Milk and Autoimmunity

The aetiology of multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system (CNS), involves environmental factors that disrupt immunological self-tolerance to the myelin antigens in genetically susceptible individuals, but the identity of these factors and how they initiate or exacerbate autoaggression is unknown. One of the most important candidate autoantigens in MS is the myelin oligodendrocyte glycoprotein (MOG). MOG is a minor component of CNS myelin that can be targeted by both encephalitogenic (inflammatory) T cell and demyelinating autoantibody responses in experimental animals. Immune effector mechanisms triggered by these MOG-specific autoimmune responses can then act in synergy resulting in experimental autoimmune encephalomyelitis (EAE), a disease that reproduces the clinical and pathological features of MS in both rodents and non-human primates. Recent studies indicate that autoimmune responses to MOG are more often associated with pediatric rather than adult onset MS, but why this is the case is obscure. Intriguingly MOG exhibits a high degree of structural and sequence homology with the N-terminal Ig V-like domain of the milk protein Btn1a1 and this results in extensive immunological cross-reactivity (molecular mimicry) between the two proteins. We previously reported that as a consequence of this cross-reactive response immunization with Btn1a1 can induce EAE in genetically susceptible rodents. This led us to speculate that neonatal sensitization by Btn1a1 might play an important role in establishing self-tolerance not only to itself but also MOG in the sucking neonate. We have now exploited the availability of Btn1a1-deficient “knock-out” mice to demonstrate that neonatal exposure to Btn1a1 in maternal milk initiates an immunoregulatory response that cross-reacts with MOG to provide an endogenous level of protection against MOG-induced EAE. These studies demonstrate the importance of neonatal exposure to Btn1a1 in establishing immunological self-tolerance to a clinically relevant target implicated in the pathogenesis of MS. We suggest that appropriate modifications to the composition of milk/milk substitutes given to neonates will strengthen induction of intrinsic immunoregulatory circuits that play a critical role in the initiation of tissue specific autoimmune disease.