Nephritogenic tubulointerstitial antigens.

Ever increasing numbers of immune mechanisms and types of nephritogenic antigen-antibody systems are being identified in model systems of immune injury in the renal tubulointerstitial tissues (Table 1). Some of these nephritogenic model systems are also suspected or established in subsets of human immune tubulointerstitial nephritis (TIN) [1, 2]. The nephritogenic immune mechanisms include direct antibody reactions with structural or cell surface antigens and non-native antigens either trapped in the kidney or available for reaction in the circulation to form immune complexes. Cellular immune reactions play varying and sometimes dominant roles as well and may involve antigen systems similar to those of the antibody dominated lesions. When antibodies react with structural antigens, an immune deposit is typically formed. The injury produced by these immune deposit-related antibody reactions is usually generated by subsequent cellular and humoral mediator activation, which may include the production of factors such as cytokines and growth factors from renal cells themselves. The nephritogenic antigens may also be elements of the renal tubular cell surface. In addition to forming immune deposits, antibody reactions with these cell surface elements may lead to selective damage to the individual renal tubular cells. Glomerular examples of selective antibody-induced epithelial and mesangial cell damage, which can include frank lysis in the case of the mesangial cell, occur with the assistance of mediator molecules, that is, the terminal complement cascade generating the membrane attack complex (MAC). In addition, antigens not native to the site, including drugs or their metabolites and products of infectious agents, may become trapped or replicated in the tubulointerstitial renal tissue, potentially becoming targets for antibody attack involving either immune deposit formation or cell surface types of injury. For example, drugs or their metabolic products can combine with renal structures and serve as targets for nephritogenic antibody reactions, or function as haptens with the potential of generating immune responses directed toward the native renal structure that serves as the carrier molecule in a hapten/carrier complex. Tubulointerstitial immune deposits can also form via immune complex mechanisms in which antigens not native to the kidney are complexed with antibody in the circulation or in situ at the site of a deposit. Since the antigen in this type of reaction is soluble and therefore free to move away from the site during dynamic interchange, these immune complex deposits are usually changing in composition relative to the antigen or antibody ratio in the adjacent body fluids. Drugs or toxins such as mercuric chloride, in addition to damaging renal tubules, can also serve as polyclonal B cell stimulants associated with a variety of autoimmune reactions, including some with anti-renal effects [3]. Molecular mimicry of antigenic epitopes between autologous antigens and foreign (often infectious agent associated) antigens can lead to formation of cross reactive antibodies which could be nephritogenic. Genetic variation in antigen content within renal structures such as the renal basement membranes can also lead to induction of humoral (and cellular) immune responses when introduced, for example, in the form of renal transplants. The identification of antigens involved in cellular immune reactions as inducers of injury in the kidney lags behind that of antigens in nephritogenic antibody reactions. A role for cellular immune reactions can be shown in models, and the contribution of this arm of the immune response is potentially very important in many forms of TIN in humans, which are characterized by mononuclear interstitial infiltrates usually dominated by T cells with varying preponderance of T helper (CD4+) and T suppressor/cytotoxic (CD8+) phenotypes [2, 4]. Such antigens would be sought by their ability to react with sensitized T cells. The antigens, as well as their location and physical state, determine in large measure what type of immunopathogenic process will develop (immune deposit, cell injury, etc.) in the event of a nephritogenic humoral (or cellular) immune response. For this reason, the identification of the nephritogenic antigen provides a useful means of subdividing the various forms of immunologically-induced TIN.