Upshaw-Schulman症候群の糸球体障害には補体活性とADAMTS13欠損が関連している可能性がある

Introduction: Upshaw-Schulman syndrome (USS) is a congenital form of thrombotic thrombocytopenic purpura (TTP) associated with loss-of-function mutations in the ADAMTS13 gene, possibly leading to aberrant complement activation and vascular injury. However, USS is extremely rare, and there have been no systematic studies correlating histopathological severity with local ADAMTS13 expression and complement activation. Materials and methods: Here, we compared histopathological features, ADAMTS13 immunoreactivity, and immunoreactivity of complement proteins C4d and C5b-9 among renal biopsy tissues from five USS cases, ten acquired TTP cases, and eleven controls. Results: Pathological analysis revealed chronic glomerular sclerotic changes in the majority of USS cases (4 of 5), with minor glomerular pathology in the remaining case. In two of these four severe cases, more than half of the glomerular segmental sclerosis area was localized in the perihilar region. The average number of ADAMTS13-positive cells per glomerulus was significantly lower in USS cases than controls (p < 0.05). Conversely, C4d staining was significantly more prevalent in the glomerular capillary walls of USS cases than controls (p < 0.05), while C5b-9 staining did not differ significantly among groups. Conclusions: These findings suggest that the severity of glomerular injury in USS is associated with deficient ADAMTS13 expression and local complement activation, particularly in vascular regions with higher endothelial shear stress. We suggest that C4d immunostaining provides evidence for complement-mediated glomerular damage in USS.博士（医学）・甲第792号・令和3年3月15日Copyright © 2018 Elsevier Ltd. All rights reserved

Impact of age-dependent adventitia inflammation on structural alteration of abdominal aorta in hyperlipidemic mice.

The adventitia is suggested to contribute to vascular remodeling; however, the site-selective inflammatory responses in association with the development of atherosclerosis remain to be elucidated.Wild-type or apolipoprotein E knockout male C57BL/6J background mice were fed standard chow for 16, 32, and 52 weeks, and the morphology of the aortic arch, descending aorta, and abdominal aorta was compared. Atheromatous plaque formation progressed with age, particularly in the aortic arch and abdominal aorta but not in the descending aorta. In addition, we found that the numbers of macrophages, T-lymphocytes, and microvessels, assessed by anti-F4/80, CD3, and CD31 antibodies, were higher in the adventitia of the abdominal aorta at 52 weeks. These numbers were positively correlated with plaque formation, but negatively correlated with elastin content, resulting in the enlargement of the total vessel area. In aortic tissues, interleukin-6 levels increased in the atheromatous plaque with age, whereas the level of regulated on activation, normal T cell expressed and secreted (RANTES) increased with age, and compared with other sites, it was particularly distributed in inflammatory cells in the adventitia of the abdominal aorta.This study suggests that adventitial inflammation contributes to the age-dependent structural alterations, and that the activation/inactivation of cytokines/chemokines is involved in the process

Impact of age on the region-specific concentrations of cytokine/chemokine in aortic tissue.

<p>Tissue concentrations of IL-6 (<b>A</b>), IL-10 (<b>B</b>), and RANTES (<b>C</b>) in the aortic arch (a), descending aorta (b), and abdominal aorta (c) of 16-, 32-, and 52-week-old apo E^−/− mice (red) and wild-type mice (yellow). The graphs present mean values of 3–4 samples. *p<0.05 vs. the respective region in 52-week-old wild-type mice; ^†p<0.05 vs. aortic arch, and <b>^#</b>p<0.05 vs. the descending aorta in apo E^−/− mice at 52 weeks.</p

Impact of age on the structure of the aorta in wild-type and apo E^−/− mice.

<p>(<b>A–C</b>) Atheromatous plaque area (<b>A</b>), elastin area (<b>B</b>), and collagen deposition (<b>C</b>) at each age and aorta region in apo E^−/− and wild-type mice. (<b>D–F</b>) Representative images of hematoxylin–eosin (<b>D</b>), Victoria blue (<b>E</b>), and picrosirius red (<b>F</b>) staining in the abdominal aorta of apo E^–/– mice at 52 weeks. Data are expressed as mean ± SEM [16 weeks: wild-type (n = 9), apo E^–/– mice (n = 5–6); 32 weeks: wild-type (n = 5–7), apo E^–/– mice (n = 6–7); 52 weeks: wild-type (n = 10), apo E^–/–- mice (n = 9–11)]. **p<0.01, ***p<0.001 vs. wild-type mice. Scale bar, 100 µm.</p

Impact of hyperlipidemia on the characteristics of the mice.

<p>Data are expressed as mean ± SEM (Parentheses indicate the number examined).</p><p>*P<0.05, **P<0.001, ***P<0.0001 vs. wild-type.</p><p>BW, body weight; SBP, systolic blood pressure; HR, heart rate; T-Cho, total cholesterol.</p><p>Apo E^−/−, apo E knockout mice.</p