Absence of  “Original Antigenic Sin” in Autoimmunity Provides an Unforeseen Platform for Immune Therapy

I n this issue of The Journal of Experimental Medicine , Tuohy et al. study the spreading of the autoimmune response to myelin antigens in experimental autoimmune encephalo-myelitis (EAE) and its likely human counterpart, multiple sclerosis (MS) (1). They demonstrate that as disease develops in EAE and MS, reactivity to the initiating antigen diminishes , and an orderly and definable set of new immune reactivities arises. The data are clear and the scope of the study in humans and in experimental animals is broad. For example, the investigators elegantly look at T cells in the central nervous system (CNS) in EAE to see whether the reduction in peripheral activity is due to sequestration of such T cells in the brain and spinal cord. The answer to this question is a resounding " no. " Loss of reactivity is not due to sequestration of the immune response in the CNS. The implications of this study present challenges to the doctrine of " original antigenic sin, " and to the hope of developing antigen-specific therapy for autoimmune disease. In organ-specific autoimmune diseases such as MS, rheu-matoid arthritis, and insulin-dependent diabetes mellitus (IDDM), there are vigorous debates among experts on which antigen triggered the autoimmune response. Furthermore, there are arguments about which antigens dominate the diverse immune responses that can be detected at the site of disease. Thus, in MS, where an apparent autoimmune T and B cell response occurs in myelin sheath of the CNS, there are arguments whether the initial or dominant immune response might be directed at myelin basic protein (MBP; references 2–4), myelin oligodendroglial glycopro-tein (MOG; references 5, 6), proteolipid protein (PLP; reference 7), or various other myelin antigens (8). For IDDM, investigators argue whether the primary response is against glutamic acid decarboxylase (9, 10), insulin (11), heat shock protein 65 (12), or other islet cell antigens. The concept of epitope spreading described by Lehmann et al. for EAE describes how antigen-specific autoimmune responses can spread to different epitopes on one protein, termed " intramolecular epitope spreading " (13), to other epi-topes on other structural proteins, termed " intermolecular epitope spreading " (14), at the site of disease (Fig. 1). Thus, in EAE induced with an injection of an epitope of PLP, the immune reactivity of populations or ensembles of T cells can spread to other epitopes on PLP, and then on to other myelin antigens such as MBP …