Elsevier

Clinical Immunology

Volume 122, Issue 2, February 2007, Pages 125-134
Clinical Immunology

Short Analytical Review
Autoimmunity versus tolerance: Can dying cells tip the balance?

https://doi.org/10.1016/j.clim.2006.07.012Get rights and content

Abstract

Apoptosis is a physiological process of self-destruction for cells that are damaged or programmed to die. Apoptosis occurs through a series of regulated events that allow cellular debris to be contained and efficiently phagocytosed without initiating a proinflammatory immune response. Recent data have linked physiological apoptosis and the uptake of apoptotic cells by macrophages and some subsets of dendritic cells to the maintenance of peripheral immune tolerance. However, when cells die through necrosis, spilling their intracellular contents, or are infected with various pathogens, activation of antigen-presenting cells and induction of an immune response can occur. Receptors for extrinsic pathogen-associated structures, such as membrane bound Toll-like receptors (TLRs) or intracellular Nod-like receptors (NLRs) can also respond to cross-reactive host molecules from dying cells and may focus autoimmune responses onto these antigens. Several autoimmune disorders have been linked to defects in the apoptotic process. Defective apoptosis of immune cells leads to autoimmunity, as in autoimmune lymphoproliferative syndrome (ALPS) associated with mutations in the death receptor Fas. Defective clearance of apoptotic cell debris can also lead to autoantibody production. We will discuss how cell death and apoptotic cell clearance may affect the finely tuned balance between peripheral immune tolerance and autoimmunity.

Section snippets

Overview

Apoptosis, or programmed cell death, is a physiological process occurring in cells that are damaged or no longer useful, including embryogenesis and tissue homeostasis. During apoptosis the cell is degraded by a series of regulated steps that allow rapid uptake and removal of cellular debris by phagocytes without causing inflammation. By contrast, cells that die by necrosis spill their cellular contents including molecules that stimulate inflammation and dendritic cell activation that can prime

Cell death: general mechanisms

Apoptosis, also referred to as programmed cell death, is a morphologically identifiable form of cell death characterized by a complex series of processes that adhere to a strict timeline (Fig. 1). The initiating signals for cell death are integrated by a number of mechanisms, including interactions between pro and anti-apoptotic members of the bcl-2 protein family. If a critical threshold is reached, the mitochondrial outer membrane becomes permeable to large molecules (MOMP). Mitochondria

Engulfment of dying cells and presentation of self-antigens

In order for activation of the adaptive immune response by antigens derived from dying cells, efficient presentation and costimulation by antigen-presenting cells is necessary (Fig. 2). Macrophages and particular subsets of dendritic cells are responsible for clearance of dying cells in the tissues. Once engulfed, antigens derived from the dead cells are processed and presented at the cell surface associated with the major histocompatibility complex (MHC). Classically, MHC class II molecules,

Immunogenicity versus tolerance to antigens from dying cells

Since apoptosis occurs physiologically in many tissues, one proposed model for inducing peripheral tolerance is that immature DCs constantly survey their immunological milieu through endocytosis and phagocytosis mediated by scavenger receptors and uptake of apoptotic cell debris. Whether or not a particular subset of dendritic cells is specialized for the uptake of apoptotic cells is controversial: in the mouse, the CD8+ ‘lymphoid’ subset of dendritic cells has been most often implicated [13],

Mechanisms of apoptotic cell recognition and uptake

A better understanding of how antigens from dying cells may or may not trigger autoimmunity will come from elucidating the molecular pathways by which phagocytes sense and take up these cells, and how these processes impact the maturation and antigen-presenting capability of these cells. There has been significant recent progress in identifying the molecules involved in apoptotic cell recognition and uptake. Most of these systems involve indirect recognition of the PS on the extracellular

When uptake goes wrong

Under normal circumstances, apoptotic cells are rapidly cleared by phagocytes [53]. However, if uptake is impaired, or cell death enhanced, apoptotic material may build up to a point that overwhelms the uptake systems discussed above. In these circumstances, it has been suggested that self-tolerance breaks down due to the priming of autoreactive lymphocytes by more efficient antigen-presenting cells that would then take up apoptotic material. If uptake of apoptotic cells is delayed, secondary

Conclusion

Defects in apoptosis and the clearance of apoptotic cells have been linked to several autoimmune diseases, especially SLE. Many mouse disease models implicate apoptotic cell uptake mediators such as Mer/Tyro3 and MFG-E8 as having critical roles in protecting against autoimmunity by efficiently clearing self-antigens associated with apoptotic cells. As discussed here, the uptake of apoptotic cells by immature dendritic cells has been shown to promote tolerance, whereas cell debris in combination

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