Introduction

The immune system has evolved a wide variety of potent mechanisms for the elimination of pathogens. As these mechanisms are potentially damaging to the host, an essential feature of the adaptive immune response is that it should be able to distinguish self from non-self and respond, when appropriate, only to the latter. The failure of the immune system to make this distinction can result in autoreactive cells mounting immune responses against self tissues, causing life-threatening pathology. There are now an increasing number of diseases in which an autoimmune process has been implicated in the pathogenesis, including RA, insulin-dependent diabetes mellitus (IDDM), multiple sclerosis, thyrotoxicosis, systemic lupus erythematosus (SLE), autoimmune haemolytic anaemia and myasthenia gravis to name a few. In order to avoid the damaging reactions that can cause this type of disease, the immune system has evolved a number of strategies for preventing autoreactive cells from making responses against host tissues, thus maintaining a state of self-tolerance.

In broad terms, mechanisms of self-tolerance can be categorized into two different classes. In the first, tolerance is maintained by both intra- and extrathymic mechanisms. Autoreactive T cells that encounter self-antigen within the thymus are clonally deleted (Kappler, Roehm & Marrack, 1987) while autoreactive cells that escape this process are either rendered anergic (Mueller, Jenkins & Schwartz, 1989), a state thought to result from the non-immunogenic presentation of self-antigens, or simply fail to respond to self-antigens, a state known as clonal indifference (Ohashi et al., 1991).