural killer T (iNKT) cells has been dependent on utilizing combinations of monoclonal antibodies or CD1d tetramers, which do not allow for the most specific analysis of this T-cell subpopulation. A novel monoclonal antibody (clone 6B11), specific for the invariant CDR3 loop of human canonical Valpha24Jalpha18 TCR alpha chain, was developed and used to specifically characterize iNKT cells. In healthy individuals studied for up to 1 year, a wide but stable frequency of circulating iNKT cells (range: 0.01-0.92%) was observed, with no differences in frequency by gender. Four stable iNKT cell subsets were characterized in peripheral blood based on the expression of CD4 and CD8, with CD8(+) iNKT cells being a phenotypic and functionally different subset from CD4(+) and double negative iNKT cells; in particular, LAG-3 was preferentially expressed on CD8(+) iNKT cells. In addition, a strong negative linear correlation between the frequency of total iNKT cells and percentage of the CD4(+) subset was observed. In terms of their potential association with disease, patients at risk for type 1 diabetes had significantly expanded frequencies of double negative iNKT cells when compared to matched controls and first-degree relatives. Moreover, peripheral blood CD4(+) iNKT cells were the highest producers of interleukin-4, while the production of interferon-gamma and tumour necrosis factor-alpha was similar amongst all iNKT cell subsets. These differences in iNKT cell subsets suggest that in humans the relative ratio of iNKT cell subsets may influence susceptibility vs. resistance to immune-mediated diseases.
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PMID:Characterization of human invariant natural killer T subsets in health and disease using a novel invariant natural killer T cell-clonotypic monoclonal antibody, 6B11. 1766 44

Natural Killer T (NKT) cells can effect both T cell development and peripheral immune responses through T(H)1/T(H)2 cytokines. Some humans with Type 1 Diabetes Mellitus (T1DM) have numerical and functional NKT deficiencies that contribute to disease severity. Correcting these deficiencies inhibits diabetes in the non-obese diabetic (NOD) T1DM model, which shares similar deficiencies. Here we show that antibodies to CD1d, when given during early thymic development, induce specific increases in surface TCR of developing NOD and C57BL/6 CD4(+)CD8(+) (DP) invariant NKT (iNKT) cells. However, the addition of anti-CD1d causes distinct strain-specific population changes in response to treatment. These changes include: (1) a dose-dependent increase in NOD iNKT(TCR)(+) cells and, conversely, (2) an inhibition of B6 iNKT(TCR)(+) cell production. The observed NOD iNKT expansions correlated with diabetes inhibition in an in vitro T1DM system, suggesting that intrathymic anti-CD1d treatment may correct NOD numerical iNKT deficiencies through developmental TCR enhancement.
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PMID:Antibodies to CD1d enhance thymic expression of invariant NKT TCR and increase the presence of NOD thymic invariant NKT cells. 1829 32

The application of anti-CD3 F(ab')(2) monoclonal antibodies has recently been expanded to treat established autoimmune diseases, including type 1 diabetes. However, the mechanism underlying their effect remains largely unclear. We report that short-phase administration of anti-CD3 F(ab')(2) antibodies efficiently allowed 80% of new-onset, nonobese diabetic (NOD) mice to significantly regain both normoglycemia and pancreatic beta cell-specific autoantigen (ie, glutamic acid decarboxylase and insulin) tolerance, with both effects lasting more than 40 weeks. The responsible mechanism appears to involve the induction and maintenance of a population of immunoregulatory CD1d-restricted natural killer T (NKT) cells, which were marked by an enhanced Th2 response and secretion of elevated levels of interleukin-10. In vivo neutralization of interleukin-4 and/or interleukin-10 bioactivity abrogated this anti-CD3-mediated effect. Importantly, when the cotransfer of NKT cells from the livers of anti-CD3-treated mice and splenocytes from untreated, acutely diabetic NOD mice was performed in NOD-severe combined immunodeficient mice, the NKT cells were sufficient to either delay or prevent the onset of diabetes compared with controls where only splenocytes were introduced. These data suggest that CD1d-restricted NKT cells may play a critical role in anti-CD3 antibody-induced diabetes remission and the restoration of immune tolerance.
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PMID:Induction of active tolerance and involvement of CD1d-restricted natural killer T cells in anti-CD3 F(ab')2 treatment-reversed new-onset diabetes in nonobese diabetic mice. 1834 26

CD1d-restricted natural killer T (NKT) cells and CD4+CD25+ regulatory T (Treg) cells are two thymus-derived subsets of regulatory T cells that play an important role in the maintenance of self-tolerance. Yet the functional changes of the two subsets of regulatory T cells in the development of diabetes in non-obese diabetic (NOD) mice remain unclear, and how NKT cells and CD4+CD25+ Treg cells cooperate functionally in the regulation of autoimmune diabetes is also uncertain. We provide evidence that in NOD mice, an animal model of human type 1 diabetes, the functions of both NKT cells and CD4+CD25+ Treg cells decrease in an age-dependent manner. We show that treatment with alpha-galactosylceramide increases the size of the CD4+CD25+ Treg cell compartment in NOD mice, and augments the expression of forkhead/winged helix transcription factor and the potency of CD4+CD25+ Treg cells to inhibit proliferation of CD4+CD25- T cells. Our data indicate that NKT cells and CD4+CD25+ Treg cells might cooperate in the prevention of autoimmune diabetes in NOD mice treated with alpha-galactosylceramide. Induced cooperation of NKT cells and CD4+CD25+ Treg cells could serve as a strategy to treat human autoimmune disease, such as type 1 diabetes.
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PMID:Cooperation of invariant NKT cells and CD4+CD25+ T regulatory cells in prevention of autoimmune diabetes in non-obese diabetic mice treated with alpha-galactosylceramide. 1846 23

Type 1 NKT cells play a critical role in controlling the strength and character of adaptive and innate immune responses. We have previously reported deficiencies in the numbers and function of NKT cells in the NOD mouse strain, which is a well-validated model of type 1 diabetes and systemic lupus erythematosus. Genetic control of thymic NKT cell numbers was mapped to two linkage regions: Nkt1 on distal chromosome 1 and Nkt2 on chromosome 2. Herein, we report the production and characterization of a NOD.Nkrp1(b).Nkt2b(b) congenic mouse strain, which has increased thymic and peripheral NKT cells, a decreased incidence of type 1 diabetes, and enhanced cytokine responses in vivo and increased proliferative responses in vitro following challenge with alpha-galactosylceramide. The 19 highly differentially expressed candidate genes within the congenic region identified by microarray expression analyses included Pxmp4. This gene encodes a peroxisome-associated integral membrane protein whose only known binding partner is Pex19, an intracellular chaperone and component of the peroxisomal membrane insertion machinery encoded by a candidate for the NKT cell control gene Nkt1. These findings raise the possibility that peroxisomes play a role in modulating glycolipid availability for CD1d presentation, thereby influencing NKT cell function.
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PMID:Congenic analysis of the NKT cell control gene Nkt2 implicates the peroxisomal protein Pxmp4. 1871 12

Semi-invariant NK T cell (iNKT) deficiency has long been associated with the pathogenesis of type 1 diabetes (T1D), but the linkage between this the deficiency and T1D susceptibility gene(s) remains unclear. We analyzed NOD mice subcongenic for resistant alleles of Idd9 locus in search for protective mechanisms against T1D, and found that iNKT cell development was significantly enhanced with a more advanced mature phenotype and function in mice containing Idd9.1 sublocus of B10 origin. The enhanced iNKT cell development and function suppressed effector function of diabetogenic T cells. Elimination of iNKT cells by CD1d deficiency almost abolished T1D protection in these mice. Interestingly, although the iNKT cells were responsible for a Th2 orientated cytokine profile that is often regarded as a mechanism of T1D prevention, our data suggests that the Th2 bias played little if any role for the protection. In addition, dendritic cells from the congenic NOD mice showed increased abilities to engage and potentiate iNKT cells, suggesting that a mechanism mediated by dendritic cells or other APCs may be critical for the enhanced development and maturation of iNKT cells. The products of T1D susceptibility gene(s) in Idd9.1 locus may be a key factor for this mechanism.
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PMID:Enhanced early expansion and maturation of semi-invariant NK T cells inhibited autoimmune pathogenesis in congenic nonobese diabetic mice. 1898 Oct 96


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