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Query: UMLS:C0024312 (lymphopenia)
 4,859 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Spontaneous type 1 diabetes in BB rats is dependent on the RT1(u) MHC haplotype and homozygosity for an allele at the Lyp locus, which is responsible for a peripheral T-lymphopenia. Genetic studies have shown that there are other, as yet unidentified, genetic loci contributing to diabetes susceptibility in this strain. BB rats carrying wild-type Lyp alleles are not lymphopenic and are resistant to spontaneous diabetes (DR). Here we show that thymectomy and exposure to one sublethal dose of gamma-irradiation (TX-R) at 4 weeks of age result in the rapid development of insulitis followed by diabetes in 100% of DR rats. Administration of CD4(+)45RC(-) T-cells from unmanipulated, syngeneic donors immediately after irradiation prevents the disease. Splenic T-cells from TX-R-induced diabetic animals adoptively transfer type 1 diabetes to T-deficient recipients. ACI, WF, WAG, BN, LEW, PVG, and PVG.RT1(u) strains are resistant to TX-R-induced insulitis/diabetes. Genetic analyses revealed linkage between regions on chromosomes 1, 3, 4, 6, 9, and 16, and TX-R-induced type 1 diabetes in a cohort of nonlymphopenic F(2) (Wistar Furth x BBDP) animals. This novel model of TX-R-induced diabetes in nonlymphopenic BB rats can be used to identify environmental and cellular factors that are responsible for the initiation of antipancreatic autoimmunity.
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PMID:Thymectomy and radiation-induced type 1 diabetes in nonlymphopenic BB rats. 1235 36

Diabetes in the biobreeding (BB) rat results from autoimmune destruction of pancreatic beta cells and thereby it is sharing many features with human type 1 diabetes. Independent crossing studies have demonstrated that diabetes in the BB rat is explained by at least three recessively acting genes termed Iddm1 (major histocompatibility complex), Iddm2 (lymphopenia), Iddm3 (unknown). About 50% of Iddm1 and Iddm2 homozygous first backcross hybrids (BC1) usually develop diabetes. However, 75% of these homozygotes become diabetic when using diabetic BB/HRI and diabetes-resistant BN/Mol rats. That prompted us to carry out a cross between BB/OK and BN/Crl rats in order to localise diabetogenic gene(s) of BB and/or BN rats. Fifty nine Iddm1 and Iddm2 homozygous [(BNxBB)F1xBB] BC1 hybrids (35 M, 24 F) were observed for diabetes occurrence up to an age of 30 weeks. All hybrids were used in a genome-wide scan carried out with 238 microsatellite markers covering about 92% of the genome. Significantly more Iddm1 and Iddm2 homozygous BC1 hybrids became diabetic (69 vs. 50%, p<0.003) with an age at onset of 91+/-31 days. Significant deviations from expected allele distribution between diabetic and non-diabetic BC1 hybrids were found at loci on chromosomes 1, 2, 3, 9, 10, 15, 16 and 19, with the strongest effect observed at locus D10Mgh2, where more heterozygous (91%) than homozygous diabetics (44%) were found. We conclude that BN rats possess more than one gene contributing to type 1 diabetes development.
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PMID:Alleles of diabetes-resistant BN rats contribute to insulin-dependent type 1 diabetes mellitus. 1265 25

The thymus is the unique lymphoid organ inside which a confrontation occurs throughout life between neuroendocrine self-antigens and a recently evolved system with original recombination machinery driving random generation of immune response diversity. Through transcription of neuroendocrine genes in the thymus stromal network and expression of cognate receptors by immature T cells, the neuroendocrine system regulates early T cell differentiation. In addition and more specifically, intrathymic presentation of neuroendocrine self-antigens by, or in close association with, major histocompatibility complex (MHC) proteins is responsible for the establishment of central immune self-tolerance of neuroendocrine principles. All members of the insulin gene (INS) family are expressed in the thymus stroma according to a precise hierarchy and cell topography: IGF2 (thymic epithelial cells) > IGF1 (thymic macrophages) >> INS (thymic medullary epithelial cells and/or dendritic cells). Given this hierarchical pattern in gene expression, the protein IGF-2 is more tolerated than INS. Igf2 transcription is defective in the thymus of bio-breeding (BB) rat, one animal model of type 1 diabetes (T1DM). This thymus-specific defect in Igf2 expression may explain both the absence of central tolerance to INS-secreting beta cells and the lymphopenia (including lack of regulatory RT6(+) T cells) in diabetes-prone BB rats. INS B:9-23 and the homologous sequence of IGF-2 compete for binding to DQ8, an MHC class II allele conferring major susceptibility to T1DM. In young DQ8(+) T1DM patients, INS B:9-23 presentation by DQ8 elicits a dominant IFN-gamma secretion by isolated PBMCs, whereas presentation of the IGF-2 self-antigen promotes a dominant regulatory interleukin-10 secretion. These data demonstrate that opposite immune responses are driven by MHC presentation of a self-antigen (here, IGF-2) and an autoantigen (INS, as "altered" self). The important tolerogenic properties of thymic self-antigens deserve now to be exploited for prevention and/or cure of devastating autoimmune diseases such as T1DM.
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PMID:Role of the thymus in the development of tolerance and autoimmunity towards the neuroendocrine system. 1279 58

Allergy and autoimmunity are both examples of deregulated immunity characterized by inflammation and injury of targeted tissues that have until recently been considered disparate disease processes. However, recent findings have implicated mast cells, in coordination with granulocytes and other immune effector cells, in the pathology of these two disorders. The BioBreeding (BB) DRlyp/lyp rat develops an autoimmune insulin-dependent diabetes similar to human type 1 diabetes mellitus (T1DM), whereas the BBDR+/+ rat does not. To better understand immune processes during development of T1DM, gene expression profiling at day (d) 40 (before insulitis) and d65 (before disease onset) was conducted on pancreatic lymph nodes of DRlyp/lyp, DR+/+, and Wistar-Furth (WF) rats. The eosinophil-recruiting chemokine, eotaxin, and the high-affinity IgE receptor (FcepsilonRI) were up-regulated >5-fold in d65 DRlyp/lyp vs d65 DR+/+ pancreatic lymph nodes by microarray (p < 0.05) and quantitative RT-PCR studies (p < 0.05). DR+/+, WF, and d40 DRlyp/lyp animals possessed normal pancreatic histology; however, d65 DRlyp/lyp animals possessed eosinophilic insulitis. Therefore, immunohistochemistry for pancreatic eotaxin expression was conducted, revealing positive staining of d65 DRlyp/lyp islets. Islets of d65 DR+/+ rats also stained positively, consistent with underlying diabetic predisposition in the BB lineage, whereas WF islets did not. Other differentially expressed transcripts included those associated with eosinophils, mast cells, and lymphocytes. These data support an important role for these inflammatory mediators in BB rat T1DM and suggest that the lymphopenia due to the Ian5/(lyp) mutation may result in a deregulation of cells involved in insulitis and beta cell destruction.
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PMID:Involvement of eotaxin, eosinophils, and pancreatic predisposition in development of type 1 diabetes mellitus in the BioBreeding rat. 1555 96

The size of the peripheral T cell pool is remarkably stable throughout life, reflecting precise regulation of cellular survival, proliferation, and apoptosis. Homeostatic proliferation refers to the process by which T cells spontaneously proliferate in a lymphopenic host. The critical signals driving this expansion are "space," contact with self-major histocompatibility complex (MHC)/peptide complexes, and cytokine stimulation. A number of studies have delineated an association between T cell lymphopenia, compensatory homeostatic expansion, and the development of diverse autoimmune syndromes. In the nonobese diabetic mouse model of type 1 diabetes, lymphopenia-induced homeostatic expansion fuels the generation of islet-specific T cells. Excess interleukin-21 facilitates T cell cycling but limited survival, resulting in recurrent stimulation of T cells specific for self-peptide/MHC complexes. Indeed, data from several experimental models of autoimmunity indicate that a full T cell compartment restrains homeostatic expansion of self-reactive cells that could otherwise dominate the repertoire. This review describes the mechanisms that govern T cell homeostatic expansion and outlines the evidence that lymphopenia presents a risk for development of autoimmune disease.
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PMID:T cell homeostasis in tolerance and immunity. 1589 86

Lymphopenia is due to a frameshift mutation in Gimap5 on rat chromosome 4 and is linked to type 1 diabetes in the diabetes prone (DP) BB rat. The hypothesis that bone marrow derived cells confer the lymphopenia phenotype was tested by reciprocal bone marrow transplantation in 40-day-old lethally irradiated diabetes resistant (DR) congenic DR.lyp/lyp (lymphopenia and diabetes) and DR.+/+ (no lymphopenia and no diabetes) rats. In two independent series of transplants, all DR.lyp/lyp rats (n=5 and 4) receiving DR.lyp/lyp bone marrow retained lymphopenia and developed insulitis (5/5 and 4/4) as well as diabetes in some (2/5 and 3/4). Both DR.+/+ and DR.lyp/lyp rats receiving DR.+/+ bone marrow cells as well as DR.+/+ rats receiving DR.lyp/lyp bone marrow cells showed no lymphopenia or diabetes. In accordance with earlier studies in non-congenic BB rats, the DR.+/+ rats receiving DR.lyp/lyp bone marrow cells recapitulated an intermediary phenotype rather than the +/+ or lyp/lyp phenotypes. Our data demonstrate that BBDP rat lymphopenia and diabetes are transferred by bone marrow transplantation to syngeneic DR.lyp/lyp but not DR.+/+ recipients. The intermediary recapitulation of DR.lyp/lyp T cells in recipient DR.+/-/+/- rats suggests that radiation resistant +/-/+/- T cells, the Gimap5 mutation in bone marrow cells, or both may not support the development of lymphopenia.
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PMID:DR.lyp/lyp bone marrow maintains lymphopenia and promotes diabetes in lyp/lyp but not in +/+ recipient DR.lyp BB rats. 1624 25

A series of recent studies in humans and the NOD mouse model have highlighted the central role that autoimmunity directed against insulin, in particular the insulin B chain 9-23 peptide, may play in the pathogenesis of type 1 diabetes. Both pathogenic and protective T-cell clones recognizing the B:9-23 peptide have been produced. This report describes the successful creation of BDC12-4.1 T-cell receptor (TCR) transgenic mice with spontaneous insulitis in F1 mice (FVB x NOD) and spontaneous diabetes in NOD.RAG(-/-) (backcross 1 generation). Disease progression is heterogeneous and is modified by a series of genetic factors including heterozygosity (H-2(g7)/H-2(q)) versus homozygosity for H-2(g7), the presence of additional T-/B-cell receptor-rearranged genes (RAG(+) versus RAG(-/-)), and the insulin 2 gene knockout (the insulin gene expressed in the NOD thymus). Despite lymphopenia, 40% of H-2(g7/g7) BDC12-4.1 TCR(+) RAG(-/-) Ins2(-/-) mice are diabetic by 10 weeks of age. As few as 13,500 transgenic T-cells from a diabetic TCR(+) RAG(-/-) mouse can transfer diabetes to an NOD.scid mouse. The current study demonstrates that the BDC12-4.1 TCR is sufficient to cause diabetes at NOD backcross 1, bypassing polygenic inhibition of insulitis and diabetogenesis.
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PMID:Transgenic insulin (B:9-23) T-cell receptor mice develop autoimmune diabetes dependent upon RAG genotype, H-2g7 homozygosity, and insulin 2 gene knockout. 1680 66

T cells undergoing lymphopenia-driven proliferation acquire effector and memory properties that can be pathogenic. Indeed, generalized lymphopenia is associated with a variety of autoimmune diseases such as type 1 diabetes. The current study was carried out to determine how CD8(+) T cells undergoing acute lymphopenic expansion respond to antigen under tolerizing conditions in vivo. Adoptive transfer of diabetes by TCR-transgenic CD8(+) T cells was enhanced following treatment of NOD. scid recipients with a high dose of soluble peptide. Furthermore, whereas TCR-transgenic CD8(+) T cells underwent clonal deletion and failed to differentiate into CTL in peptide-treated lymphoreplete recipient mice, TCR-transgenic CD8(+) T cells in a lymphopenic environment were resistant to clonal deletion, and CTL differentiation was enhanced by a high dose of soluble peptide. Moreover, peptide treatment had distinct effects on expression of the anti-apoptotic protein Bcl-X(L) in TCR-transgenic CD8(+) T cells under lymphopenic versus lymphoreplete conditions. These results demonstrate that CD8(+) T cells undergoing lymphopenia-driven expansion in NOD. scid recipients are resistant to antigen-induced tolerance, and readily differentiate into CTL upon stimulation with a high dose of soluble peptide.
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PMID:Lymphopenia-driven CD8(+) T cells are resistant to antigen-induced tolerance in NOD.scid mice. 1682 Dec 36

The objective of the present study was to determine whether sleep deprivation (SD) would promote changes in lymphocyte numbers in a type 1 diabetes model (non-obese diabetic, NOD, mouse strain) and to determine whether SD would affect female and male NOD compared to Swiss mice. The number of lymphocytes in peripheral blood after 24 and 96 h of SD (by multiple platform method) or equivalent period of time in home-cage controls was examined prior to the onset of diabetes. SD for 96 h significantly reduced lymphocytes in male Swiss mice compared to control (8.6 +/- 2.1 vs 4.1 +/- 0.7 10(3)/microL; P < 0.02). In male NOD animals, 24- and 96-h SD caused a significant decrease of lymphocytes compared to control (4.4 +/- 0.3 vs 1.6 +/- 0.5; P < 0.001 and 4.4 +/- 0.3 vs 0.9 +/- 0.1 10(3)/microL; P < 0.00001, respectively). Both 24- and 96-h SD induced a reduction in the number of lymphocytes in female Swiss (7.5 +/- 0.5 vs 4.5 +/- 0.5, 4.4 +/- 0.6 10(3)/microL; P < 0.001, respectively) and NOD mice (4 +/- 0.6 vs 1.8 +/- 0.2, 1.2 +/- 0.4 10(3)/microL; P < 0.01, respectively) compared to the respective controls. Loss of sleep induced lymphopenia in peripheral blood in both genders and strains used. Since many cases of autoimmunity present reduced numbers of lymphocytes and, in this study, it was more evident in the NOD strain, our results suggest that SD should be considered a risk factor in the onset of autoimmune disorders.
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PMID:Sleep deprivation reduces the lymphocyte count in a non-obese mouse model of type 1 diabetes mellitus. 1746 24

Spontaneous apoptosis of T lymphocytes results in marked lymphopenia in the Biobreeding diabetes-prone (BB-DP) rat leading to the development of autoimmune type 1 diabetes. The lymphopenia phenotype in these rats is linked to the lyp locus. The lyp allele harbors a frameshift mutation within the gene encoding 'GTPase of immunity-associated nucleotide binding protein 5' (GIMAP5). Mechanisms underlying the pro-survival function of GIMAP5 in T lymphocytes are unclear. Overexpression studies have shown that GIMAP5 localizes within mitochondria and the endoplasmic reticulum (ER). We have used an antiserum raised against GIMAP5 to define its localization in rat primary T lymphocytes. We present evidence that endogenous GIMAP5 is associated with a sedimentable subcellular fraction that is distinct from mitochondria and the ER. These data are further supported by confocal microscopy using a GIMAP5 construct with an intact C-terminal membrane anchor. Nonetheless, T cells isolated from GIMAP5(lyp/lyp) rats display rapid loss of mitochondrial membrane potential. Our findings suggest that GIMAP5 regulates T lymphocyte survival by mechanisms that operate upstream of mitochondria.
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PMID:GIMAP5 regulates mitochondrial integrity from a distinct subcellular compartment. 1765 28


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