Peripheral tolerance induction: lessons from immune privileged sites and tissues

Immune privilege is finally emerging from the curiosity shop into the mainstream of immunology. Immune privileged tissues and sites play a critical role in creating the privileged status, in part by creating peripheral tolerance among antigen-specific T and B cells. While the old idea of "antigen sequestration behind blood: tissue barriers and at sites without efferent lymphatics" seems effete, it appears that a novel view of antigen sequestration is emerging that requires that both immunologic ignorance and peripheral tolerance be considered as relevant to the privileged state. We have argued that immune privilege is an evolutionary adaptation that enables "vulnerable" tissues to arrange for immune protection without suffering the consequences of immunopathogenic damage. In the case of the eye (our organ of interest), privilege enables the eye to avoid immunogenic inflammation. For this specialized organ of sense, inflammation is an unavoidable cause of blindness because inflammation disrupts microanatomic arrangements, and maintenance of the microanatomy of the visual axis is essential for sight. Because immune privilege requires active participation of the immune system for its induction and its maintenance, and since this participation involves the systemic immune apparatus, the tolerance achieved by antigens placed in privileged sites is actually systemic. Therefore, the strategies that are used by privileged sites and tissues to create tolerance parochially, may actually have relevance for creating tolerance of antigenic materials placed at nonprivileged sites of the body.