Immunologically privileged sites seem to be unusual in three ways. First, communication between the privileged site and the body is atypical in that extracellular fluid does not pass through conventional lymphatics, although proteins placed in these sites do leave and can have immunological effects. Privileged sites are generally surrounded by tissue barriers that exclude naive lymphocytes. The brain, for example, is guarded by the blood–brain barrier. Second, soluble factors that affect the course of an immune response are produced in privileged sites. The anti-inflammatory transforming growth factor (TGF)-β seems to be particularly important in this regard. Under homeostatic conditions, antigens recognized in concert with TGF-β tend to induce Treg responses, rather than pro-inflammatory TH17 responses, which are induced by TGF-β in the presence of IL-6 (see Section 9-21). Third, the expression of Fas ligand in immunologically privileged sites may provide a further level of protection by inducing the apoptosis of Fas-bearing effector lymphocytes that enter these sites.
Paradoxically, antigens sequestered in immunologically privileged sites are often targets of autoimmune attack; for example, brain and spinal cord autoantigens such as myelin basic protein are targeted in the autoimmune disease multiple sclerosis, a chronic inflammatory demyelinating disease of the central nervous system (see Fig. 15.1). Thus, the tolerance normally shown to these antigens cannot be due to previous deletion of the self-reactive T cells. In experimental autoimmune encephalomyelitis (EAE), a mouse model for multiple sclerosis, mice become diseased only when they are immunized with myelin antigens and adjuvants, which cause infiltration of the central nervous system with antigen-specific TH17 and TH1 cells that induce a local inflammatory response that damages nerve tissue.
Thus, some antigens expressed in immunologically privileged sites induce neither tolerance nor lymphocyte activation in normal circumstances, but if auto-reactive lymphocytes are activated elsewhere, these autoantigens can become targets for autoimmune attack. Likely, T cells specific for antigens sequestered in immunologically privileged sites are in a state of immunological ignorance. Further evidence comes from the eye disease sympathetic ophthalmia (Fig. 15.8). If one eye is ruptured by a blow or other trauma, an autoimmune response to eye proteins can occur, although this happens only rarely. Once the response is induced, it often attacks both eyes. Immunosuppression—and, rarely, removal of the damaged eye, the source of antigen—is required to preserve vision in the undamaged eye.
Unsurprisingly, effector T cells can enter immunologically privileged sites when such sites become infected. Effector T cells can enter most tissues after activation (see Chapter 11), but accumulation of cells is seen only when antigen is recognized in the site, triggering the production of cytokines that alter tissue barriers.
15-6 Autoreactive T cells that express particular cytokines may be nonpathogenic or may suppress pathogenic lymphocytes.
As described in Chapter 9, CD4 T cells can differentiate into various types of effector lineages, namely, TH1, TH2, and TH17 cells. These effector subsets evolved to control different types of infections and orchestrate distinct types of responses, as reflected in their different effects on antigen-presenting cells, B cells, and innate cells such as macrophages, eosinophils, and neutrophils (see Chapters 9–11). A similar paradigm holds true for autoimmunity: certain T-cell-mediated autoimmune diseases such as type 1 diabetes mellitus (see Fig. 15.1) depend on TH1 cells to cause disease, whereas others, such as psoriasis (an autoimmune disease of the skin), depend on TH17 cells.