Autoimmune diseases

  • William J. Karpus
Part of the Progress in Inflammation Research book series (PIR)


Experimental models of autoimmune disease have been used to dissect the mechanisms of disease pathogenesis in the corresponding human diseases. This chapter will deal with experimental autoimmune encephalomyelitis (EAE) as a model for human multiple sclerosis (MS) and experimental autoimmune diabetes (EAD) in the NOD mouse as a model for human diabetes. In the case of these tissue-specific autoimmune diseases, the autoreactive lymphocytes originate in lymph nodes and must migrate to either the central nervous system (CNS) in the case of EAE or the pancreas in the case of EAD. The accepted paradigm of leukocyte migration from blood into tissue involves a number of molecular events including selectin binding, chemokine binding, integrin binding and activation, and extravasation [1, 2]. Therefore, chemokines have a central role in the pathogenesis of tissue-specific autoimmune diseases. The approaches that have been used to study the role of chemokines in animal models of autoimmune disease included assessing tissue-specific temporal chemokine expression patterns, assessing corresponding chemokine receptor expression patterns on the tissue-infiltrating leukocytes, using neutralizing anti-chemokine therapy, employing chemokine and/or chemokine receptor knockout mice in the various disease models, and making transgenic mice that overexpress certain chemokines in specific tissues. This has resulted in the identification of subsets of the chemokine and chemokine receptor families that play a role in disease pathogenesis. This chapter will review the role of chemokines and their receptors in EAE and EAD as examples of tissue-specific autoimmune diseases.


Experimental Autoimmune Encephalomyelitis Experimental Allergic Encephalomyelitis Chemokine Receptor Expression Chemokine mRNA Experimental Autoimmune Encephalomyelitis Development 
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  1. 1.
    Butcher EC (1992) Leukocyte-endothelial cell adhesion as an active, multi-step process: a combinatorial mechanism for specificity and diversity in leukocyte targeting. Adv Exp Med Biol 323: 181–194PubMedGoogle Scholar
  2. 2.
    Springer TA (1994) Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell 76: 301–314PubMedCrossRefGoogle Scholar
  3. 3.
    Segal BM (2003) Experimental Autoimmune encephalomyelitis: cytokines, effector T cells, and antigen-presenting cells in a prototypical Th1-mediated autoimmune disease. Curr Allergy Asthma Rep 3: 86–93PubMedCrossRefGoogle Scholar
  4. 4.
    Glabinski AR, Tani M, Tuohy VK, Tuthill RJ, Ransohoff RM (1995) Central nervous system chemokine mRNA accumulation follows initial leukocyte entry at the onset of acute murine experimental autoimmune encephalomyelitis. Brain, Behavior, & Immunity 9: 315–330CrossRefGoogle Scholar
  5. 5.
    Godiska R, Chantry D, Dietsch GN, Gray PW (1995) Chemokine expression in murine experimental allergic encephalomyelitis. J Neuroimmunol 58: 167–176PubMedCrossRefGoogle Scholar
  6. 6.
    Kennedy KJ, Strieter RM, Kunkel SL, Lukacs NW, Karpus WJ (1998) Acute and relapsing experimental autoimmune encephalomyelitis are regulated by differential expression of the CC chemokines macrophage inflammatory protein-1α and monocyte chemotactic protein-1. J Neuroimmunol 92: 98–108PubMedCrossRefGoogle Scholar
  7. 7.
    Hulkower K, Brosnan CF, Aquino DA, Cammer W, Kulshrestha S, Guida MP, Rapoport DA, Berman JW (1993) Expression of CSF-1, c-fms, and MCP-1 in the central nervous system of rats with experimental allergic encephalomyelitis. J Immunol 150: 2525–2533PubMedGoogle Scholar
  8. 8.
    Ransohoff RM, Hamilton TA, Tani M, Stoler MH, Shick HE, Major JA, Estes ML, Thomas DM, Tuohy VK (1993) Astrocyte expression of mRNA encoding cytokines IP-10 and JE/MCP-1 in experimental autoimmune encephalomyelitis. FASEB J 7: 592–600PubMedGoogle Scholar
  9. 9.
    Asensio VC, Lassmann S, Pagenstecher A, Steffensen SC, Henriksen SJ, Campbell IL (1999) C10 is a novel chemokine expressed in experimental inflammatory demyelinating disorders that promotes recruitment of macrophages to the central nervous system. Am J Pathol 154: 1181–1191PubMedGoogle Scholar
  10. 10.
    Glabinski AR, Tuohy VK, Ransohoff RM (1998) Expression of chemokines RANTES, MIP-1alpha and GRO-alpha correlates with inflammation in acute experimental autoimmune encephalomyelitis. Neuroimmunomodulation 5: 166–171PubMedCrossRefGoogle Scholar
  11. 11.
    Glabinski AR, Tani M, Strieter RM, Tuohy VK, Ransohoff RM (1997) Synchronous synthesis of α-and β-chemokines by cells of diverse lineage in the central nervous system of mice with relapses of chronic experimental autoimmune encephalomyelitis. Am J Pathol 150: 617–630PubMedGoogle Scholar
  12. 12.
    Karpus WJ, Lukacs NW, McRae BL, Strieter RM, Kunkel SL, Miller SD (1995) An important role for the chemokine macrophage inflammatory protein-1α in the pathogenesis of the T cell-mediated autoimmune disease, experimental autoimmune encephalomyelitis. J Immunol 155: 5003–5010PubMedGoogle Scholar
  13. 13.
    Fife BT, Kennedy KJ, Paniagua MC, Lukacs NW, Kunkel SL, Luster AD, Karpus WJ (2001) CXCL10 (IFN-gamma-inducible protein-10) control of encephalitogenic CD4+ T cell accumulation in the central nervous system during experimental autoimmune encephalomyelitis. J Immunol 166: 7617–7624PubMedGoogle Scholar
  14. 14.
    Karpus WJ, Fife BT, Kennedy KJ (2003) Immunoneutralization of chemokines for the prevention and treatment of central nervous system autoimmune disease. Methods 29: 362–368PubMedCrossRefGoogle Scholar
  15. 15.
    Kohler RE, Caon AC, Willenborg DO, Clark-Lewis I, McColl SR (2003) A role for macrophage inflammatory protein-3α/CC chemokine ligand 20 in immune priming during T cell-mediated inflammation of the central nervous system. J Immunol 170: 6298PubMedGoogle Scholar
  16. 16.
    Karpus WJ, Ransohoff RM (1998) Chemokine regulation of experimental autoimmune encephalomyelitis: temporal and spatial expression patterns govern disease pathogenesis. J Immunol 161: 2667–2671PubMedGoogle Scholar
  17. 17.
    Huang DR, Wang J, Kivisakk P, Rollins BJ, Ransohoff RM (2001) Absence of monocyte chemoattractant protein 1 in mice leads to decreased local macrophage recruitment and antigen-specific T helper cell type 1 immune response in experimental autoimmune encephalomyelitis. J Exp Med 193: 713–726PubMedCrossRefGoogle Scholar
  18. 18.
    Klein RS, Izikson L, Means T, Gibson HD, Lin E, Sobel RA, Weiner HL, Luster AD (2004) IFN-inducible protein 10/CXC chemokine ligand 10-independent induction of experimental autoimmune encephalomyelitis. J Immunol 172: 550–559PubMedGoogle Scholar
  19. 19.
    Elhofy A, Wang J, Tani M, Fife BT, Kennedy KJ, Bennett J, Huang D, Ransohoff RM, Karpus WJ (2005) Transgenic expression of CCL2 in the central nervous system prevents experimental autoimmune encephalomyelitis. J Leukoc Biol 77: 229–237PubMedCrossRefGoogle Scholar
  20. 20.
    Karpus WJ, Lukacs NW, Kennedy KJ, Smith WS, Hurst SD, Barrett TA (1997) Differential CC chemokine-induced enhancement of T helper cell cytokine production. J Immunol 158: 4129–4136PubMedGoogle Scholar
  21. 21.
    Gu L, Tseng S, Horner RM, Tam C, Loda M, Rollins BJ (2000) Control of TH2 polarization by the chemokine monocyte chemoattractant protein-1. Nature 404: 407–411PubMedCrossRefGoogle Scholar
  22. 22.
    Jiang Y, Salafranca MN, Adhikari S, Xia Y, Feng L, Sonntag MK, deFiebre CM, Pennell NA, Streit WJ, Harrison JK (1998) Chemokine receptor expression in cultured glia and rat experimental allergic encephalomyelitis. J Neuroimmunol 86: 1–12PubMedCrossRefGoogle Scholar
  23. 23.
    Charles PC, Weber KS, Cipriani B, Brosnan CF (1999) Cytokine, chemokine and chemokine receptor mRNA expression in different strains of normal mice: implications for establishment of a Th1/Th2 bias. J Neuroimmunol 100: 64–73PubMedCrossRefGoogle Scholar
  24. 24.
    Rajan AJ, Asensio VC, Campbell IL, Brosnan CF (2000) Experimental autoimmune encephalomyelitis on the SJL mouse: effect of gamma delta T cell depletion on chemokine and chemokine receptor expression in the central nervous system. J Immunol 164: 2120–2130PubMedGoogle Scholar
  25. 25.
    Matejuk A, Vandenbark AA, Burrows GG, Bebo BF Jr., Offner H (2000) Reduced chemokine and chemokine receptor expression in spinal cords of TCR BV8S2 transgenic mice protected against experimental autoimmune encephalomyelitis with BV8S2 protein. J Immunol 164: 3924–3931PubMedGoogle Scholar
  26. 26.
    Rottman JB, Slavin AJ, Silva R, Weiner HL, Gerard CG, Hancock WW (2000) Leukocyte recruitment during onset of experimental allergic encephalomyelitis is CCR1 dependent. Eur J Immunol 30: 2372–2377PubMedCrossRefGoogle Scholar
  27. 27.
    Fife BT, Huffnagle GB, Kuziel WA, Karpus WJ (2000) CC chemokine receptor 2 is critical for induction of experimental autoimmune encephalomyelitis. J Exp Med 192: 899–906PubMedCrossRefGoogle Scholar
  28. 28.
    Gao JL, Wynn TA, Chang Y, Lee EJ, Broxmeyer HE, Cooper S, Tiffany HL, Westphal H, Kwon-Chung J, Murphy PM (1997) Impaired host defense, hematopoiesis, granulomatous inflammation and type 1-type 2 cytokine balance in mice lacking CC chemokine receptor 1. J Exp Med 185: 1959–1968PubMedCrossRefGoogle Scholar
  29. 29.
    Izikson L, Klein RS, Charo IF, Weiner HL, Luster AD (2000) Resistance to experimental autoimmune encephalomyelitis in mice lacking the CC chemokine receptor (CCR)2. J Exp Med 192: 1075–1080PubMedCrossRefGoogle Scholar
  30. 30.
    Tran EH, Kuziel WA, Owens T (2000) Induction of experimental autoimmune encephalomyelitis in C57BL/6 mice deficient in either the chemokine macrophage inflammatory protein-1alpha or its CCR5 receptor. Eur J Immunol 30: 1410–1415PubMedCrossRefGoogle Scholar
  31. 31.
    Gaupp S, Pitt D, Kuziel WA, Cannella B, Raine CS (2003) Experimental autoimmune encephalomyelitis (EAE) in CCR2(-/-) mice: susceptibility in multiple strains. Am J Pathol 162: 139–150PubMedGoogle Scholar
  32. 32.
    Hesselgesser J, Ng HP, Liang M, Zheng W, May K, Bauman JG, Monahan S, Islam I, Wei GP, Ghannam A et al (1998) Identification and characterization of small molecule functional antagonists of the CCR1 chemokine receptor. J Biol Chem 273: 15687–15692PubMedCrossRefGoogle Scholar
  33. 33.
    Liang M, Mallari C, Rosser M, Ng HP, May K, Monahan S, Bauman JG, Islam I, Ghannam A, Buckman B et al (2000) Identification and characterization of a potent, selective, and orally active antagonist of the CC chemokine receptor-1. J Biol Chem 275: 19000–19008PubMedCrossRefGoogle Scholar
  34. 34.
    Delovitch TL, Singh B (1997) The nonobese diabetic mouse as a model of autoimmune diabetes: immune dysregulation gets the NOD. Immunity 7: 727–738PubMedCrossRefGoogle Scholar
  35. 35.
    Christen U, Von Herrath MG (2002) Transgenic animal models for type 1 diabetes: linking a tetracycline-inducible promoter with a virus-inducible mouse model. Transgenic Res 11: 587–595PubMedCrossRefGoogle Scholar
  36. 36.
    Meagher C, Sharif S, Hussain S, Cameron MJ, Arreaza GA, Delovitch TL (2003) Cytokines and chemokines in the pathogenesis of murine type 1 diabetes. Adv Exp Med Biol 520: 133–158PubMedGoogle Scholar
  37. 37.
    Arimilli S, Ferlin W, Solvason N, Deshpande S, Howard M, Mocci S (2000) Chemokines in autoimmune diseases. Immunol Rev 177: 43–51PubMedCrossRefGoogle Scholar
  38. 38.
    Cardozo AK, Proost P, Gysemans C, Chen MC, Mathieu C, Eizirik DL (2003) IL-1beta and IFN-gamma induce the expression of diverse chemokines and IL-15 in human and rat pancreatic islet cells, and in islets from pre-diabetic NOD mice. Diabetologia 46: 255–266PubMedGoogle Scholar
  39. 39.
    Bradley LM, Asensio VC, Schioetz LK, Harbertson J, Krahl T, Patstone G, Woolf N, Campbell IL, Sarvetnick N (1999) Islet-specific Th1, but not Th2, cells secrete multiple chemokines and promote rapid induction of autoimmune diabetes. J Immunol 162: 2511–2520PubMedGoogle Scholar
  40. 40.
    Cameron MJ, Arreaza GA, Grattan M, Meagher C, Sharif S, Burdick MD, Strieter RM, Cook DN, Delovitch TL (2000) Differential expression of CC chemokines and the CCR5 receptor in the pancreas is associated with progression to type I diabetes. J Immunol 165: 1102–1110PubMedGoogle Scholar
  41. 41.
    Christen U, McGavern DB, Luster AD, Von Herrath MG, Oldstone MB (2003) Among CXCR3 chemokines, IFN-gamma-inducible protein of 10 kDa (CXC chemokine ligand (CXCL) 10) but not monokine induced by IFN-gamma (CXCL9) imprints a pattern for the subsequent development of autoimmune disease. J Immunol 171: 6838–6845PubMedGoogle Scholar
  42. 42.
    Kim SH, Cleary MM, Fox HS, Chantry D, Sarvetnick N (2002) CCR4-bearing T cells participate in autoimmune diabetes. J Clin Invest 110: 1675–1686PubMedCrossRefGoogle Scholar
  43. 43.
    Camacho SA, Heath WR, Carbone FR, Sarvetnick N, LeBon A, Karlsson L, Peterson PA, Webb SR (2001) A key role for ICAM-1 in generating effector cells mediating inflammatory responses. Nat Immunol 2: 523–529PubMedCrossRefGoogle Scholar
  44. 44.
    Savinov AY, Wong FS, Stonebraker AC, Chervonsky AV (2003) Presentation of antigen by endothelial cells and chemoattraction are required for homing of insulin-specific CD8+ T cells. J Exp Med 197: 643–656PubMedCrossRefGoogle Scholar
  45. 45.
    Grewal IS, Rutledge BJ, Fiorillo JA, Gu L, Gladue RP, Flavell RA, Rollins BJ (1997) Transgenic monocyte chemoattractant protein-1 (MCP-1) in pancreatic islets produces monocyte-rich insulitis without diabetes. Abrogation by a second transgene expressing systemic MCP-1. J Immunol 159: 401–408PubMedGoogle Scholar
  46. 46.
    Morimoto J, Yoneyama H, Shimada A, Shigihara T, Yamada S, Oikawa Y, Matsushima K, Saruta T, Narumi S (2004) CXC chemokine ligand 10 neutralization suppresses the occurrence of diabetes in nonobese diabetic mice through enhanced beta cell proliferation without affecting insulitis. J Immunol 173: 7017–7024PubMedGoogle Scholar
  47. 47.
    Frigerio S, Junt T, Lu B, Gerard C, Zumsteg U, Hollander GA, Piali L (2002) Beta cells are responsible for CXCR3-mediated T-cell infiltration in insulitis. Nat Med 8: 1414–1420PubMedCrossRefGoogle Scholar
  48. 48.
    Ransohoff RM, Bacon KB (2000) Chemokine receptor antagonism as a new therapy for multiple sclerosis. Expert Opin Investig Drugs 9: 1079–1097PubMedCrossRefGoogle Scholar
  49. 49.
    Liang M, Mallari C, Rosser M, Ng HP, May K, Monahan S, Bauman JG, Islam I, Ghannam A, Buckman B et al (2000) Identification and characterization of a potent, selective, and orally active antagonist of the CC chemokine receptor-1. J Biol Chem 275: 19000–19008PubMedCrossRefGoogle Scholar

Copyright information

© Birkhäuser Verlag Basel/Switzerland 2007

Authors and Affiliations

  • William J. Karpus
    • 1
  1. 1.Department of PathologyNorthwestern University Feinberg School of MedicineChicagoUSA

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