International Immunology, Vol. 16, No. 3, pp. 489-499,
March 2004
© 2004 Japanese Society for Immunology
Tolerance induction by molecular mimicry: prevention and suppression of experimental autoimmune encephalomyelitis with the milk protein butyrophilin
1 Department of Biochemistry, 2 School of Psychological Science and 3 Neuroimmunology Laboratory; La Trobe University, Bundoora, Victoria 3086, Australia 4 Department of Pharmacology, School of Medicine, University of Santiago de Compostela, Santiago de Compostela 15705, Spain 5 Department of Neurology, Saitama Medical School, Saitama 350-0495, Japan
P. Mañá and D. Liñares
Correspondence to: P. Mañá, Department of Pharmacology, School of Medicine, University of Santiago de Compostela, Santiago de Compostela 15705, Spain. E-mail: vaques{at}usc.es
Transmitting editor: C. Martinez-A
Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system. Although the etiology of MS remains unknown, studies in experimental autoimmune encephalomyelitis (EAE) have suggested that foreign molecules, which show molecular mimicry with myelin antigens, may play an important role as causative agents of the human disease. In this study, we investigate the molecular mimicry between the extracellular Ig-like domain of the cow’s milk protein butyrophilin (BTN) and the extracellular domain of myelin oligodendrocyte glycoprotein (MOG), a candidate autoantigen in MS. Interestingly, we found that as a result of a non-pathogenic cross-reactivity that is localized to a subdominant region of MOG, treatment of C57BL/6 mice with BTN either before or after immunization with MOG was shown to prevent and also suppress the clinical manifestations of EAE. BTN treatment resulted in a significant reduction in both proliferation and production of Th1-related cytokines (IFN-
, IL-2, IL-12 and granulocyte macrophage colony stimulating factor) in response to MOG. This specific inhibition was consistently associated with an up-regulation in IL-10 secretion. Furthermore, adoptive transfer of BTN-specific T cells prior to active immunization with MOG resulted in a transitory reduction of the clinical symptoms. Our results suggest that the clinical improvement associated with BTN treatment involved the combination of both anergy and regulatory cells secreting high levels of IL-10. In conclusion, we show that despite the traditional link between molecular mimicry and pathogenic immune response, environmental agents that share homology with autoantigens may also represent a source of cells with a protective phenotype.
Keywords: anergy, IL-10, milk, molecular mimicry, myelin oligodendrocyte glycoprotein
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