The gene rearrangements that occur during lymphocyte development in the central lymphoid organs inevitably result in the generation of some lymphocytes with affinity for self antigens. Such lymphocytes are normally removed from the repertoire or held in check by a variety of mechanisms. These generate a state of self-tolerance in which an individual’s immune system does not attack the normal tissues of the body. Autoimmunity represents a breakdown or failure of the mechanisms of self-tolerance. Therefore, we first revisit the mechanisms that keep the lymphocyte repertoire self-tolerant and see how these may fail. We then discuss a selection of autoimmune diseases that illustrate the various pathogenic mechanisms by which autoimmunity can damage the body. How genetic and environmental factors predispose to or trigger autoimmunity are then considered. In the remaining part of the chapter, we discuss the adaptive immune responses to nonself tissue antigens that cause transplant rejection.
The making and breaking of self-tolerance.
As we learned in Chapter 8, the immune system takes advantage of surrogate markers of self and nonself to identify and delete potentially self-reactive lymphocytes. Despite this, some self-reactive lymphocytes escape elimination and can subsequently be activated to cause autoimmunity. In addition, many lymphocytes with some degree of self-reactivity can also respond to foreign antigens; therefore, if all weakly self-reactive lymphocytes were eliminated, the function of the immune system would be impaired.
15-1 A critical function of the immune system is to discriminate self from nonself.
The immune system has very powerful effector mechanisms that can eliminate a variety of pathogens. Early in the study of immunity it was realized that these could, if turned against the host, cause severe tissue damage. The concept
The making and breaking of self‑tolerance.
Autoimmune diseases and pathogenic mechanisms.
The genetic and environmental basis of autoimmunity.
Responses to alloantigens and transplant rejection.
Fig. 15.1 Some common autoimmune diseases. The diseases listed are among the most common autoimmune diseases and will be used as examples in this part of the chapter. They are listed in order of prevalence.
of autoimmunity was first presented at the beginning of the 20th century by Paul Ehrlich, who described it as ‘horror autotoxicus.’ Autoimmune responses resemble normal immune responses to pathogens in that they are specifically activated by antigens—in this case self antigens, or autoantigens—and give rise to autoreactive effector cells and antibodies, called autoantibodies, against the self antigen. When dysregulated reactions to self tissues occur they cause a variety of chronic syndromes called autoimmune diseases. These syndromes are quite varied in their severity, their tissue distribution, and effector mechanisms that are critical in causing tissue damage (Fig. 15.1).
Collectively, autoimmune disorders affect approximately 5% of the populations of Western countries, and their incidence is on the rise. Nevertheless, their relative individual rarity indicates that the immune system has evolved multiple mechanisms to prevent self-injury. The most fundamental principle underlying these mechanisms is the discrimination of self from nonself, but this discrimination is not easy to achieve. B cells recognize the three-dimensional shape of an epitope, but an epitope presented by a pathogen can be indistinguishable from one originating in humans. Similarly, short peptides derived from the processing of pathogen antigens can be identical to self peptides. So how does a lymphocyte know what ‘self’ really is if there are no unique molecular signatures of self?