Altered Apoptosis And Inducible Nitric Oxide Synthase In Cutaneous Lupus Erythematosus

Altered Apoptosis And Inducible Nitric Oxide Synthase In Cutaneous Lupus Erythematosus

 

Apoptosis is a form of programmed cell death that is characterized by several distinct morphological changes, such as cell shrinkage, plasma membrane blebbing, and nuclear condensation, in response to the activation of several factors and receptors specific for the apoptotic pathway. The biochemical hallmark of apoptotic cell death is the degradation of DNA into oligosome-sized fragments by specific endonucleases and the formation of small vesicles from the cell surface, also known as apoptotic bodies. In 1994, a potentially crucial role in the initiation of the autoimmune reaction cascade was attributed to UVinduced keratinocyte apoptosis by Casciola-Rosen and coworkers. More recently, the potential significance of apoptosis in the pathogenesis of CLE has been emphasized by further investigation. Using different staining techniques to detect nuclei with DNA damage, an increased number of apoptotic keratinocytes was found in skin lesions of various subtypes with this disease. Furthermore, a significant increase of apoptotic nuclei was also seen in UV-induced lesions of patients with various manifestations of CLE after phototesting. This was in striking contrast to healthy controls with a proper clearance of apoptotic cells after UVA and UVB irradiation. The hypothesis that clearance of apoptotic cells in the skin of the majority of patients with CLE is either impaired or delayed is in analogy to the growing evidence that defects in the clearance of apoptotic cells may be important in triggering the immune response in SLE. Impaired clearance for dying cells may explain accumulation of apoptotic and subsequently of secondary necrotic cells in various tissues of these patients. Interestingly, lymph node biopsies from patients with SLE have been investigated to determine whether a defect in engulfment of apoptotic cell material can also be observed in germinal centers. A characteristic feature of lymphatic germinal centers is the presence of specialized phagocytes, usually referred to as tingible body macrophages (TBM). Under healthy conditions TBM remove apoptotic cells very efficiently in the early phase of apoptosis. However, in a subgroup of patients with SLE apoptotic cells accumulate in the germinal centers. This may be due to impaired phagocytic activity or caused by the absence of TBM. Instead of normal clearance, apoptosis might progress allowing cells to enter the late stages of apoptotic cell death, including secondary necrosis. Moreover, systemic autoimmunity has been noted in mice deficient for molecules potentially involved in the clearance of apoptotic cells including serum amyloid P (SAP), c-Mer, C4, IgM, or C1q. SAP is a member of a family of proteins termed pentraxins that bind to apoptotic cells and then interact directly with phagocyte receptors or with C1q. C1q and a related protein, mannose binding lectin (MBL), function as collectins, which are proteins with globular lectin-like heads and collagenlike tails that bind to and flag late-apoptotic cells for disposal by phagocytosis. Interestingly, the surface blebs of apoptotic keratinocytes bind C1q, an early component of the complement cascade. The C1q-binding protein that was initially identified to be present in apoptotic plasma membrane blebs is calreticulin, and autoantibodies to calreticulin can interfere with this binding. The binding of C1q to apoptotic cells has been postulated to facilitate the clearance of these cells by macrophages that express a C1q cell surface receptor. A potential role for C1q in the clearance of apoptotic debris and in the genesis of CLE is suggested by two observations. First, patients with complete congenital C1q deficiency frequently develop LElike photosensitive eruptions at an early stage. Second, mice with C1q deficiency show an SLE-like disease associated with an accumulation of apoptotic cells in the kidneys. However, the clearance of UV-induced apoptotic keratinocytes was not observed to be altered in C1qdeficient mice. Nitric oxide (NO), a pleiotropic molecule synthesized by a family of nitric oxide synthases, is an important regulator of apoptosis and has an implication in the course of various autoimmune diseases. Interestingly, this molecule appears to have differential effects upon the various cell types within the skin and has been shown to play a role in the pathogenesis of CLE. Aberrant regulation of inducible nitric oxide synthase (iNOS) expression has been noted in UV-induced lesions of patients with CLE. In contrast to healthy controls, patients with various subtypes of this disease were noted to have significantly delayed and prolonged expression of iNOS, suggesting that the kinetics of iNOS induction and the time span of local iNOS expression might play an important role in the pathogenesis of CLE. Moreover, the clinically normalappearing skin of patients with active SLE also demonstrated elevated levels of iNOS in both the epidermis and adjacent vascular endothelium. It has further been reported that elevated levels of iNOS and serum nitrite correlated with established indices of disease activity and titers of anti-dsDNA antibodies in patients with SLE.

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