New approaches to antibody-mediated disease - lessons from characterizing helper T-cell responses to the RHD protein

Abstract

The key pathogenic contribution of antibodies in conditions such as haemolytic disease of the newborn (HDN) and autoimmune haemolytic anaemia (AIHA) has been recognized for many years. However, although the production of such antibodies is largely thymus-dependent, offering a potential therapeutic target, little attention has been focused on the T helper-(Th-) cells responsible. The RhD protein provides an ideal opportunity to study Th-cells that drive pathogenic antibody production, since it bears major antigens in both HDN and AIHA. Mapping studies have determined the fine specificity of Rh-reactive Th-cells that are activated to proliferate in donors who have been alloimmunized with RhD-positive erythrocytes, and in AIHA patients. In addition to identifying antigenic peptides that could be used to modulate the responses, this work demonstrates that Th-cells of different specificities proliferate in the two groups, even when restricted by the same MHC class II element. Our explanation is that the allo-response targets abundantly presented peptides from the antigen, whereas the autoreactive Th-cells activated in AIHA are specific for subdominant or cryptic epitopes, which allows them to escape the processes of self-tolerance. Nonetheless, the respective peptides recognized by the proliferating allo-or auto-reactive Th-cells could, if given by a tolerogenic mucosal route, form the basis of a novel prophylaxis or therapy for Rh antibody-mediated disease. Alternatively, it may be possible to exploit in vivo the finding that the RhD protein carries regulatory epitopes that elicit Th cytokines such as IL-10, which can inhibit the proliferative responses in vitro.