The mechanisms by which regulatory T cells suppress immune responses are not fully defined, but their inhibitory activity may be mediated in part by the secretion of immunosuppressive cytokines such as IL-10 and TGF-β, which inhibit lymphocyte activation and effector functions. Regulatory T cells also express CTLA-4, which may bind to B7 molecules on APCs and reduce their ability to activate T cells via CD28.
Deletion by apoptosis. T cells that recognize self antigens may receive signals that promote their death by apoptosis. Two mechanisms of deletion of mature T cells have been proposed, based mainly on studies in mice. It is postulated that if T cells recognize self antigens, they upregulate a pro-apoptotic member of the Bcl-2 family called Bim, which triggers apoptosis by the mitochondrial pathway (Chapter 2). Another mechanism of apoptosis involves the death receptor Fas (a member of the TNF receptor family), which can be engaged by its ligand coexpressed on the same or neighboring cells. The importance of this pathway of self-tolerance is illustrated by the discovery that FAS mutations are responsible for an autoimmune disease called the autoimmune lymphoproliferative syndrome (ALPS), characterized by lymphadenopathy and production of autoantibodies.
Some self antigens are hidden (sequestered) from the immune system, because the tissues in which these antigens are located do not communicate with the blood and lymph. As a result, unless released into the circulation, these antigens fail to elicit immune responses and are essentially ignored by the immune system. This is believed to be the case for antigens that are only found in the testis, eye, and brain, all of which are called immune-privileged sites because antigens located in these sites tend to be shielded from the immune system. If the antigens are released from these tissues, for example, as a consequence of trauma or infection, the result may be an immune response that leads to prolonged tissue inflammation and injury. This is the postulated mechanism for post-traumatic orchitis and uveitis.
Mechanisms of Autoimmunity: General Principles
Now that we have summarized the principal mechanisms of self-tolerance, we can ask how these mechanisms might break down to give rise to pathologic autoimmunity.
Infections, inflammation, tissue injury
Failure of Activationself-tolerance of tissue APCs
Influx of self-reactive lymphocytes into tissues
Activation of self-reactive lymphocytes
Tissue injury: autoimmune disease
Fig. 5.20 Pathogenesis of autoimmunity. Autoimmunity results from multiple factors, including susceptibility genes that may interfere with self-tolerance and environmental triggers (such as infections, tissue injury, and inflammation) that promote lymphocyte entry into tissues, activation of self-reactive lymphocytes, and tissue damage.
Unfortunately, there are no simple answers to this question, and the underlying causes of most human autoimmune diseases remain to be determined. The best guess is that breakdown of self-tolerance and development of autoimmunity result from the combined effects of susceptibility genes, which influence lymphocyte tolerance, and environmental factors, such as infections or tissue injury, that alter the display of and responses to self antigens (
Fig. 5.20
Most autoimmune diseases are complex multigenic disorders. There is abundant evidence that inherited genes play a role in the development of autoimmune diseases.
Autoimmune diseases have a tendency to run in families, and there is a greater incidence of the same disease in monozygotic than in dizygotic twins.