UV Light Apoptosis and Autoimmunity

The link between photosensitivity and the induction of autoimmune disease can be understood through a model centered on the apoptotic cell. Apoptosis is a process of programmed cell death during which intracellular antigens are translocated to the cell surface, allowing for detection by the immune system (Casciola-Rosen and Rosen 1997, Casciola-Rosen et al. 1994, 1995, 1999, Schultz and Harrington 2003). Because apoptosis is required for the development and maintenance of tissue homeostasis in multicellular organisms, the immune system has developed mechanisms to cope with the removal of apoptotic debris. Under noninflammatory conditions, immature dendritic cells (DCs) or local macrophages phagocytose apoptotic cells and prevent the development of autoantibodies in a process of tolerance (White and Rosen 2003).If the balance is distorted by an increase in the production of apoptotic cells, by an increase in the amount of inflammatory cytokines, or by a deficiency in the proteins involved in clearance, apoptotic debris may be processed by antigen-presenting cells (APCs) and may gain access to major histocompatibility complex (MHC) class I and II pathways to efficiently stimulate CD4+ and CD8+ cells (Rovere-Querini and Dumitriu 2003). This would promote the development of autoantibodies, possibly leading to the development of autoimmunity (Fig. 18.1).

It is unlikely that the development of autoimmunity relies solely on the inability of the immune system to cope with apoptotic debris. Rather, it is likely a combination of factors relating to the inefficient killing and removal of T and B cells in the setting of

UV Light

t TNF

Translocation of intracellular antigens to the cell surface

Virus, Bacteria, Drug t TNF

Translocation of intracellular antigens to the cell surface

DEFECTIVE CLEARANCE

Suprathreshold of autoantigens

Immature DC

Antigen Presenting Cell

Antigen Presenting Cell

C2,C3,C4

C2,C3,C4

NORMAL CLEARANCE

Expression of PS, CD36, avß3 and (Xvß5 on phagocyte

Macrophage uptake with release of noninflammatory cytokines

AUTOIMMUNE

NORMAL

Fig. 18.1. Model for the pathogenesis of cutaneous lupus erythematosus.Apoptotic cells are usually cleared by noninflammatory pathways that involve macrophages. If this system is overloaded, by either an increase in proapoptotic signals or a decrease in clearance mechanisms, apoptotic debris can be taken up by DCs to initiate an immune response.ADCC,antibody-dependent cellular cytotoxicity; DC, dendritic cell; PS,phosphatidylserine;TNF,tumor necrosis factor; UV,ultra-violet specific autoantigen triggers, leading to the development of autoreactive T cells (Kretz-Rommel and Rubin 1999, Takeuchi et al. 1995). The importance of eliminating autoreactive T and B cells has been demonstrated by the presence of autoimmunity in Fas-deficient mice and humans and in mice overexpressing the anti-apoptotic protein Bcl-2 in B cells (Mevorach 2003, Watanabe-Fukunaga et al. 1992).

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