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Animal Models in Autoimmune Diseases: Lessons Learned from Mouse Models for Sjögren’s Syndrome

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Abstract

The mouse model is the one of the most frequently used and well-established animal models, and is currently used in many research areas. To date, various mouse models have been utilized to elucidate underlying causes of multifactorial autoimmune conditions, including pathological immune components and specific signaling pathways. This review summarizes the more recent mouse models for Sjögren’s syndrome, a systemic autoimmune disease characterized by lymphocytic infiltration in the exocrine glands, such as the salivary and lacrimal glands, and loss of secretory function, resulting in dry mouth and dry eyes in patients. Although every Sjögren’s syndrome mouse model resembles the major symptoms or phenotypes of Sjögren’s syndrome conditions in humans, the characteristics of each model are variable. Moreover, to date, there is no single mouse model that can completely replicate the human conditions. However, unique features of each mouse model provide insights into the roles of potential etiological and immunological factors in the development and progression of Sjögren’s syndrome. Here, we will overview the Sjögren’s syndrome mouse models. Lessons from these mouse models will aid us to understand underlying immune dysregulation in autoimmune diseases in general, and will guide us to direct future research towards appropriate diagnostic and therapeutic strategies.

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References

  1. Taebel DW (1990) The importance of animals in biomedical research. Wis Med J 89(155):158

    Google Scholar 

  2. Wolf SD, Dittel BN, Hardardottir F, Janeway CA Jr (1996) Experimental autoimmune encephalomyelitis induction in genetically B cell-deficient mice. J exp med 184:2271–2278

    Article  PubMed  CAS  Google Scholar 

  3. Bolstad AI, Wassmuth R, Haga HJ, Jonsson R (2001) HLA markers and clinical characteristics in Caucasians with primary Sjögren’s syndrome. J Rheumatol 28:1554–1562

    PubMed  CAS  Google Scholar 

  4. Perez P, Anaya JM, Aguilera S et al (2009) Gene expression and chromosomal location for susceptibility to Sjögren’s syndrome. J Autoimmun 33:99–108

    Article  PubMed  CAS  Google Scholar 

  5. Hu Y, Nakagawa Y, Purushotham KR, Humphreys-Beher MG (1992) Functional changes in salivary glands of autoimmune disease-prone NOD mice. Am J Physiol 263:E607–E614

    PubMed  CAS  Google Scholar 

  6. Humphreys-Beher MG (1996) Animal models for autoimmune disease-associated xerostomia and xerophthalmia. Adv Dent Res 10:73–75

    Article  PubMed  CAS  Google Scholar 

  7. Delaleu N, Immervoll H, Cornelius J, Jonsson R (2008) Biomarker profiles in serum and saliva of experimental Sjögren’s syndrome: associations with specific autoimmune manifestations. Arthritis Res Ther 10:R22

    Article  PubMed  Google Scholar 

  8. Roescher N, Vosters JL, Yin H, Illei GG, Tak PP, Chiorini JA (2011) Effect of soluble ICAM-1 on a Sjögren’s syndrome-like phenotype in NOD mice is disease stage dependent. PLoS One 6:e19962

    Article  PubMed  CAS  Google Scholar 

  9. Brayer JB, Cha S, Nagashima H et al (2001) IL-4-dependent effector phase in autoimmune exocrinopathy as defined by the NOD.IL-4-gene knockout mouse model of Sjögren’s syndrome. Scand J Immunol 54:133–140

    Article  PubMed  CAS  Google Scholar 

  10. Cha S, Brayer J, Gao J et al (2004) A dual role for interferon-gamma in the pathogenesis of Sjögren’s syndrome-like autoimmune exocrinopathy in the nonobese diabetic mouse. Scand J Immunol 60:552–565

    Article  PubMed  CAS  Google Scholar 

  11. Brayer J, Lowry J, Cha S et al (2000) Alleles from chromosomes 1 and 3 of NOD mice combine to influence Sjögren’s syndrome-like autoimmune exocrinopathy. J Rheumatol 27:1896–1904

    PubMed  CAS  Google Scholar 

  12. Cha S, Nagashima H, Brown VB, Peck AB, Humphreys-Beher MG (2002) Two NOD Idd-associated intervals contribute synergistically to the development of autoimmune exocrinopathy (Sjögren’s syndrome) on a healthy murine background. Arthritis Rheum 46:1390–1398

    Article  PubMed  CAS  Google Scholar 

  13. Lee BH, Tudares MA, Nguyen CQ (2009) Sjögren’s syndrome: an old tale with a new twist. Arch Immunol Ther Exp 57:57–66

    Article  Google Scholar 

  14. Doyle ME, Boggs L, Attia R et al (2007) Autoimmune dacryoadenitis of NOD/LtJ mice and its subsequent effects on tear protein composition. Am J Pathol 171:1224–1236

    Article  PubMed  CAS  Google Scholar 

  15. Nguyen C, Cornelius J, Singson E, Killedar S, Cha S, Peck AB (2006) Role of complement and B lymphocytes in Sjögren’s syndrome-like autoimmune exocrinopathy of NOD.B10-H2b mice. Mol Immunol 43:1332–1339

    Article  PubMed  CAS  Google Scholar 

  16. Killedar SJ, Killedar SY, Eckenrode SE et al (2006) Early pathogenic events associated with Sjögren’s syndrome (SjS)-like disease of the NOD mouse using microarray analysis. Lab Invest 86:1243–1260

    Article  PubMed  CAS  Google Scholar 

  17. Cha S, Van Blockland SC, Versnel MA et al (2001) Abnormal organogenesis in salivary gland development may initiate adult onset of autoimmune exocrinopathy. Exp Clin Immunogenet 18:143–160

    Article  PubMed  CAS  Google Scholar 

  18. Bulosan M, Pauley KM, Yo K et al (2009) Inflammatory caspases are critical for enhanced cell death in the target tissue of Sjögren’s syndrome before disease onset. Immunol Cell Biol 87:81–90

    Article  PubMed  CAS  Google Scholar 

  19. Ridgway WM, Peterson LB, Todd JA et al (2008) Gene-gene interactions in the NOD mouse model of type 1 diabetes. Adv Immunol 100:151–175

    Article  PubMed  Google Scholar 

  20. Stojanovich L, Marisavljevich D (2008) Stress as a trigger of autoimmune disease. Autoimmun Rev 7:209–213

    Article  PubMed  Google Scholar 

  21. Ishimaru N, Arakaki R, Watanabe M, Kobayashi M, Miyazaki K, Hayashi Y (2003) Development of autoimmune exocrinopathy resembling Sjögren’s syndrome in estrogen-deficient mice of healthy background. Am J Pathol 163:1481–1490

    Article  PubMed  CAS  Google Scholar 

  22. Ohyama Y, Carroll VA, Deshmukh U, Gaskin F, Brown MG, Fu SM (2006) Severe focal sialadenitis and dacryoadenitis in NZM2328 mice induced by MCMV: a novel model for human Sjögren’s syndrome. J Immunol 177:7391–7397

    PubMed  CAS  Google Scholar 

  23. Lagenaur LA, Manning WC, Vieira J, Martens CL, Mocarski ES (1994) Structure and function of the murine cytomegalovirus sgg1 gene: a determinant of viral growth in salivary gland acinar cells. J Virol 68:7717–7727

    PubMed  CAS  Google Scholar 

  24. Cavanaugh VJ, Deng Y, Birkenbach MP, Slater JS, Campbell AE (2003) Vigorous innate and virus-specific cytotoxic T-lymphocyte responses to murine cytomegalovirus in the submaxillary salivary gland. J Virol 77:1703–1717

    Article  PubMed  CAS  Google Scholar 

  25. Fleck M, Kern ER, Zhou T, Lang B, Mountz JD (1998) Murine cytomegalovirus induces a Sjögren’s syndrome-like disease in C57Bl/6-lpr/lpr mice. Arthritis rheum 41:2175–2184

    Article  PubMed  CAS  Google Scholar 

  26. Skarstein K, Nerland AH, Eidsheim M, Mountz JD, Jonsson R (1997) Lymphoid cell accumulation in salivary glands of autoimmune MRL mice can be due to impaired apoptosis. Scand J Immunol 46:373–378

    Article  PubMed  CAS  Google Scholar 

  27. Ichikawa Y, Arimori K, Yoshida M et al (1995) Abnormal expression of apoptosis-related antigens, Fas and bcl-2, on circulating T-lymphocyte subsets in primary Sjögren’s syndrome. Clin Exp Rheumatol 13:307–313

    PubMed  CAS  Google Scholar 

  28. Fleck M, Zhang HG, Kern ER, Hsu HC, Muller-Ladner U, Mountz JD (2001) Treatment of chronic sialadenitis in a murine model of Sjögren’s syndrome by local fasL gene transfer. Arthritis rheum 44:964–973

    Article  PubMed  CAS  Google Scholar 

  29. Whitacre CC (2001) Sex differences in autoimmune disease. Nat Immunol 2:777–780

    Article  PubMed  CAS  Google Scholar 

  30. Ishimaru N, Saegusa K, Yanagi K, Haneji N, Saito I, Hayashi Y (1999) Estrogen deficiency accelerates autoimmune exocrinopathy in murine Sjögren’s syndrome through fas-mediated apoptosis. Am J Pathol 155:173–181

    Article  PubMed  CAS  Google Scholar 

  31. Kassi E, Moutsatsou P, Sekeris CE, Moutsopoulos HM, Manoussakis MN (2003) Oestrogen receptors in cultured epithelial cells from salivary glands of Sjögren’s syndrome patients. Rheumatology (Oxford) 42:1120–1122

    Article  CAS  Google Scholar 

  32. Valimaa H, Savolainen S, Soukka T et al (2004) Estrogen receptor-beta is the predominant estrogen receptor subtype in human oral epithelium and salivary glands. J Endocrinol 180:55–62

    Article  PubMed  CAS  Google Scholar 

  33. Shim GJ, Warner M, Kim HJ et al (2004) Aromatase-deficient mice spontaneously develop a lymphoproliferative autoimmune disease resembling Sjögren’s syndrome. Proc Natl Acad Sci USA 101:12628–12633

    Article  PubMed  CAS  Google Scholar 

  34. Ishimaru N, Arakaki R, Omotehara F et al (2006) Novel role for RbAp48 in tissue-specific, estrogen deficiency-dependent apoptosis in the exocrine glands. Mol Cell Biol 26:2924–2935

    Article  PubMed  CAS  Google Scholar 

  35. Ishimaru N, Arakaki R, Yoshida S, Yamada A, Noji S, Hayashi Y (2008) Expression of the retinoblastoma protein RbAp48 in exocrine glands leads to Sjögren’s syndrome-like autoimmune exocrinopathy. J exp med 205:2915–2927

    Article  PubMed  CAS  Google Scholar 

  36. Arakaki R, Ishimaru N, Hayashi Y (2010) Immunotherapeutic targets in estrogen deficiency-dependent Sjögren’s syndrome-related manifestations. Immunotherapy 2:339–346

    Article  PubMed  CAS  Google Scholar 

  37. Groom J, Kalled SL, Cutler AH et al (2002) Association of BAFF/BLyS overexpression and altered B cell differentiation with Sjögren’s syndrome. J Clin Invest 109:59–68

    PubMed  CAS  Google Scholar 

  38. Batten M, Groom J, Cachero TG et al (2000) BAFF mediates survival of peripheral immature B lymphocytes. J Exp Med 192:1453–1466

    Article  PubMed  CAS  Google Scholar 

  39. Fletcher CA, Sutherland AP, Groom JR et al (2006) Development of nephritis but not sialadenitis in autoimmune-prone BAFF transgenic mice lacking marginal zone B cells. Eur J Immunol 36:2504–2514

    Article  PubMed  CAS  Google Scholar 

  40. Qian Y, Qin J, Cui G et al (2004) Act1, a negative regulator in CD40- and BAFF-mediated B cell survival. Immunity 21:575–587

    Article  PubMed  CAS  Google Scholar 

  41. Qian Y, Giltiay N, Xiao J et al (2008) Deficiency of Act1, a critical modulator of B cell function, leads to development of Sjögren’s syndrome. Eur J Immunol 38:2219–2228

    Article  PubMed  CAS  Google Scholar 

  42. Ambrus JL Jr, Pippin J, Joseph A et al (1993) Identification of a cDNA for a human high-molecular-weight B-cell growth factor. Proc Natl Acad Sci USA 90:6330–6334

    Article  PubMed  CAS  Google Scholar 

  43. Shen L, Suresh L, Li H et al (2009) IL-14 alpha, the nexus for primary Sjögren’s disease in mice and humans. Clin Immunol 130:304–312

    Article  PubMed  CAS  Google Scholar 

  44. Shen L, Zhang C, Wang T et al (2006) Development of autoimmunity in IL-14alpha-transgenic mice. J Immunol 177:5676–5686

    PubMed  CAS  Google Scholar 

  45. Shen L, Suresh L, Wu J et al (2010) A role for lymphotoxin in primary Sjögren’s disease. J Immunol 185:6355–6363

    Article  PubMed  CAS  Google Scholar 

  46. Nguyen CQ, Sharma A, Lee BH, She JX, Mcindoe RA, Peck AB (2009) Differential gene expression in the salivary gland during development and onset of xerostomia in Sjögren’s syndrome-like disease of the C57BL/6.NOD-Aec1Aec2 mouse. Arthritis Res Ther 11:R56

    Article  PubMed  Google Scholar 

  47. Hjelmervik TO, Petersen K, Jonassen I, Jonsson R, Bolstad AI (2005) Gene expression profiling of minor salivary glands clearly distinguishes primary Sjögren’s syndrome patients from healthy control subjects. Arthritis Rheum 52:1534–1544

    Article  PubMed  CAS  Google Scholar 

  48. Robinson CP, Brayer J, Yamachika S et al (1998) Transfer of human serum IgG to nonobese diabetic Igmu null mice reveals a role for autoantibodies in the loss of secretory function of exocrine tissues in Sjögren’s syndrome. Proc Natl Acad Sci USA 95:7538–7543

    Article  PubMed  CAS  Google Scholar 

  49. Nguyen CQ, Gao J-H, Kim H, Saban DR, Cornelius JG, Peck AB (2007) IL-4-STAT6 signal transduction-dependent induction of the clinical phase of Sjögren’s syndrome-like disease of the nonobese diabetic mouse. J Immunol 179:382–390

    PubMed  CAS  Google Scholar 

  50. Van Blokland SC, Versnel MA (2002) Pathogenesis of Sjögren’s syndrome: characteristics of different mouse models for autoimmune exocrinopathy. Clin Immunol 103:111–124

    Article  PubMed  Google Scholar 

  51. Scofield RH, Asfa S, Obeso D, Jonsson R, Kurien BT (2005) Immunization with short peptides from the 60-kDa Ro antigen recapitulates the serological and pathological findings as well as the salivary gland dysfunction of Sjögren’s syndrome. J Immunol 175:8409–8414

    PubMed  CAS  Google Scholar 

  52. Iizuka M, Wakamatsu E, Tsuboi H et al (2010) Pathogenic role of immune response to M3 muscarinic acetylcholine receptor in Sjögren’s syndrome-like sialoadenitis. J Autoimmun 35:383–389

    Article  PubMed  CAS  Google Scholar 

  53. Bymaster FP, Mckinzie DL, Felder CC, Wess J (2003) Use of M1-M5 muscarinic receptor knockout mice as novel tools to delineate the physiological roles of the muscarinic cholinergic system. Neurochem Res 28:437–442

    Article  PubMed  CAS  Google Scholar 

  54. Kurien BT, Asfa S, Li C, Dorri Y, Jonsson R, Scofield RH (2005) Induction of oral tolerance in experimental Sjögren’s syndrome autoimmunity. Scand J Immunol 61:418–425

    Article  PubMed  CAS  Google Scholar 

  55. Ohlsson M, Jonsson R, Brokstad KA (2002) Subcellular redistribution and surface exposure of the Ro52, Ro60 and La48 autoantigens during apoptosis in human ductal epithelial cells: a possible mechanism in the pathogenesis of Sjögren’s syndrome. Scand J Immunol 56:456–469

    Article  PubMed  CAS  Google Scholar 

  56. Espinosa A, Dardalhon V, Brauner S et al (2009) Loss of the lupus autoantigen Ro52/Trim21 induces tissue inflammation and systemic autoimmunity by disregulating the IL-23-Th17 pathway. J Exp Med 206:1661–1671

    Article  PubMed  CAS  Google Scholar 

  57. Dawson LJ, Fox PC, Smith PM (2006) Sjögrens syndrome—the non-apoptotic model of glandular hypofunction. Rheumatology (Oxford) 45:792–798

    Article  CAS  Google Scholar 

  58. Soyfoo MS, Steinfeld S, Delporte C (2007) Usefulness of mouse models to study the pathogenesis of Sjögren’s syndrome. Oral Dis 13:366–375

    Article  PubMed  CAS  Google Scholar 

  59. Sakai A, Sugawara Y, Kuroishi T, Sasano T, Sugawara S (2008) Identification of IL-18 and Th17 cells in salivary glands of patients with Sjögren’s syndrome, and amplification of IL-17-mediated secretion of inflammatory cytokines from salivary gland cells by IL-18. J Immunol 181:2898–2906

    PubMed  CAS  Google Scholar 

  60. Nguyen CQ, Hu MH, Li Y, Stewart C, Peck AB (2008) Salivary gland tissue expression of interleukin-23 and interleukin-17 in Sjögren’s syndrome: findings in humans and mice. Arthritis Rheum 58:734–743

    Article  PubMed  CAS  Google Scholar 

  61. Katsifis GE, Rekka S, Moutsopoulos NM, Pillemer S, Wahl SM (2009) Systemic and local interleukin-17 and linked cytokines associated with Sjögren’s syndrome immunopathogenesis. Am J Pathol 175:1167–1177

    Article  PubMed  CAS  Google Scholar 

  62. Yokota Y (2001) Id and development. Oncogene 20:8290–8298

    Article  PubMed  CAS  Google Scholar 

  63. Bain G, Cravatt CB, Loomans C, Alberola-Ila J, Hedrick SM, Murre C (2001) Regulation of the helix-loop-helix proteins, E2A and Id3, by the Ras-ERK MAPK cascade. Nat Immunol 2:165–171

    Article  PubMed  CAS  Google Scholar 

  64. Pan L, Sato S, Frederick JP, Sun XH, Zhuang Y (1999) Impaired immune responses and B-cell proliferation in mice lacking the Id3 gene. Mol Cell Biol 19:5969–5980

    PubMed  CAS  Google Scholar 

  65. Li H, Dai M, Zhuang Y (2004) A T cell intrinsic role of Id3 in a mouse model for primary Sjögren’s syndrome. Immunity 21:551–560

    Article  PubMed  CAS  Google Scholar 

  66. Guo Z, Li H, Han M, Xu T, Wu X, Zhuang Y (2011) Modeling Sjögren’s syndrome with Id3 conditional knockout mice. Immunol Lett 135:34–42

    Article  PubMed  CAS  Google Scholar 

  67. Hayakawa I, Tedder TF, Zhuang Y (2007) B-lymphocyte depletion ameliorates Sjögren’s syndrome in Id3 knockout mice. Immunology 122:73–79

    Article  PubMed  CAS  Google Scholar 

  68. Sellam J, Miceli-Richard C, Gottenberg JE et al (2008) Is inhibitor of differentiation 3 involved in human primary Sjögren’s syndrome? Rheumatology (Oxford) 47:437–441

    Article  CAS  Google Scholar 

  69. Fayard E, Moncayo G, Hemmings BA, Hollander GA (2010) Phosphatidylinositol 3-kinase signaling in thymocytes: the need for stringent control. Sci Signal 3:re5

    Article  PubMed  Google Scholar 

  70. Garcon F, Patton DT, Emery JL et al (2008) CD28 provides T-cell costimulation and enhances PI3K activity at the immune synapse independently of its capacity to interact with the p85/p110 heterodimer. Blood 111:1464–1471

    Article  PubMed  CAS  Google Scholar 

  71. Oak JS, Deane JA, Kharas MG et al (2006) Sjögren’s syndrome-like disease in mice with T cells lacking class 1A phosphoinositide-3-kinase. Proc Natl Acad Sci USA 103:16882–16887

    Article  PubMed  CAS  Google Scholar 

  72. Fruman DA, Bismuth G (2009) Fine tuning the immune response with PI3K. Immunol Rev 228:253–272

    Article  PubMed  CAS  Google Scholar 

  73. Hooks JJ, Moutsopoulos HM, Geis SA, Stahl NI, Decker JL, Notkins AL (1979) Immune interferon in the circulation of patients with autoimmune disease. N Engl J Med 301:5–8

    Article  PubMed  CAS  Google Scholar 

  74. Boumba D, Skopouli FN, Moutsopoulos HM (1995) Cytokine mRNA expression in the labial salivary gland tissues from patients with primary Sjögren’s syndrome. Br J Rheumatol 34:326–333

    Article  PubMed  CAS  Google Scholar 

  75. Gao J, Killedar S, Cornelius JG, Nguyen C, Cha S, Peck AB (2006) Sjögren’s syndrome in the NOD mouse model is an interleukin-4 time-dependent, antibody isotype-specific autoimmune disease. J Autoimmun 26:90–103

    Article  PubMed  CAS  Google Scholar 

  76. Nguyen CQ, Yin H, Lee BH, Chiorini JA, Peck AB (2011) IL17: potential therapeutic target in Sjögren’s syndrome using adenovirus-mediated gene transfer. Lab Invest 91(1):54–62

    Google Scholar 

  77. Nguyen CQ, Yin H, Lee BH, Carcamo WC, Chiorini JA, Peck AB (2010) Pathogenic effect of interleukin-17A in induction of Sjögren’s syndrome-like disease using adenovirus-mediated gene transfer. Arthritis Res Ther 12:R220

    Article  PubMed  CAS  Google Scholar 

  78. Hsu HC, Yang P, Wang J et al (2008) Interleukin 17-producing T helper cells and interleukin 17 orchestrate autoreactive germinal center development in autoimmune BXD2 mice. Nat Immunol 9:166–175

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by NIH/NIDCR grant DE019644 (SC).

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Correspondence to Seunghee Cha.

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Lee, B.H., Gauna, A.E., Pauley, K.M. et al. Animal Models in Autoimmune Diseases: Lessons Learned from Mouse Models for Sjögren’s Syndrome. Clinic Rev Allerg Immunol 42, 35–44 (2012). https://doi.org/10.1007/s12016-011-8288-5

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