Molecular Genetic Analysis of the Idd4 Locus Implicates the IFN Response in Type 1 Diabetes Susceptibility in Nonobese Diabetic Mice1

High-resolution mapping and identification of the genes responsible for type 1 diabetes (T1D) has proved difficult because of the multigenic etiology and low penetrance of the disease phenotype in linkage studies. Mouse congenic strains have been useful in refining Idd susceptibility loci in the NOD mouse model and providing a framework for identification of genes underlying complex autoimmune syndromes. Previously, we used NOD and a nonobese diabetes-resistant strain to map the susceptibility to T1D to the Idd4 locus on chromosome 11. Here, we report high-resolution mapping of this locus to 1.4 megabases. The NOD Idd4 locus was fully sequenced, permitting a detailed comparison with C57BL/6 and DBA/2J strains, the progenitors of T1D resistance alleles found in the nonobese diabetes-resistant strain. Gene expression arrays and quantitative real-time PCR were used to prioritize Idd4 candidate genes by comparing macrophages/dendritic cells from congenic strains where allelic variation was confined to the Idd4 interval. The differentially expressed genes either were mapped to Idd4 or were components of the IFN response pathway regulated in trans by Idd4. Reflecting central roles of Idd4 genes in Ag presentation, arachidonic acid metabolism and inflammation, phagocytosis, and lymphocyte trafficking, our combined analyses identified Alox15, Alox12e, Psmb6, Pld2, and Cxcl16 as excellent candidate genes for the effects of the Idd4 locus.

[1]  T. Kita,et al.  Cutting Edge: SR-PSOX/CXC Chemokine Ligand 16 Mediates Bacterial Phagocytosis by APCs Through its Chemokine Domain1 , 2003, The Journal of Immunology.

[2]  H. Kuhn,et al.  Mammalian arachidonate 15-lipoxygenases structure, function, and biological implications. , 2002, Prostaglandins & other lipid mediators.

[3]  A. Paterson,et al.  Two genetic loci regulate T cell-dependent islet inflammation and drive autoimmune diabetes pathogenesis. , 2000, American journal of human genetics.

[4]  W. Frankel,et al.  NOR/Lt Mice: MHC-Matched Diabetes-Resistant Control Strain for NOD Mice , 1992, Diabetes.

[5]  久松浩.  Newly Identified Pair of Proteasomal Subunits Regulated Reciprocally by Interferon γ , 1997 .

[6]  Angelo J. Canty,et al.  Sex-Specific Effect of Insulin-Dependent Diabetes 4 on Regulation of Diabetes Pathogenesis in the Nonobese Diabetic Mouse1 , 2005, The Journal of Immunology.

[7]  C. Fox.  Genetic regulation of contingent macrophage- and T-cell-dependent steps in islet inflammation , 1999 .

[8]  B. Charlton,et al.  Administration of Silica Particles or Anti-Lyt2 Antibody Prevents β-Cell Destruction in NOD Mice Given Cyclophosphamide , 1988, Diabetes.

[9]  M. Harada,et al.  Promotion of spontaneous diabetes in non-obese diabetes-prone mice by cyclophosphamide , 1984, Diabetologia.

[10]  G. Eisenbarth,et al.  Interferon alpha--a potential link in the pathogenesis of viral-induced type 1 diabetes and autoimmunity. , 2004, Clinical immunology.

[11]  J. Todd,et al.  Genetic control of autoimmune diabetes in the NOD mouse. , 1995, Annual review of immunology.

[12]  Janet M. Allen,et al.  Phospholipase D and immune receptor signalling. , 2002, Seminars in immunology.

[13]  H C Thomas,et al.  Polymorphisms in interferon-induced genes and the outcome of hepatitis C virus infection: roles of MxA, OAS-1 and PKR , 2003, Genes and Immunity.

[14]  E. Leiter,et al.  Subcongenic analysis of the Idd13 locus in NOD/Lt mice: evidence for several susceptibility genes including a possible diabetogenic role for beta 2-microglobulin. , 1998, Journal of immunology.

[15]  E. Schadt,et al.  Ultrafine mapping of SNPs from mouse strains C57BL/6J, DBA/2J, and C57BLKS/J for loci contributing to diabetes and atherosclerosis susceptibility. , 2005, Diabetes.

[16]  J. Naggert,et al.  Genomic analysis of the C57BL/Ks mouse strain , 1995, Mammalian Genome.

[17]  K. Tanaka,et al.  cDNA cloning and interferon gamma down-regulation of proteasomal subunits X and Y. , 1994, Science.

[18]  Lei Zhao,et al.  Lipoxygenase genes and their targeted disruption. , 2002, Prostaglandins & other lipid mediators.

[19]  Q. Mi,et al.  Congenic mapping of the diabetogenic locus Idd4 to a 5.2-cM region of chromosome 11 in NOD mice: identification of two potential candidate subloci. , 2002, Diabetes.

[20]  Alexander E. Kel,et al.  MATCHTM: a tool for searching transcription factor binding sites in DNA sequences , 2003, Nucleic Acids Res..

[21]  E. Leiter,et al.  Use of recombinant congenic and congenic strains of NOD mice to identify a new insulin-dependent diabetes resistance gene , 1994, The Journal of experimental medicine.

[22]  Paul A Lyons,et al.  Combining mouse congenic strains and microarray gene expression analyses to study a complex trait: the NOD model of type 1 diabetes. , 2002, Genome research.

[23]  Terence P. Speed,et al.  A comparison of normalization methods for high density oligonucleotide array data based on variance and bias , 2003, Bioinform..

[24]  E. Butcher,et al.  Differential Chemokine Responses and Homing Patterns of Murine TCRαβ NKT Cell Subsets 1 , 2003, The Journal of Immunology.

[25]  R. Stoughton,et al.  Genetics of gene expression surveyed in maize, mouse and man , 2003, Nature.

[26]  A. Naji,et al.  I-Ag7-mediated antigen presentation by B lymphocytes is critical in overcoming a checkpoint in T cell tolerance to islet beta cells of nonobese diabetic mice. , 1999, Journal of immunology.

[27]  C. Bartsocas,et al.  Genetics of type 1 diabetes mellitus. , 2006, Pediatric endocrinology reviews : PER.

[28]  Luc J. Smink,et al.  Fine Mapping, Gene Content, Comparative Sequencing, and Expression Analyses Support Ctla4 and Nramp1 as Candidates for Idd5.1 and Idd5.2 in the Nonobese Diabetic Mouse 1 , 2004, The Journal of Immunology.

[29]  F. Pociot,et al.  Variation in antiviral 2',5'-oligoadenylate synthetase (2'5'AS) enzyme activity is controlled by a single-nucleotide polymorphism at a splice-acceptor site in the OAS1 gene. , 2005, American journal of human genetics.

[30]  K. Tanaka,et al.  Newly identified pair of proteasomal subunits regulated reciprocally by interferon gamma , 1996, The Journal of experimental medicine.

[31]  J. Danska,et al.  Development and function of diabetogenic T-cells in B-cell-deficient nonobese diabetic mice. , 2001, Diabetes.

[32]  C. Clish,et al.  Reduced Inflammation and Tissue Damage in Transgenic Rabbits Overexpressing 15-Lipoxygenase and Endogenous Anti-inflammatory Lipid Mediators 1 , 2003, The Journal of Immunology.

[33]  R. Tibshirani,et al.  Significance analysis of microarrays applied to the ionizing radiation response , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[34]  Nunzio Bottini,et al.  A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes , 2004, Nature Genetics.

[35]  D. Finegood,et al.  Phagocytosis of apoptotic cells by macrophages from NOD mice is reduced. , 2002, Diabetes.

[36]  Charles N. Serhan,et al.  Lipid mediator class switching during acute inflammation: signals in resolution , 2001, Nature Immunology.

[37]  T. Speed,et al.  Summaries of Affymetrix GeneChip probe level data. , 2003, Nucleic acids research.

[38]  Camillo Ricordi,et al.  The insulin gene is transcribed in the human thymus and transcription levels correlate with allelic variation at the INS VNTR-IDDM2 susceptibility locus for type 1 diabetes , 1997, Nature Genetics.

[39]  Luc J. Smink,et al.  Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease , 2003, Nature.

[40]  Sharon Engel,et al.  A transmembrane CXC chemokine is a ligand for HIV-coreceptor Bonzo , 2000, Nature Immunology.

[41]  S. Martin,et al.  Development of type 1 diabetes despite severe hereditary B-cell deficiency. , 2001, The New England journal of medicine.

[42]  A. Pertsemlidis,et al.  Association of extensive polymorphisms in the SLAM/CD2 gene cluster with murine lupus. , 2004, Immunity.

[43]  E. Wingender,et al.  MATCH: A tool for searching transcription factor binding sites in DNA sequences. , 2003, Nucleic acids research.

[44]  E. Oliw,et al.  Functional Expression and Cellular Localization of a Mouse Epidermal Lipoxygenase* , 1996, The Journal of Biological Chemistry.

[45]  R. Gibbs,et al.  PipMaker--a web server for aligning two genomic DNA sequences. , 2000, Genome research.

[46]  J. Todd,et al.  Polygenic control of autoimmune diabetes in nonobese diabetic mice , 1993, Nature Genetics.

[47]  T. Kita,et al.  Cell surface‐anchored SR‐PSOX/CXC chemokine ligand 16 mediates firm adhesion of CXC chemokine receptor 6‐expressing cells , 2004, Journal of leukocyte biology.

[48]  M. Zeleňáková,et al.  B lymphocytes are essential for the initiation of T cell-mediated autoimmune diabetes: analysis of a new "speed congenic" stock of NOD.Ig mu null mice , 1996, The Journal of experimental medicine.

[49]  Steven J. Schrodi,et al.  A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. , 2004, American journal of human genetics.

[50]  S. Bourgoin,et al.  Phospholipases D1 and D2 Coordinately Regulate Macrophage Phagocytosis1 , 2004, The Journal of Immunology.

[51]  Yoshitaka Takahashi,et al.  Arachidonate 12-lipoxygenases. , 2002, Prostaglandins & other lipid mediators.

[52]  Dan S. Prestridge,et al.  SIGNAL SCAN 4.0: additional databases and sequence formats , 1996, Comput. Appl. Biosci..

[53]  F. Pociot,et al.  OAS1 splice site polymorphism controlling antiviral enzyme activity influences susceptibility to type 1 diabetes. , 2005, Diabetes.

[54]  J. Todd,et al.  Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus , 1997, Nature Genetics.

[55]  Mark S. Anderson,et al.  The NOD mouse: a model of immune dysregulation. , 2005, Annual review of immunology.

[56]  E. Leiter,et al.  Genes and cellular requirements for autoimmune diabetes susceptibility in nonobese diabetic mice. , 2001, Current directions in autoimmunity.

[57]  K. Schwarz,et al.  Structural plasticity of the proteasome and its function in antigen processing. , 2001, Critical reviews in immunology.

[58]  H. Kolb,et al.  Development of type 1 diabetes despite severe hereditary B lymphocyte deficiency: No pathogenic role of B lymphocytes , 2000 .

[59]  D. Serreze,et al.  Transgenic rescue implicates β2-microglobulin as a diabetes susceptibility gene in nonobese diabetic (NOD) mice , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[60]  N J Cox,et al.  Seven regions of the genome show evidence of linkage to type 1 diabetes in a consensus analysis of 767 multiplex families. , 2001, American journal of human genetics.

[61]  M. Takashina,et al.  Replacement of proteasome subunits X and Y by LMP7 and LMP2 induced by interferon‐γ for acquirement of the functional diversity responsible for antigen processing , 1994, FEBS letters.

[62]  J. Todd,et al.  IDDM2-VNTR-encoded susceptibility to type 1 diabetes: dominant protection and parental transmission of alleles of the insulin gene-linked minisatellite locus. , 1996, Journal of autoimmunity.