Autoimmunity and the kidney

Abstract

The pathogenesis of autoimmune disease can be considered under two broad headings: firstly, the failure of the mechanisms by which tolerance to self antigens is maintained, and secondly the processes on the effector side of the immune system that lead to tissue damage once tolerance is broken. In this article we propose to highlight recent developments, with particular reference to renal autoimmunity, and then to consider some of the therapeutic implications of our improved understanding of pathogenesis. There are three classical mechanisms of tolerance: 1) the deletion or inactivation of autoreactive clones of lymphocytes; 2) the active suppression of such autoreactive cells; and 3) the sequestration or masking of autoantigens so that they are not visible to the immune system. Recent experiments have confirmed the existence and advanced our understanding of a T cell clonal deletion/inactivation mechanism [1–3], whereas evidence for suppressor systems in the maintenance of tolerance is, as yet, lacking [4, 5]. However, as considered below, it is too soon to conclude that suppression has no part to play in self tolerance. A substantial body of work indicates a crucial role for T cells in the maintenance of self tolerance. While it seems clear that some degree of tolerance is imposed on T cells [6], self-reactive T cells can readily be demonstrated in normal individuals [7] and may indeed be vital for the correct development of the immune system [8]. Although tolerance at the T cell level may have some part to play, to understand tolerance it is necessary to consider the manner in which T cells interact with self (and foreign) antigens. A major difference between the T cell and its receptor (antibody) on the one hand and the T cell and its receptor on the other, is that the former can interact with free antigen, whereas the latter can only interact with antigen on cell surfaces, bound to products of the major histocompatibility complex (MHC). Understanding of this binding between antigen and MHC products has lately advanced rapidly. It is now clear that the immune response (Ir) gene phenomenon, in which it can be demonstrated that possession of a particular MHC gene allows an immune response to a particular antigen, is due largely to the specific molecular interactions between the two [9]. The features of an antigen that enable this association to occur are emerging, both for interaction with MHC molecules in general [10, 11] and for specific MHC molecules [12]. The combination of antigen and MHC molecule is then recognized by the T cell receptor. These three elements—antigen, MHC encoded molecule, and T cell receptor—confer the essential specificity on the immune (or autoimmune) response. Since tolerance requires the specific inactivation of T cells, it seems likely on first principles that it would also be restricted by MHC molecules, and there is indeed experimental support for this [13, 14]. What is known about these three critical elements will be discussed with reference to renal autoimmunity.