Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0024312 (lymphopenia)
 4,859 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The BB rat is among the best models of insulin-dependent diabetes mellitus--with onset and pathogenesis closely resembling the human disease. One unusual feature is a severe T-cell lymphopenia, which appears to be inherited as a recessive trait controlled by a single gene, Lyp. Based on genetic analysis of several crosses, we show that development of diabetes involves at least three genes: Lyp, which is tightly linked to the neuropeptide Y (Npy) gene on chromosome 4, a gene linked to the major histocompatibility complex (MHC) on chromosome 20, and a third unmapped gene for which the Fischer rat strain carries an allele conferring resistance.
 ...
PMID:Genetic dissection of autoimmune type I diabetes in the BB rat. 130 51

Diabetes prone biobreeding rats display several abnormalities in T cell numbers, T cell function and T cell surface phenotype which are associated with the onset of spontaneous disease. One of the most pronounced abnormalities in these animals is a marked T cell lymphopenia which is evident in both CD4+ and CD8+ peripheral T cell subsets. To gain a better understanding as to the nature of T cell responses in these animals, we have utilized RT-PCR to analyze the cytokine mRNA profiles of mitogen activated peripheral T cells derived from lymphopenic and non-lymphopenic animals. Our results suggest that inheritance of the lymphopenia gene, Lyp, is associated with a unique cytokine profile most similar to that previously described for mouse medullary thymocytes. In addition, cell surface staining of peripheral T cells from diabetes prone animals revealed a high frequency of Thyl+ cells, which is characteristic of both thymocytes and recent thymic emigrants. Following thymectomy, T cell responsiveness to a number of different stimuli is greatly reduced on a cell for cell basis as is the absolute number of surviving T cells. Taken collectively, our results suggest that the majority of the peripheral T cell pool in these diabetic prone rats consists of short lived, recent thymic emigrants which most likely also contain the effector cells required for initiation of diabetes.
 ...
PMID:T cells from BB-DP rats show a unique cytokine mRNA profile associated with the IDDM1 susceptibility gene, Lyp. 873 69

The lymphopenia gene (lyp) on rat chromosome 4 is closely linked to autoimmune diabetes in the BioBreeding (BB) rat. Lyp controls the number of peripheral lymphocytes by reducing T cells of the RT6+ phenotype by almost 90%. Following nine cycle of marker-assisted cross-intercross breeding we have developed congenic lyp/lyp, lyp/+ and +/+ (wildtype) rats on the background of DR rats. Prediabetic and insulitis free lyp/lyp, lyp/+ and +/+ rats were used to determine the effect of lyp on cytokine expression in the thymus. In situ hybridization of thymus cryosections showed that the interferon gamma (IFN gamma) mRNA expression was highest in lyp/lyp rats and the hybridization signal was restricted to the medullary compartment. The frequency of IFN gamma and interleukin (IL)-10 mRNA expressing cells in isolated thymocytes determined by quantitative image analysis, demonstrated an increased IFN gamma: IL-10 ratio in thymocytes from lyp/lyp homozygotes compared to lyp/+ and +/+ rats. This confirmed a lyp gene dose-dependent segregation of the IFN gamma high phenotype. Recombinant human glutamic acid decarboxylase (GAD65) increased the number of IFN gamma and IL-10 mRNA expressing thymocytes after in vitro culture. We conclude that the quantitative ratio of cytokine producing thymocytes is associated with the lyp genotype. These potentially autoreactive thymocytes may explain the establishment of beta-cell directed autoimmunity in the BB rat despite peripheral lymphopenia.
 ...
PMID:The lymphopenia (lyp) gene controls the intrathymic cytokine ratio in congenic BioBreeding rats. 924 99

Lyp controls lymphopenia and T-cell mediated autoimmune diabetes in the BioBreeding (BB) rat possibly by interacting with T-cell maturation in the thymus. The protooncogene vav (p95) is involved in T-cell activation and in the intrathymic selection of developing T cells. We have previously reported increased production of IFN-gamma of self reactive thymocytes in the thymus medulla of Lyp/Lyp BB rats. Lymphopenia and diabetes may therefore be linked to an increase in thymocyte activation leading to a bias in thymocyte development. The purpose of this study was therefore to investigate whether the expression of p95"a" in primary lymphoid tissues from congenic Lyp/Lyp, Lyp/+ and +/+ BB rats was correlated to the Lyp genotype using in situ hybridization and reverse transcription (RT)-PCR. It was found that the expression of vav mRNA in the thymus was increased in Lyp/Lyp compared to Lyp/+ and +/+ rats (p < 0.05). Western blot analysis revealed that the amount of p95 vav protein in Lyp/Lyp thymus was also increased. The results show that vav expression correlates with the lymphopenia phenotype and diabetes development in congenic Lyp/Lyp BB rats. An increase in the availability of p95vav during the development and activation of thymocytes in Lyp/Lyp BB rats may therefore contribute to the generation of islet autoreactivity, lymphopenia or both.
 ...
PMID:Differential expression of p95vav in primary lymphoid tissue of BB rats congenic for the lymphopenia gene. 1043 93

The rat diabetes susceptibility gene, Lyp or Lymphopenia, has been localized to RNO4. Proximal to Lyp are the genes caspase-2 (Casp2) and pancreatic trypsin 1 (Prss1), while neuropeptide Y (Npy) is the closest distally positioned gene. In human, the three genes are syntenic on HSA7, but they are not on a conserved segment: CASP2 and PRSS1 are localized to 7q35, while NPY is localized to 7p15.1. This raises the question whether the human homologue of Lyp is linked to CASP2/PRSS1 or to NPY. We present a comparative map of the Lyp region in rat and human, assigning the gene to a 1.3-Mb segment between RNY3 and ABP1 at 7q35.
 ...
PMID:Comparative mapping of the human homologue of the rat diabetes susceptibility gene lyp to a 1.3-Mb segment on HSA7. 1077 70

The Lyp locus controls diabetes development in rats. The diabetogenic allele in diabetes-prone BB rats is responsible for T cell lymphopenia characterized by the absence of regulatory T cells. We present refined genetic and radiation hybrid maps of the Lyp region on rat chromosome 4, a single 800-kb rat yeast artificial chromosome and a rat P1-derived artificial chromosome (PAC) contig corresponding to approximately 550 kb, both encompassing the entire candidate region. The contig, consisting of 48 PACs, gives 3- to 12-fold coverage. Genetic, radiation hybrid, and physical data were all in agreement and supported the same marker order. Nine genes and ESTs were identified in the contig in addition to a rat EST from the University of Iowa rat EST database-all possible candidate genes for Lyp. Alignment of our rat PAC contig with sequenced human PAC/BAC contigs confirms the position within the region of 3 of the 10 candidates and identifies an additional 8 genes/ESTs as candidates. These data will facilitate identification of Lyp.
 ...
PMID:A sequence-ready PAC contig of a 550-kb region on rat chromosome 4 including the diabetes susceptibility gene Lyp. 1105 48

Diabetes-prone (DP) BB rats spontaneously develop insulin-dependent diabetes resembling human type 1 diabetes. They also exhibit lifelong T-cell lymphopenia. Functional and genetic data support the hypothesis that the gene responsible for the lymphopenia, Lyp, is also a diabetes susceptibility gene, named Iddm1. We constructed a 550-kb P1-derived artificial chromosome contig of the region. Here, we present a corrected genetic map reducing the genetic interval to 0.2 cM and the physical interval to 150-290 kb. A total of 13 genes and six GenomeScan models are assigned to the homologous human DNA segment on HSA7q36.1, 8 of which belong to the family of immune-associated nucleotides (Ian genes). Two of these are orthologous to mouse Ian1 and -4, both excellent candidates for Iddm1. In normal rats, they are expressed in the thymus and T-cell regions of the spleen. In the thymus of lymphopenic rats, Ian1 exhibits wild-type expression patterns, whereas Ian4 expression is reduced. Mutational screening of their coding sequences revealed a frameshift mutation in Ian4 among lymphopenic rats. The mutation results in a truncated protein in which the COOH-terminal 215 amino acids-including the anchor localizing the protein to the outer mitochondrial membrane-are replaced by 19 other amino acids. We propose that Ian4 is identical to Iddm1.
 ...
PMID:The diabetes-prone BB rat carries a frameshift mutation in Ian4, a positional candidate of Iddm1. 1203 88

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.
 ...
PMID:Thymectomy and radiation-induced type 1 diabetes in nonlymphopenic BB rats. 1235 36