Ultraviolet-Radiation-Induced Keratinocyte Apoptosis in C1q-Deficient Mice

Abstract

Exposure to ultraviolet B radiation is an important trigger of both systemic and cutaneous disease flares in individuals with systemic lupus erythematosus. More than 90% of individuals with homozygous C1q deficiency develop a systemic-lupus-erythematosus-like illness, which is typically associated with a severe photosensitive rash. Apoptotic, human keratinocytes have been shown in vitro to bind C1q, in the absence of antibody. These observations, together with the hypothesis that a major source of the autoantigens driving the immune response in systemic lupus erythematosus comes from apoptotic cells, led us to investigate the effects of murine C1q deficiency on ultraviolet-radiation-induced keratinocyte apoptosis in vivo. In this work, we demonstrated C1q binding to apoptotic murine keratinocytes in vitro and showed for the first time that C1q is also present on sunburn cells in vivo. In addition to C1q, we detected C3 deposition on sunburn cells in both wild-type and C1q-deficient mice, suggesting activation of the alternative pathway. Following acute ultraviolet exposure in vivo, no difference in the rate of clearance of sunburn cells was found in C1q-deficient mice from three different genetic backgrounds, compared with strain-matched wild-type controls. Furthermore, chronic ultraviolet exposure did not result in the production of autoantibodies or the development of glomerulonephritis. Our findings suggest that C1q does not play a critical role in the physiologic clearance of apoptotic murine keratinocytes in vivo.

Autoantibodies against Complement C1q Specifically Target C1q Bound on Early Apoptotic Cells

“…1) clones producing Abs specific for human C1q could be generated that were able to bind C1q even under high salt conditions, i.e., in the presence of 1 M NaCl. All clones were also positive for murine C1q and showed no crossreactivity, as judged by immunohistochemical staining of spleen sections 4 The online version of this article contains supplemental material.…”

“…has a strong link back to SLE, because homozygous C1q deficiency is the strongest disease susceptibility gene for the development of SLE (3,4). However, most patients with SLE have no primary C1q deficiency.…”

“…Complement, especially C1q, the first component of the classical pathway of complement, is considered to be involved in the pathogenesis of SLE. This view is based on the following observations: First, almost all patients with C1q deficiency develop a lupus-like syndrome, with homozygous C1q deficiency being the strongest disease susceptibility gene for the development of SLE (3,4). Second, a substantial number of patients with SLE develop hypocomplementemia with depletion of C1q and other components of the classical pathway of complement (5) and C1q is deposited in affected tissues (6,7).…”

Mini‐review: A pivotal role for innate immunity in the clearance of apoptotic cells

“…Similarly, despite the fact that C1q is able to bind to apoptotic keratinocytes [4], it does not seem to contribute to the uptake of apoptotic cells in the skin [48]. C1q supports the uptake of apoptotic cells by macrophages but not by renal mesangial cells [49], indicating that a defect in clearance by mesangial cells cannot explain the increased numbers of apoptotic cells in glomeruli from C1q-deficient mice [35].…”

Apoptotic cell and phagocyte interplay: recognition and consequences in different cell systems

“…It has also been observed some tissue-specific differences between the recognition molecules. For example, the presence of the bridging molecule C1q, the first component of complement, can be crucial for apoptotic cell clearance in the kidney (Taylor et al 2000) but not in the skin (Pickering et al 2001) of C1q-deficient mice. These findings point out to the need of detailed in vitro studies of different tissues, from mouse with genetic deletions of the different molecules involved in apoptotic cell clearance.…”