Decreased Clearance of Apoptotic Cells

There is growing evidence in patients with SLE and autoimmune mouse models that defects in the clearance of apoptotic cells may be important in triggering the immune response. First, in the absence of apoptotic cell uptake, multiple apoptotic bodies can be found in tissues, and these remnants are often associated with the presence of autoimmune disease (Botto et al. 1998, Potter et al. 2003, Scott et al. 2001). Second, deficiencies in the receptor tyrosine kinases Tyro 3, Axl, and Mer lead to autoimmunity (Cohen et al. 2002, Lu and Lemke 2001), and Mer knockout mice have impaired phagocytosis and clearance of apoptotic cells, leading to increased numbers of nuclear autoantibodies (Scott et al. 2001). Third, there is abnormal clearance of apoptotic lymphocytes and fragments by macrophages in SLE (Hermann et al. 1998). Finally, there is impaired uptake of apoptotic cells and macrophages in germinal centers in some patients with SLE (Baumann et al. 2002), and uptake of apoptotic poly-morphonuclear leukocytes and macrophages was increased by the addition of serum from healthy patients (Ren et al. 2003).

Apoptotic cells display an array of surface ligands to provide uptake signals to local and circulating phagocytic cells. These ligands cause a "tether and tickle" response in the phagocyte to induce macropinocytosis and the secretion of noninflammatory cytokines. The "tether" signal is thought to be mediated through phos-phatidylserine (PS), which is flipped to the outer cell membrane early in the apoptotic process (Hoffmann et al. 2001). PS likely causes attachment of the phagocyte to the apoptotic cell, whereby other receptors are needed to mediate the "tickle" response or change in actin skeleton in the phagocyte to mediate macropinocytosis (Somersan and Bhardwaj 2001). Other receptors that are likely to be important in uptake include CD36, avß3 and aVß5 integrins, and CD68 (Hoffmann et al. 2001). Engagement of these receptors in the right inflammatory setting causes the phagocyte to suppress the immune response through production of IL-10, transforming growth factor (TGF) ß, platelet activating factor, and prostaglandin E (Gaipl et al. 2003, Huynh et al. 2002, Somersan and Bhardwaj 2001). Uptake of apoptotic cells also decreases the amount of IL-12 secreted by the macrophage (Kim et al. 2003). The amount of PS displayed on the cell surface maybe important for macrophage uptake (Borisenko et al. 2003), as may timing, as uptake by macrophages of very early apoptotic cells expressing low levels of PS did not result in any cytokine production, suggesting that early uptake was not associated with inflammation (Kurosaka et al. 2003).

In the absence of PS, or in the presence of inflammatory mediators, other signals may dominate. Annexin I, which colocalizes with PS on the cell membrane, is also important for uptake (Arur et al. 2003), but phagocytosis through this ligand induces the humoral immune response (Gaipl et al. 2003). Collectins, complement, and pen-traxins are also important in the uptake of apoptotic cells by macrophages, and deficiencies in these proteins are a strong predictor of autoimmunity (Nauta et al. 2003).

C1q is a component of the classical complement pathway. It is structurally homologous to the collectin family of proteins and contains a collagen-like tail and globu lar head with binding domains. Early complement deficiency is a strong predictor for the development of SLE (Pickering et al. 2001). Individuals with homozygous C1q deficiency have a 98% likelihood of developing a lupus syndrome (Walport et al. 1998) and develop photosensitive eruptions (Bowness et al. 1994). C1q knockout mice develop high titers of autoantibodies and glomerulonephritis characterized histologically by immune deposits and multiple apoptotic bodies (Botto et al. 1998). Complement components are necessary for the uptake of apoptotic cells (Mevorach et al. 1998, Taylor et al. 2000), and C1q has been demonstrated to bind to apoptotic cells and to induce complement activation (Nauta et al. 2002) as well as uptake by macrophage via the CD91 and calreticulin (CRT) receptor (Ogden et al. 2001).

There is evidence that suggests that C1q may be important in the pathogenesis of photosensitive LE. First, in vitro studies demonstrate that C1q binds directly and specifically to surface blebs of apoptotic human keratinocytes (Korb and Ahearn 1997). Second, SCLE has been linked to a low-producing variant of the C1q gene (Racila et al. 2003). Interestingly, UV-irradiated C1q knockout mice do not demonstrate an alteration in the rate of clearance of SBCs after UV exposure, and chronic UV exposure does not alter systemic disease (Pickering et al. 2001). However, this was done on a C57BL/6 background, and there is evidence that the manifestations of C1q deficiency depend on genetic background, with acceleration of the presence of the production of autoantibodies and severity of renal disease in the MRL/MpJ background (Mitchell et al. 2002). UV irradiation studies have not been reported in these mice. It is likely that persistence of apoptotic and necrotic keratinocyte cells leads to phagocytosis by immature DCs, which can then gain access to the MHC class I and II pathway and initiate a primary response (Rovere et al. 2000b).

Other collectins and complement components may also play a role in the clearance of apoptotic cells. C3 has been shown on sunburn cells in C1q-deficient mice, and it is likely that C3 opsonic fragments play a role in the recognition and removal of sunburn cells in skin (Pickering et al. 2001). It is likely that C2, C3, and C4 complement deficiencies, also associated with SCLE, play a role in decreased clearance of apop-totic cells. There is redundancy in the clearance mechanism, demonstrating the importance of presenting apoptotic debris to the immune system. Clearly, defects in different clearance mechanisms may be important for different diseases.

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