HLA-D/DR Expression on Epithelial Cells: The Finger on the Trigger?“ zy I. TODD,~ M. LONDEI: zyx R. PUJOL-BORRELL,~ R. MIRAKIAN,~ M. FELDMANN: AND G. F. BOTTAZZO~ zyxw bDepartment zyxw of Immunology Middlesex Hospital Medical School London W1 P 9PG, United Kingdom ‘The Charing Cross Sunley Medical Research Center London W6 8L W, United Kingdom HLA-D/DR EXPRESSION IN AUTOIMMUNITY Investigations of the immune system have indicated a variety of mechanisms whereby self-tolerance could be maintained and whose breakdown or bypass might therefore lead to autoimmunity.’ Our present knowledge is insufficient to fully discriminate between the possibilities, although it seems reasonable that where potential autoantigens are normally inaccessible to the immune system, T cells specific for these self-determinants will not be detected. One example of a “hidden” antigen is the thyroid-associated microsomal/microvillar antigen (TMAg) of the follicular epithelial cells (thyrocytes).’ The surface expression of this molecule is normally restricted to the apical border facing the interior of the thyroid follicles where it is not exposed to cells of the immune system.’ However, in the autoimmune thyroid disease (ATD) of Graves’ thyrotoxicosis, follicles can be isolated expressing TMAg on their basal vascular border where it would be available for immune pre~entation.~ Immunization against an antigen requires not only that it can be seen by lymphocytes, but that it be seen in an immunogenic form. The presentation of foreign antigen to helper T cells is usually accomplished in the context of major histocompati- bility complex (MHC) class I1 molecule^.^ These molecules are of restricted tissue distribution. They are mainly associated with cells of the immune system, of which the class 11+ macrophages and dendritic cells have been principally implicated in antigen presentation. It might be assumed that these cell types must also function in the presentation of autoantigens. However, expression of class I1 molecules has been noted on other cells not principally associated with immune functions, including capilliary endothelium and a variety of epithelia either in normal tissues (e.g., mammary, small intestine)6 or in skin and/or gut in circumstances such as graft-versus-host disease, dermatoses, and parasitic infestation.’ With regard to organ-specific autoimmunity, we found that human thyrocytes, which are normally HLA-D/DRd negative, could be induced to express HLA-D/DR antigens by culture with mitogenic plant lectins.* Yet even more significant was our ‘I. Todd is supported by the Wellcome Trust Foundation, and M. Londei and R. Pujol-Borrell dThe term HLA-D/DR is used in this article zyxw to indicate any or all of the products of the are supported by the Juvenile Diabetes Foundation International. HLA-D region (i.e., DR, DQ, DP). 241