Study on the pathological effects of scleroderma-associated autoantibodies, anti-CENP B and anti-TOPO 1, on vascular endothelial cells
Date Issued
2011
Date
2011
Author(s)
Lai, Pei-Hsuan
Abstract
Systemic sclerosis (SSc) is a systemic autoimmune disorder characterized by immune activation, vascular injury, inflammation, and fibrosis in the skin and various internal organs. Raynaud’s phenomenon (RP) is the most common clinical manifestation in the early stage of the disease. RP is a clinical reflection of digital microvascular damage that causing insufficient blood flow in the end of digital and toes in systemic sclerosis (SSc). When the patients suffer from RP, abnormal digital vasoconstriction in response to coldness occurs. It is conceivable that RP is elicited by the immune-mediated vascular endothelial cell injury. Histologically, mononuclear cells such as lymphocytes and monocytes are recruited into the connective tissues, leading to fibroblast activation, collagen accumulation, and tissue hypoxia. Although the initial event leading to the development of SSc is still poorly understood, an important characteristic feature of the disease is the production of a variety of autoantibodies to nuclear antigens. In clinical setting, two unique autoantibodies, anti-centromere (anti-CENP B) and anti-topoisomerase1 (anti-TOPO1), are found elevated in SSc sera concomitantly with RP or even digital skin necrosis. However, the real mechanism of the correlation among autoantibodies and vascular endothelial cell damage remains unclear.
Here, we use the calf pulmonary artery endothelial cells (CPAE) as a model to clarify the affections of these two autoantibodies on vascular biology. We found that the adenosine triphosphate(ATP) production was significantly decreased when cells were incubated with anti-CENP B. Besides, the amount of lactate dehydrogenase (LDH) was increased under treatment of these antibodies. These results suggested that the incubation of autoantibodies with CPAE would destroy cell function and induce cell necrosis. Moreover, the flow cytometrical analysis by annexin V/PI double staining demonstrated that the percentage of apoptotic cell was increased upon antibody treatment. Also, we noticed that the antibody-treated cells tended to become senescence as detected by the senescence-associated β-gal staining and telomere DNA measurement. For elucidating the molecular basis of cell damage, we noted that the antibodies would induce p53 expression in the cells. In conclusion, our data revealed the cytotoxic roles of anti-CENP B and anti-TOPO 1 antibodies on vascular endothelial of patients with SSc through p53 related signaling pathway.
Subjects
systemic sclerosis(SSc)
Raynaud’s phenomenon(RP)
autoantibody
anti-centromere(anti-CENP B)
anti-topoisomerase1(anti-TOPO1)
vascular endothelial cells
Type
thesis
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