Tolerance induction by molecular mimicry: prevention and suppression of experimental autoimmune encephalomyelitis with the milk protein butyrophilin

Abstract

Multiple sclerosis (MS) is a common in¯ammatory 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 signi®cant reduction in both proliferation and production of T h 1-related cytokines (IFN-g, IL-2, IL-12 and granulocyte macrophage colony stimulating factor) in response to MOG. This speci®c inhibition was consistently associated with an up-regulation in IL-10 secretion. Furthermore, adoptive transfer of BTN-speci®c 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.

Loss of the Surface Antigen 3G11 Characterizes a Distinct Population of Anergic/Regulatory T Cells in Experimental Autoimmune Encephalomyelitis

“…The phenomenon of anergic T cells producing IL-10 has been reported in several recent studies (19,37,38). More recently, Mana et al (39) showed that repeatedly injected superantigen induced a tolerant state, resulting from a combination of both clonal anergy and cytokine-mediated immunosuppression involved in the up-regulation of IL-10 and TGF-␤. Our present study shows that IL-10 plays an important role in the immunoregulation by 3G11 Ϫ T cells.…”

Butyrophilins: an emerging family of immune regulators

“…Treatment of mice with BTN1A1 protein, either before or during experimental induction of EAE, suppressed disease development, which correlated with a cross-reactivity of MOG-specific T cells to BTN1A1 [21]. Furthermore, autoantibodies purified from multiple sclerosis patients bound to bovine butyrophilin, again demonstrating the similarities between the two proteins [21,22]. These studies would also benefit from follow-up analyses identifying which cells the antibody is inhibiting in vivo.…”

“…The anti-Btnl1 antibody worsened the EAE score at low MOG concentrations, enhanced Th2 responses to KLH/ova immunization, and exacerbated allergic asthma; consistent with the blockade of a negative regulator of T cells. However, the use of the anti-Btnl1 antibody to modulate EAE in vivo may be confounded by the strong structural similarity of Btn and Btnl proteins with MOG, as was the case with BTN1A1 [21,22]. Treatment of mice with BTN1A1 protein, either before or during experimental induction of EAE, suppressed disease development, which correlated with a cross-reactivity of MOG-specific T cells to BTN1A1 [21].…”

Nutritional and technological aspects of milk fat globule membrane material

“…Recently, it has been reported that BTN can modulate the encephalitogenic T-cell response to MOG in EAE related to human MS. However, Mana et al (2004) reported that treatment of C57BL/6 mice with BTN, either before or after immunization with MOG, prevented or suppressed the clinical manifestation of EAE. Therefore, the consumption of dairy products enriched with MFGM could modulate the pathogenic response to MOG in a positive direction.…”