, Volume 68, Issue 3, pp 205–217 | Cite as

Evaluation of a DLA-79 allele associated with multiple immune-mediated diseases in dogs

  • Steven G. Friedenberg
  • Greg Buhrman
  • Lhoucine Chdid
  • Natasha J. Olby
  • Thierry Olivry
  • Julien Guillaumin
  • Theresa O’Toole
  • Robert Goggs
  • Lorna J. Kennedy
  • Robert B. Rose
  • Kathryn M. Meurs
Original Article


Immune-mediated diseases are common and life-threatening disorders in dogs. Many canine immune-mediated diseases have strong breed predispositions and are believed to be inherited. However, the genetic mutations that cause these diseases are mostly unknown. As many immune-mediated diseases in humans share polymorphisms among a common set of genes, we conducted a candidate gene study of 15 of these genes across four immune-mediated diseases (immune-mediated hemolytic anemia, immune-mediated thrombocytopenia, immune-mediated polyarthritis (IMPA), and atopic dermatitis) in 195 affected and 206 unaffected dogs to assess whether causative or predictive polymorphisms might exist in similar genes in dogs. We demonstrate a strong association (Fisher’s exact p = 0.0004 for allelic association, p = 0.0035 for genotypic association) between two polymorphic positions (10 bp apart) in exon 2 of one allele in DLA-79, DLA-79*001:02, and multiple immune-mediated diseases. The frequency of this allele was significantly higher in dogs with immune-mediated disease than in control dogs (0.21 vs. 0.12) and ranged from 0.28 in dogs with IMPA to 0.15 in dogs with atopic dermatitis. This allele has two non-synonymous substitutions (compared with the reference allele, DLA-79*001:01), resulting in F33L and N37D amino acid changes. These mutations occur in the peptide-binding pocket of the protein, and based upon our computational modeling studies, are likely to affect critical interactions with the peptide N-terminus. Further studies are warranted to confirm these findings more broadly and to determine the specific mechanism by which the identified variants alter canine immune system function.


Canine Immune-mediated disease Dog leukocyte antigen Major histocompatibility complex class Ib 


Compliance with ethical standards


This study was funded in part by a National Institutes of Health T32 training award provided to Dr. Friedenberg (5T32OD011130-07). Some DNA samples and associated phenotypic data were provided by the Cornell Veterinary Biobank, a resource built with the support of NIH grant R24-GM082910 and the Cornell University College of Veterinary Medicine.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

Informed consent

Informed consent was obtained from the owners of all animal participants included in the study.

Supplementary material

251_2015_894_MOESM1_ESM.pdf (22 kb)
Online Resource 1 Detailed breakdown of dogs, breeds, genotyping cohorts, and diseases used as cases and controls for evaluation of the association of DLA-79*001:02 with various autoimmune diseases. Only dogs in the top table were included in the final analysis; dogs in the bottom table were included in the original targeted resequencing or validation cohort 1 but were eliminated from the final analysis in order to balance cases and controls within breeds. Genotyping cohorts labels are as follows: TR, dogs genotyped with targeted resequencing; 1, dogs genotyped by custom Sequenom array; 2, dogs genotyped by Sanger sequencing or endpoint genotyping. Abbreviations: AD atopic dermatitis, IMHA immune-mediated hemolytic anemia, ITP immune-mediated thrombocytopenia, IMPA immune-mediated polyarthritis, TR targeted resequencing. (PDF 21 kb)
251_2015_894_MOESM2_ESM.pdf (11 kb)
Online Resource 2 Predicted DLA-79 binding peptides with a binding affinity less than 200 nM as determined by NetMHCpan 2.8. Peptides were derived from protein sequences of antigens implicated in the pathogenesis of canine IMHA and ITP. Abbreviations: SLC4A1 Solute Carrier 4, Member 1, ITGA2B Integrin α-Chain 2B. Note that SLC4A1 is also known as Erythrocyte Membrane Protein Band 3 (EMPB3). (PDF 11 kb)
251_2015_894_MOESM3_ESM.pdf (16 kb)
Online Resource 3 Detailed breakdown of the effect of variants identified for each gene from the targeted resequencing experiment of 16 dogs with IMHA. Numbers in the table represent the number of variants identified. (PDF 16 kb)
251_2015_894_Fig6_ESM.gif (60 kb)
Online Resource 4

Ramachandran plots for the DLA-79 wild type (a), mutant (b), and 1Q94 template (c). In the wild-type model, 92.3 % of residues are in the favored portion of the Ramachandran plot and 1.5 % are outliers. Two outliers (254, 255) are near the C-terminus, and the third (228) is outside of the peptide binding region. In the mutant model, 92.0 % of residues are within the favored region and 2.0 % are outliers. Three of the outliers are also outliers in the wild-type model and a fourth outlier (189) is also outside the peptide binding domain. Ramachandran plot of the 1Q94 template model is shown for comparison. None of the Ramachandran outliers occur in the peptide binding domain (1–181). All Ramachandran plots were calculated in MolProbity, as implemented in Phenix. (GIF 59 kb)

251_2015_894_MOESM4_ESM.tif (1.1 mb)
High-resolution image (TIF 1082 kb)
251_2015_894_Fig7_ESM.gif (332 kb)
Online Resource 5

DLA-79 has a conserved MHC class I aromatic motif. The protein model developed using the DLA-79 reference allele (dark gray) was superimposed on the template structure PDB 1Q94 (gray). The four MHC class I conserved tyrosine residues (7, 59, 159, 171) are shown as gray sticks. The four aromatic substitutions in DLA-79 are colored magenta. The additional amino acid in DLA-79 (S82) is also colored magenta. DLA-79F33 is colored dark blue, and conserved residues surrounding the F33L substitution site are colored cyan (W51, W167). Residue numbering in the figure is according to the reference structure with the exception of S82. (GIF 331 kb)

251_2015_894_MOESM5_ESM.tif (381 kb)
High-resolution image (TIF 381 kb)


  1. Adams PD, Afonine PV, Bunkóczi G et al (2010) PHENIX: a comprehensive python-based system for macromolecular structure solution. Acta Crystallogr D Biol Crystallogr 66:213–221. doi: 10.1107/S0907444909052925 PubMedCentralCrossRefPubMedGoogle Scholar
  2. Allen RL, Hogan L (2013) Non-classical MHC class I molecules (MHC-Ib). In: eLS. Wiley, Chichester. doi: 10.1002/9780470015902.a0024246
  3. Arnold K, Bordoli L, Kopp J, Schwede T (2006) The SWISS-MODEL workspace: a Web-based environment for protein structure homology modelling. Bioinformatics 22:195–201. doi: 10.1093/bioinformatics/bti770 CrossRefPubMedGoogle Scholar
  4. Barber RM, Schatzberg SJ, Corneveaux JJ et al (2011) Identification of risk loci for necrotizing meningoencephalitis in Pug dogs. J Hered 102(Suppl 1):S40–S46. doi: 10.1093/jhered/esr048 CrossRefPubMedGoogle Scholar
  5. Bayer AL, Pugliese A, Malek TR (2013) The IL-2/IL-2R system: from basic science to therapeutic applications to enhance immune regulation. Immunol Res 57:197–209. doi: 10.1007/s12026-013-8452-5 PubMedCentralCrossRefPubMedGoogle Scholar
  6. Benkert P, Biasini M, Schwede T (2011) Toward the estimation of the absolute quality of individual protein structure models. Bioinformatics 27:343–350. doi: 10.1093/bioinformatics/btq662 PubMedCentralCrossRefPubMedGoogle Scholar
  7. Biasini M, Bienert S, Waterhouse A et al (2014) SWISS-MODEL: modelling protein tertiary and quaternary structure using evolutionary information. Nucleic Acids Res 42:W252–W258. doi: 10.1093/nar/gku340 PubMedCentralCrossRefPubMedGoogle Scholar
  8. Bogdanos DP, Smyk DS, Rigopoulou EI et al (2012) Twin studies in autoimmune disease: genetics, gender and environment. J Autoimmun 38:J156–J169. doi: 10.1016/j.jaut.2011.11.003 CrossRefPubMedGoogle Scholar
  9. Bolger AM, Lohse M, Usadel B (2014) Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics 30:2114–2120. doi: 10.1093/bioinformatics/btu170 PubMedCentralCrossRefPubMedGoogle Scholar
  10. Brenke R, Kozakov D, Chuang G-Y et al (2009) Fragment-based identification of druggable “hot spots” of proteins using Fourier domain correlation techniques. Bioinformatics 25:621–627. doi: 10.1093/bioinformatics/btp036 PubMedCentralCrossRefPubMedGoogle Scholar
  11. Buhrman G, O’Connor C, Zerbe B et al (2011) Analysis of binding site hot spots on the surface of Ras GTPase. J Mol Biol 413:773–789. doi: 10.1016/j.jmb.2011.09.011 PubMedCentralCrossRefPubMedGoogle Scholar
  12. Burnett RC, Geraghty DE (1995) Structure and expression of a divergent canine class I gene. J Immunol 155:4278–4285PubMedGoogle Scholar
  13. Callan MB, Werner P, Mason NJ et al (2013) Polymorphisms in canine platelet glycoproteins identify potential platelet antigens. Comp Med 63:348–354PubMedCentralPubMedGoogle Scholar
  14. Carr AP, Panciera DL, Kidd L (2002) Prognostic factors for mortality and thromboembolism in canine immune-mediated hemolytic anemia: a retrospective study of 72 dogs. J Vet Intern Med 16:504–509CrossRefPubMedGoogle Scholar
  15. Castiblanco J, Arcos-Burgos M, Anaya J-M (2013) What is next after the genes for autoimmunity? BMC Med 11:197–206. doi: 10.1186/1741-7015-11-197 PubMedCentralCrossRefPubMedGoogle Scholar
  16. Catchpole B, Adams JP, Holder AL et al (2013) Genetics of canine diabetes mellitus: are the diabetes susceptibility genes identified in humans involved in breed susceptibility to diabetes mellitus in dogs? Vet J 195:139–147. doi: 10.1016/j.tvjl.2012.11.013 CrossRefPubMedGoogle Scholar
  17. Chase K, Sargan D, Miller K et al (2006) Understanding the genetics of autoimmune disease: two loci that regulate late onset Addison’s disease in Portuguese water dogs. Int J Immunogenet 33:179–184. doi: 10.1111/j.1744-313X.2006.00593.x PubMedCentralCrossRefPubMedGoogle Scholar
  18. Cho JH, Gregersen PK (2011) Genomics and the multifactorial nature of human autoimmune disease. N Engl J Med 365:1612–1623. doi: 10.1056/NEJMra1100030 CrossRefPubMedGoogle Scholar
  19. Cingolani P, Platts A, Wang LL et al (2012) A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3. Fly (Austin) 6:80–92. doi: 10.4161/fly.19695 CrossRefGoogle Scholar
  20. Clements DN, Gear RNA, Tattersall J et al (2004) Type I immune-mediated polyarthritis in dogs: 39 cases (1997–2002). J Am Vet Med Assoc 224:1323–1327CrossRefPubMedGoogle Scholar
  21. Corato A, Shen CR, Mazza G et al (1997) Proliferative responses of peripheral blood mononuclear cells from normal dogs and dogs with autoimmune haemolytic anaemia to red blood cell antigens. Vet Immunol Immunopathol 59:191–204CrossRefPubMedGoogle Scholar
  22. Costenbader KH, Gay S, Alarcón-Riquelme ME et al (2012) Autoimmunity reviews. Autoimmun Rev 11:604–609. doi: 10.1016/j.autrev.2011.10.022 CrossRefPubMedGoogle Scholar
  23. Cotsapas C, Hafler DA (2013) Immune-mediated disease genetics: the shared basis of pathogenesis. Trends Immunol 34:22–26. doi: 10.1016/ CrossRefPubMedGoogle Scholar
  24. Cotsapas C, Voight BF, Rossin E et al (2011) Pervasive sharing of genetic effects in autoimmune disease. PLoS Genet 7, e1002254. doi: 10.1371/journal.pgen.1002254 PubMedCentralCrossRefPubMedGoogle Scholar
  25. Day MJ (1999) Antigen specificity in canine autoimmune haemolytic anaemia. Vet Immunol Immunopathol 69:215–224CrossRefPubMedGoogle Scholar
  26. de Almeida DE, Holoshitz J (2011) MHC molecules in health and disease: at the cusp of a paradigm shift. Self Nonself 2:43–48. doi: 10.4161/self.2.1.15757 PubMedCentralCrossRefPubMedGoogle Scholar
  27. DePristo MA, Banks E, Poplin R et al (2011) A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet 43:491–498. doi: 10.1038/ng.806 PubMedCentralCrossRefPubMedGoogle Scholar
  28. Eames HL, Corbin AL, Udalova IA (2015) Interferon regulatory factor 5 in human autoimmunity and murine models of autoimmune disease. Transl Res. doi: 10.1016/j.trsl.2015.06.018 PubMedGoogle Scholar
  29. Emsley P, Lohkamp B, Scott WG, Cowtan K (2010) Features and development of Coot. Acta Crystallogr D Biol Crystallogr 66:486–501. doi: 10.1107/S0907444910007493 PubMedCentralCrossRefPubMedGoogle Scholar
  30. Ettinger R, Kuchen S, Lipsky PE (2008) Interleukin 21 as a target of intervention in autoimmune disease. Ann Rheum Dis 67(Suppl 3):iii83–iii86. doi: 10.1136/ard.2008.098400 CrossRefPubMedGoogle Scholar
  31. Famula TR, Belanger JM, Oberbauer AM (2003) Heritability and complex segregation analysis of hypoadrenocorticism in the standard poodle. J Small Anim Pract 44:8–12CrossRefPubMedGoogle Scholar
  32. Gee K, Guzzo C, Che Mat NF et al (2009) The IL-12 family of cytokines in infection, inflammation and autoimmune disorders. Inflamm Allergy Drug Targets 8:40–52CrossRefPubMedGoogle Scholar
  33. Ghoreschi K, Laurence A, O’Shea JJ (2009) Janus kinases in immune cell signaling. Immunol Rev 228:273–287. doi: 10.1111/j.1600-065X.2008.00754.x PubMedCentralCrossRefPubMedGoogle Scholar
  34. Graumann MB, DeRose SA, Ostrander EA, Storb R (1998) Polymorphism analysis of four canine MHC class I genes. Tissue Antigens 51:374–381CrossRefPubMedGoogle Scholar
  35. Greer KA, Wong AK, Liu H et al (2010) Necrotizing meningoencephalitis of Pug dogs associates with dog leukocyte antigen class II and resembles acute variant forms of multiple sclerosis. Tissue Antigens 76:110–118. doi: 10.1111/j.1399-0039.2010.01484.x PubMedGoogle Scholar
  36. Gregersen PK, Diamond B, Plenge RM (2012) GWAS implicates a role for quantitative immune traits and threshold effects in risk for human autoimmune disorders. Curr Opin Immunol 24:538–543. doi: 10.1016/j.coi.2012.09.003 CrossRefPubMedGoogle Scholar
  37. Guex N, Peitsch MC, Schwede T (2009) Automated comparative protein structure modeling with SWISS-MODEL and Swiss-PdbViewer: a historical perspective. Electrophoresis 30(Suppl 1):S162–S173. doi: 10.1002/elps.200900140 CrossRefPubMedGoogle Scholar
  38. Hoof I, Peters B, Sidney J et al (2009) NetMHCpan, a method for MHC class I binding prediction beyond humans. Immunogenetics 61:1–13. doi: 10.1007/s00251-008-0341-z PubMedCentralCrossRefPubMedGoogle Scholar
  39. Huang AA, Moore GE, Scott-Moncrieff JC (2012) Idiopathic immune-mediated thrombocytopenia and recent vaccination in dogs. J Vet Intern Med 26:142–148. doi: 10.1111/j.1939-1676.2011.00850.x CrossRefPubMedGoogle Scholar
  40. Iyer SS, Cheng G (2012) Role of interleukin 10 transcriptional regulation in inflammation and autoimmune disease. Crit Rev Immunol 32:23–63PubMedCentralCrossRefPubMedGoogle Scholar
  41. Jiang H, Ware R, Stall A et al (1995) Murine CD8+ T cells that specifically delete autologous CD4+ T cells expressing V beta 8 TCR: a role of the Qa-1 molecule. Immunity 2:185–194CrossRefPubMedGoogle Scholar
  42. Jiang H, Wu Y, Liang B et al (2005) An affinity/avidity model of peripheral T cell regulation. J Clin Invest 115:302–312. doi: 10.1172/JCI23879 PubMedCentralCrossRefPubMedGoogle Scholar
  43. Johnson KC, Mackin A (2012) Canine immune-mediated polyarthritis: part 1: pathophysiology. J Am Anim Hosp Assoc 48:12–17. doi: 10.5326/JAAHA-MS-5744 CrossRefPubMedGoogle Scholar
  44. Kennedy LJ, Barnes A, Ollier WER, Day MJ (2006a) Association of a common dog leucocyte antigen class II haplotype with canine primary immune-mediated haemolytic anaemia. Tissue Antigens 68:502–508. doi: 10.1111/j.1399-0039.2006.00715.x CrossRefPubMedGoogle Scholar
  45. Kennedy LJ, Quarmby S, Happ GM et al (2006b) Association of canine hypothyroidism with a common major histocompatibility complex DLA class II allele. Tissue Antigens 68:82–86. doi: 10.1111/j.1399-0039.2006.00614.x CrossRefPubMedGoogle Scholar
  46. Kiefer F, Arnold K, Künzli M et al (2009) The SWISS-MODEL Repository and associated resources. Nucleic Acids Res 37:D387–D392. doi: 10.1093/nar/gkn750 PubMedCentralCrossRefPubMedGoogle Scholar
  47. Kim H-J, Wang X, Radfar S et al (2011) CD8+ T regulatory cells express the Ly49 class I MHC receptor and are defective in autoimmune prone B6-Yaa mice. Proc Natl Acad Sci 108:2010–2015. doi: 10.1073/pnas.1018974108 PubMedCentralCrossRefPubMedGoogle Scholar
  48. Korman BD, Kastner DL, Gregersen PK, Remmers EF (2008) STAT4: genetics, mechanisms, and implications for autoimmunity. Curr Allergy Asthma Rep 8:398–403PubMedCentralCrossRefPubMedGoogle Scholar
  49. Kozakov D, Hall DR, Chuang G-Y et al (2011) Structural conservation of druggable hot spots in protein-protein interfaces. Proc Natl Acad Sci 108:13528–13533. doi: 10.1073/pnas.1101835108 PubMedCentralCrossRefPubMedGoogle Scholar
  50. Lee B, Richards FM (1971) The interpretation of protein structures: estimation of static accessibility. J Mol Biol 55:379–400CrossRefPubMedGoogle Scholar
  51. Lewis DC, Meyers KM (1996) Canine idiopathic thrombocytopenic purpura. J Vet Intern Med 10:207–218CrossRefPubMedGoogle Scholar
  52. Li L, Bouvier M (2004) Structures of HLA-A*1101 complexed with immunodominant nonamer and decamer HIV-1 epitopes clearly reveal the presence of a middle, secondary anchor residue. J Immunol 172:6175–6184. doi: 10.4049/jimmunol.172.10.6175 CrossRefPubMedGoogle Scholar
  53. Li H, Durbin R (2009) Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25:1754–1760. doi: 10.1093/bioinformatics/btp324 PubMedCentralCrossRefPubMedGoogle Scholar
  54. London N, London N, Raveh B et al (2011) Rosetta FlexPepDock web server—high resolution modeling of peptide-protein interactions. Nucleic Acids Res 39:W249–W253. doi: 10.1093/nar/gkr431 PubMedCentralCrossRefPubMedGoogle Scholar
  55. Massey J, Boag A, Short AD et al (2013a) MHC class II association study in eight breeds of dog with hypoadrenocorticism. Immunogenetics 65:291–297. doi: 10.1007/s00251-013-0680-2 CrossRefPubMedGoogle Scholar
  56. Massey J, Rothwell S, Rusbridge C et al (2013b) Association of an MHC class II haplotype with increased risk of polymyositis in Hungarian Vizsla dogs. PLoS One 8, e56490. doi: 10.1371/journal.pone.0056490 PubMedCentralCrossRefPubMedGoogle Scholar
  57. Massey J, Short AD, Catchpole B et al (2014) Genetics of canine anal furunculosis in the German Shepherd dog. Immunogenetics 66:311–324. doi: 10.1007/s00251-014-0766-5 CrossRefPubMedGoogle Scholar
  58. McCullough S (2003) Immune-mediated hemolytic anemia: understanding the nemesis. Vet Clin North Am Small Anim Pract 33:1295–1315. doi: 10.1016/S0195-5616(03)00123-2 CrossRefPubMedGoogle Scholar
  59. McKenna A, Hanna M, Banks E et al (2010) The genome analysis toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res 20:1297–1303. doi: 10.1101/gr.107524.110 PubMedCentralCrossRefPubMedGoogle Scholar
  60. McLaren W, Pritchard B, Rios D et al (2010) Deriving the consequences of genomic variants with the Ensembl API and SNP Effect Predictor. Bioinformatics 26:2069–2070. doi: 10.1093/bioinformatics/btq330 PubMedCentralCrossRefPubMedGoogle Scholar
  61. McPhee CG, Sproule TJ, Shin D-M et al (2011) MHC class I family proteins retard systemic lupus erythematosus autoimmunity and B cell lymphomagenesis. J Immunol 187:4695–4704. doi: 10.4049/jimmunol.1101776 PubMedCentralCrossRefPubMedGoogle Scholar
  62. Nielsen M, Lundegaard C, Blicher T et al (2007) NetMHCpan, a method for quantitative predictions of peptide binding to any HLA-A and -B locus protein of known sequence. PLoS One 2, e796. doi: 10.1371/journal.pone.0000796 PubMedCentralCrossRefPubMedGoogle Scholar
  63. Nuttall T, Uri M, Halliwell R (2013) Canine atopic dermatitis—what have we learned? Vet Rec 172:201–207. doi: 10.1136/vr.f1134 CrossRefPubMedGoogle Scholar
  64. Olivry T, DeBoer DJ, Favrot C et al (2010) Treatment of canine atopic dermatitis: 2010 clinical practice guidelines from the International Task Force on Canine Atopic Dermatitis. Vet Dermatol 21:233–248. doi: 10.1111/j.1365-3164.2010.00889.x CrossRefPubMedGoogle Scholar
  65. O’Marra SK, Delaforcade AM, Shaw SP (2011) Treatment and predictors of outcome in dogs with immune-mediated thrombocytopenia. J Am Vet Med Assoc 238:346–352. doi: 10.2460/javma.238.3.346 CrossRefPubMedGoogle Scholar
  66. Parkes M, Cortes A, van Heel DA, Brown MA (2013) Genetic insights into common pathways and complex relationships among immune-mediated diseases. Nat Rev Genet 14:661–673. doi: 10.1038/nrg3502 CrossRefPubMedGoogle Scholar
  67. Pedersen NC, Liu H, Greenfield DL, Echols LG (2012a) Multiple autoimmune diseases syndrome in Italian Greyhounds: preliminary studies of genome-wide diversity and possible associations within the dog leukocyte antigen (DLA) complex. Vet Immunol Immunopathol 145:264–276. doi: 10.1016/j.vetimm.2011.11.015 CrossRefPubMedGoogle Scholar
  68. Pedersen NC, Liu H, McLaughlin B, Sacks BN (2012b) Genetic characterization of healthy and sebaceous adenitis affected standard poodles from the United States and the United Kingdom. Tissue Antigens 80:46–57. doi: 10.1111/j.1399-0039.2012.01876.x CrossRefPubMedGoogle Scholar
  69. Piek CJ (2011) Canine idiopathic immune-mediated haemolytic anaemia: a review with recommendations for future research. Vet Q 31:129–141. doi: 10.1080/01652176.2011.604979 CrossRefPubMedGoogle Scholar
  70. Raveh B, London N, Schueler-Furman O (2010) Sub-angstrom modeling of complexes between flexible peptides and globular proteins. Proteins 78:2029–2040. doi: 10.1002/prot.22716 PubMedGoogle Scholar
  71. Rawlings DJ, Dai X, Buckner JH (2015) The role of PTPN22 risk variant in the development of autoimmunity: finding common ground between mouse and human. J Immunol 194:2977–2984. doi: 10.4049/jimmunol.1403034 CrossRefPubMedGoogle Scholar
  72. Reich NC (2013) STATs get their move on. JAKSTAT 2:e27080. doi: 10.4161/jkst.27080 PubMedCentralPubMedGoogle Scholar
  73. Rodgers JR, Cook RG (2005) MHC class Ib molecules bridge innate and acquired immunity. Nat Rev Immunol 5:459–471. doi: 10.1038/nri1635 CrossRefPubMedGoogle Scholar
  74. Romo-Tena J, Gómez-Martín D, Alcocer-Varela J (2013) CTLA-4 and autoimmunity: new insights into the dual regulator of tolerance. Autoimmun Rev 12:1171–1176. doi: 10.1016/j.autrev.2013.07.002 CrossRefPubMedGoogle Scholar
  75. Saff EB, Kuijlaars ABJ (1997) Distributing many points on a sphere. Math Intell 19:5–11. doi: 10.1007/BF03024331 CrossRefGoogle Scholar
  76. Salzmann CA, Olivry TJM, Nielsen DM et al (2011) Genome-wide linkage study of atopic dermatitis in West Highland White Terriers. BMC Genet 12:37. doi: 10.1186/1471-2156-12-37 PubMedCentralCrossRefPubMedGoogle Scholar
  77. Schrauwen I, Barber RM, Schatzberg SJ et al (2014) Identification of novel genetic risk loci in Maltese dogs with necrotizing meningoencephalitis and evidence of a shared genetic risk across toy dog breeds. PLoS One 9, e112755. doi: 10.1371/journal.pone.0112755 PubMedCentralCrossRefPubMedGoogle Scholar
  78. Selmi C, Lu Q, Humble MC (2012) Heritability versus the role of the environment in autoimmunity. J Autoimmun 39:249–252. doi: 10.1016/j.jaut.2012.07.011 CrossRefPubMedGoogle Scholar
  79. Sharma R, Fu SM, Ju S-T (2011) IL-2: a two-faced master regulator of autoimmunity. J Autoimmun 36:91–97. doi: 10.1016/j.jaut.2011.01.001 PubMedCentralCrossRefPubMedGoogle Scholar
  80. Short AD, Saleh NM, Catchpole B et al (2010) CTLA4 promoter polymorphisms are associated with canine diabetes mellitus. Tissue Antigens 75:242–252. doi: 10.1111/j.1399-0039.2009.01434.x CrossRefPubMedGoogle Scholar
  81. Short AD, Boag A, Catchpole B et al (2013) A candidate gene analysis of canine hypoadrenocorticism in 3 dog breeds. J Hered 104:807–820. doi: 10.1093/jhered/est051 CrossRefPubMedGoogle Scholar
  82. Sorrentino R (2013) Genetics of autoimmunity: an update. Immunol Lett 158:116–119. doi: 10.1016/j.imlet.2013.12.005 CrossRefPubMedGoogle Scholar
  83. Stanford SM, Bottini N (2014) PTPN22: the archetypal non-HLA autoimmunity gene. Nat Rev Rheumatol 10:602–611. doi: 10.1038/nrrheum.2014.109 PubMedCentralCrossRefPubMedGoogle Scholar
  84. Temajo NO, Howard N (2014) The mosaic of environment involvement in autoimmunity: the abrogation of viral latency by stress, a non-infectious environmental agent, is an intrinsic prerequisite prelude before viruses can rank as infectious environmental agents that trigger autoimmune diseases. Autoimmun Rev 13:635–640. doi: 10.1016/j.autrev.2013.12.003 CrossRefPubMedGoogle Scholar
  85. Van der Auwera GA, Carneiro MO, Hartl C et al (2013) From FastQ data to high confidence variant calls: the genome analysis toolkit best practices pipeline. Curr Protoc Bioinforma 11:11.10.1–11.10.33. doi: 10.1002/0471250953.bi1110s43 Google Scholar
  86. Venkataraman GM, Geraghty D, Fox J et al (2013) Canine DLA-79 gene: an improved typing method, identification of new alleles and its role in graft rejection and graft-versus-host disease. Tissue Antigens 81:204–211. doi: 10.1111/tan.12094 PubMedCentralCrossRefPubMedGoogle Scholar
  87. Visscher PM, Brown MA, McCarthy MI, Yang J (2012) Five years of GWAS discovery. Am J Hum Genet 90:7–24. doi: 10.1016/j.ajhg.2011.11.029 PubMedCentralCrossRefPubMedGoogle Scholar
  88. Voight BF, Cotsapas C (2012) Human genetics offers an emerging picture of common pathways and mechanisms in autoimmunity. Curr Opin Immunol 24:552–557. doi: 10.1016/j.coi.2012.07.013 CrossRefPubMedGoogle Scholar
  89. Wang P, Zangerl B, Werner P et al (2011) Familial cutaneous lupus erythematosus (CLE) in the German shorthaired pointer maps to CFA18, a canine orthologue to human CLE. Immunogenetics 63:197–207. doi: 10.1007/s00251-010-0499-z PubMedCentralCrossRefPubMedGoogle Scholar
  90. Weinkle TK, Center SA, Randolph JF et al (2005) Evaluation of prognostic factors, survival rates, and treatment protocols for immune-mediated hemolytic anemia in dogs: 151 cases (1993–2002). J Am Vet Med Assoc 226:1869–1880CrossRefPubMedGoogle Scholar
  91. Whitley NT, Day MJ (2011) Immunomodulatory drugs and their application to the management of canine immune-mediated disease. J Small Anim Pract 52:70–85. doi: 10.1111/j.1748-5827.2011.01024.x CrossRefPubMedGoogle Scholar
  92. Wilbe M, Jokinen P, Hermanrud C et al (2009) MHC class II polymorphism is associated with a canine SLE-related disease complex. Immunogenetics 61:557–564. doi: 10.1007/s00251-009-0387-6 CrossRefPubMedGoogle Scholar
  93. Wilbe M, Jokinen P, Truvé K et al (2010a) Genome-wide association mapping identifies multiple loci for a canine SLE-related disease complex. Nat Genet 42:250–254. doi: 10.1038/ng.525 CrossRefPubMedGoogle Scholar
  94. Wilbe M, Sundberg K, Hansen IR et al (2010b) Increased genetic risk or protection for canine autoimmune lymphocytic thyroiditis in Giant Schnauzers depends on DLA class II genotype. Tissue Antigens 75:712–719. doi: 10.1111/j.1399-0039.2010.01449.x CrossRefPubMedGoogle Scholar
  95. Wilbe M, Ziener ML, Aronsson A et al (2010c) DLA class II alleles are associated with risk for canine symmetrical lupoid onychodystropy (SLO). PLoS One 5, e12332. doi: 10.1371/journal.pone.0012332.t004 PubMedCentralCrossRefPubMedGoogle Scholar
  96. Ymer SI, Huang D, Penna G et al (2002) Polymorphisms in the Il12b gene affect structure and expression of IL-12 in NOD and other autoimmune-prone mouse strains. Genes Immun 3:151–157. doi: 10.1038/sj.gene.6363849 CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Steven G. Friedenberg
    • 1
    • 3
  • Greg Buhrman
    • 2
  • Lhoucine Chdid
    • 1
  • Natasha J. Olby
    • 1
    • 3
  • Thierry Olivry
    • 1
    • 3
  • Julien Guillaumin
    • 5
  • Theresa O’Toole
    • 6
  • Robert Goggs
    • 7
  • Lorna J. Kennedy
    • 4
  • Robert B. Rose
    • 2
    • 3
  • Kathryn M. Meurs
    • 1
    • 3
  1. 1.Department of Clinical Sciences, College of Veterinary MedicineNorth Carolina State UniversityRaleighUSA
  2. 2.Department of Molecular and Structural BiochemistryNorth Carolina State UniversityRaleighUSA
  3. 3.Comparative Medicine InstituteNorth Carolina State UniversityRaleighUSA
  4. 4.Centre for Integrated Genomic Medical ResearchUniversity of ManchesterManchesterUK
  5. 5.Department of Veterinary Clinical Sciences, College of Veterinary MedicineThe Ohio State UniversityColumbusUSA
  6. 6.Department of Clinical Sciences, Cummings School of Veterinary MedicineTufts UniversityNorth GraftonUSA
  7. 7.Department of Clinical Sciences, College of Veterinary MedicineCornell UniversityIthacaUSA

Personalised recommendations