The first mechanism proposed for distinguishing between self and nonself was that recognition of antigen by an immature lymphocyte leads to a negative signal causing lymphocyte death or inactivation. Thus, ‘self’ was thought to comprise molecules recognized by a lymphocyte shortly after it began to express its antigen receptor. Indeed, this is an important mechanism of inducing self-tolerance in lymphocytes developing in the thymus and bone marrow. The tolerance induced at this stage is known as central tolerance (see Chapter 8). Newly formed lymphocytes are especially sensitive to inactivation by strong signals through their antigen receptor, whereas the same signals activate mature lymphocytes in the periphery.
The making and breaking of self‑tolerance.
Tolerance induced to antigens recognized after lymphocytes have left the central or primary lymphoid organs is known as peripheral tolerance. An antigenic quality that correlates with self in the periphery is recognition in the absence of ‘danger’ signals that are produced by the innate immune system as a result of tissue damage or infection. Nearly all cells in the body become senescent and die, and many cells routinely undergo turnover at steady state (for example, hematopoietic cells and epithelial cells of the intestines and skin). Typically, this occurs by programmed cell death, or apoptosis. In contrast to cell death that results from physical or microbial injury, which generate damageor microbe-associated molecular patterns (DAMPs and MAMPs, respectively), death of senescent cells by apoptosis releases signals to tissue phagocytes that generally promote an anti-inflammatory response and repress presentation of antigens in an activating form. Thus, self antigens recognized in the context of normal, or physiologic, cellular turnover fail to induce pro-inflammatory cytokines (for example, IL-6 or IL-12) and co-stimulatory molecules (for example, B7.1) that would otherwise induce naive T cells to undergo effector differentiation. In these circumstances, the encounter of a naive lymphocyte with a self antigen may lead to no signal at all, or such an encounter can promote the development of regulatory lymphocytes that suppress the development of damaging effector responses. The removal of apoptotic cells by phagocytes is thus important for maintaining tissue homeostasis and activating programs in antigen-presenting cells that promote immunological tolerance. Some of the same mechanisms appear to be involved in the induction of tolerance to antigens of the commensal microbiota in the intestines, where recognition of bacterial antigens typically does not generate inflammation unless there is associated tissue damage.
Thus, several clues are used to distinguish self from nonself ligands: encounter with the ligand when the lymphocyte is immature, recognition of antigen in the context of antigen-presenting cells that have received tolerizing signals from recognition of homeostatic cell turnover signals, and binding of ligand in the absence of inflammatory cytokines or co-stimulatory signals. All of these mechanisms are error-prone because none of them distinguishes a self ligand from a foreign one at the molecular level. The immune system therefore has several additional mechanisms for controlling autoimmune responses should they start.
15-2 Multiple tolerance mechanisms normally prevent autoimmunity.