Vascular pathology in systemic scleroderma

The mechanisms of vascular lesions in systemic scleroderma (SSC) are still little studied with the current comprehensive investigations being focused on this issue. The results of a study dealing with the structural-and-morphological and molecular reasons of sclerodermic micro-angiopathy as compared with the variations and pattern of the clinical disease course are summarized in the article. The structural capillary changes were evaluated on the basis of the results of a wide-field video-capillaroscopy of the nail bed (CNB). The level of soluble adhesion molecules VCAN-1, ICAM-1 and P-selectine determined by the quantitative immune-enzyme assay described the vascular endothelium condition. Morphological examinations of dermal samplings included an identification of the lymphocytic composition of infiltrates by applying the mononuclear antibodies to markers T (CD3, CD4, CD8) and B (CD20) of lymphocytes and detection of the endothelial activation by applying the mononuclear antibodies to intercellular adhesion-1 molecule (ICAM-1). The conducted investigations revealed the structural capillary changes in all SSC patients; the nature of such changes is closely related with a clinical variation and course of the disease. The morphological signs of micro-angiopathy were detected in 98% of patients including at the early disease stage. A more pronounced perivascular infiltration with predominance of CD4+ T-lymphocytes was observed and expression of ICAM-1 to the endothelial cells was registered more often in an active disease course. Higher levels of VCAM-1, ICAM-1 and P-selective in blood were found in 80%, 45% and 48% of patients, respectively. Correlations of VCAM-1 with an activity and a progressing disease course were established. Therefore, the serological and morphological signs of vascular lesions reflect an intensity degree of sclerodermic micro-angiopathy and correlate with an SSC clinical course.     

肾移植及移植后的血管并发症

背景：尽管肾移植手术技术已相当成熟,但各移植中心难免会出现术中及术后的血管并发症。 目的：分析肾移植过程中及移植后血管并发症的诊断与处理。 方法：回顾性分析 11 例肾移植过程中、移植后血管并发症资料。移植过程中并发症：动脉吻合口狭窄2例,肾静脉横断1例,髂外动脉硬化斑块剥脱堵塞肾动脉3例,移植肾静脉扭曲1例;移植后并发症：肾外型假性动脉瘤2例,吻合口狭窄1例,移植肾动脉压迫梗阻1例。 结果与结论：肾移植中吻合口狭窄2例移植后恢复良好,分别于移植后6年及11年移植肾失功;肾静脉横断1例随访12年移植肾失功;髂外动脉硬化斑块剥脱堵塞肾动脉3例,1例移植肾当即失功,另2例分别随访6年及2年,现移植肾功能良好;移植肾静脉扭曲1例移植后出现移植肾功能延迟恢复,1个月后因重症肺部感染死亡。移植后发生的血管并发症中肾外型假性动脉瘤2例移植肾均失功;吻合口狭窄1例经置入支架后肾功能恢复正常,已随访18个月;移植肾动脉压迫梗阻1例移植后出现移植肾功能延迟恢复,3周后因重症肺部感染死亡。结果说明肾移植过程中及移植后发生血管并发症,只要诊断准确、处理及时,可取得比较满意的治疗效果。 中国组织工程研究杂志出版内容重点：组织构建;骨细胞;软骨细胞;细胞培养;成纤维细胞;血管内皮细胞;骨质疏松;组织工程全文链接：     

Immunological diagnosis of scleroderma

Systemic sclerosis is characterized by a fibrosis and a microvascular injury. These vascular lesions can affect internal organs causing severe visceral damages. The pathogenesis of this disease is complex but some immunological disorders with a production of antinuclear auto-antibodies can be useful to the clinicians, especially for an early diagnosis and to distinguish the scleroderma/myositis overlap syndromes. This review presents the target antigens and the methods of detection of the different antinuclear auto-antibodies. Sensitivity, specificity and clinical association between the antinuclear auto-antibodies and the different subclasses of scleroderma are also presented in detail.     

Genomic instability in scleroderma

Scleroderma is an enigmatic rheumatic disorder of uncertain etio-pathogenesis. Cancer has an approximately two-fold higher incidence in scleroderma patients than in the general population. There are preliminary data of acquired genetic damage in scleroderma but the significance of these observations are uncertain. To determine somatic mutation frequency at the glycophorin-A (GPA) locus in patients with limited and diffuse cutaneous scleroderma. The GPA assay measures the total somatic mutation frequency (Vf), composed of gene inactivating mutations (NO) and mutations arising from mitotic recombination (NN) in individuals heterozygous for the GPA MN blood group. Mutation frequency was determined using a validated GPA flow cytometric assay using fluorescent labeled monoclonal antibodies specific for the GPA blood groups M and N. This assay detects and enumerates progeny of red blood cell (rbc) precursor cells which have acquired genetic damage resulting in a loss of expression of one of the GPA alleles. It was found that patients with scleroderma (n = 23) had significantly elevated Vf as compared with young healthy controls (p < 0.001) and elderly controls (p = 0.03). Patients with diffuse scleroderma had higher mean Vf as compared with limited scleroderma (p = 0.055). In comparison with controls, patients with scleroderma exhibit a higher proportion of mitotic recombinant mutations than inactivating mutations (p < 0.002). There was no correlation between Vf and disease duration, age at onset or autoantibody status. We have documented evidence of acquired genetic damage at the GPA locus in scleroderma. Evidence of acquired genetic damage in this disorder may be importance in explaining both the etio-pathogenesis of scleroderma and the association of scleroderma with cancer.     

Pregnancy and scleroderma.

Scleroderma is a rare disease with a marked female excess in incidence. The pattern of age of onset, together with the effects of the disease, are such that the majority of women with scleroderma experience pregnancy prior to diagnosis. There are three questions of interest: (1) Does pregnancy adversely affect the prognosis of scleroderma? Isolated case reports suggest that renal disease, and in particular hypertensive crises, are associated with pregnancy in the absence of any renal abnormality before pregnancy. However, such events are rare. (2) Does scleroderma adversely affect either fertility or the outcome of pregnancy? Women with established scleroderma, again in case series, have a high rate of spontaneous miscarriage which is not found consistently in epidemiological studies. Prematurity and low birth rates are more frequent problems. (3) Does reproductive history influence disease and particularly Raynaud's phenomenon may antedate diagnosis by many years and might influence reproductive outcome, in general reproductive outcome is similar to that seen after diagnosis, although fertility appears to be reduced.     

Diagnosis and treatment of scleroderma

Scleroderma is a rare disease. Approximately 80% of patients are females, and one-half present before the age of 40. Some studies suggest a higher incidence and severity of disease in black females than in whites. Scleroderma affect approximately 20 new patients per million per year and has an estimated prevalence of approximately 250 patients per million in the United States, the synonyms from this desease including Progressive systemic sclerosis (PSS), or diffuse scleroderma. Scleroderma is a multisystem disorder characterized by skin thickening and vascular abnormalities. Causes of scleroderma remain mysterious. Immunologic abnormalities are suggested by the presence of characteristic autoantibodies such as ANA,anticentromere, and anti-Scl-70 antibodies. In addition to skin, the most commonly affected organs are lung and kidney. Three major diseases subsets are recognized based on the extent of skin disease. Limited disease is defined as skin fibrosis in distal extremities and some areas of face and neck. Limited diseases are also known as CREST syndrome. Diffuse disease includes patients with skin abnormalities extending to the proximal extremities (i.e., above the elbow or knee) and trunk. Localized disease manifests as patches (morphea) or bandlike (linear scleroderma) areas of skin thickening.     

Pathogenesis of telangiectasia in scleroderma

Scleroderma (progressive systemic sclerosis) is a systemic autoimmune disorder characterised by skin sclerosis, calcinosis and changes in microvasculature. The etiology of the disease is unknown but both genetic and environmental factors have been implicated. Telangiectasia (macroscopically visible dilated skin vessels) occurring primarily on the hands and face, are a prominent feature in scleroderma and are present in the majority of patients. Similarly, telangiectasia are found in patients with hereditary hemorrhagic telangiectasia (HHT), a mutational disorder of the germline genes endoglin and ALK-1, members of the TGFbeta receptor family, expressed on endothelial cells. Our study investigated the number, distribution and microscopic characteristics of telangiectasia in both limited (n = 29) and diffuse scleroderma (n = 9) and compared findings with 3 patients with HHT. In limited scleroderma, the mean number of telangiectasia (hand and face) was 36 (0-150) compared with 23 (0-135) in diffuse scieroderma. A significant correlation was observed between the number of telangiectasia on the face and on the hands (p = 0.014). The total number of telangiectasia correlated significantly with the disease duration (p = 0.009). The spatial distribution of the telangiectasia appeared to be random on both hands and foreface in contrast with the distribution of subcutaneous calcification of the hands which occurred predominantly on the distal and flexor surfaces of the first, second and fifth digits. Nailfold microscopic capillaroscopy was performed on 12 patients. No significant correlation was observed between capillary diameter or density and with total number of telangiectasia observed macroscopically. The distribution and microscopic appearance of telangiectasia in scleroderma appeared very similar to those observed in HHT. In view of these similarities we therefore conclude that telangiectactic development in scleroderma may be associated with disorders of the TGFb receptor family proteins found on the microvasculature.     

硬皮病相关microRNA研究进展

硬皮病是一种以皮肤组织和内脏器官广泛纤维化、微血管改变和免疫反应异常为特征的复杂自身免疫性疾病,其发病机制尚不明确.近年来,较多研究结果显示硬皮病、类风湿和系统性红斑狼疮等自身免疫疾病具有类似的microRNA(miRNA)调控机制.进一步了解近年来自身免疫疾病中具有重要作用的miRNA以及硬皮病致病机制相关的miRNA可增进对其研究进展的理解.     

Pregnancy issues in scleroderma

Systemic sclerosis is a systemic, inflammatory, autoimmune disease affecting the skin and viscera, manifesting pathologically with microvascular lesions, perivascular infiltration by mononuclear cells and increased deposition of extracellular collagen. The rarity of the disease as well as its propensity to appear in the early 1940s, explain the low frequency of concurrent scleroderma and pregnancy. However, the marked female excess, as well as the trend for increasing maternal age due to social change and assisted reproductive technologies, renders heightened significance to issues of fertility, pregnancy course and pregnancy outcomes. In the past, scleroderma patients were thought to be at high risk for poor fetal and maternal outcome, but more current retrospective studies show that despite an increased frequency of prematurity and small for gestational age infants, overall maternal and neonatal survival is good. Hence, at present, with close monitoring and appropriate therapy most scleroderma patients can sustain a successful pregnancy. Therapy with hydroxychloroquine and low dose steroids as well as judicious use of intravenous immunoglobulins is permitted. Renal crisis remains the most dreaded complication of a scleroderma pregnancy and necessitates prompt institution of ACE inhibitor therapy despite its potential teratogenicity. In order minimize the risk for renal crisis, pregnancies should be avoided in rapidly progressive diffuse disease as such patients are at a greater risk for developing serious cardiopulmonary and renal problems early in the disease. This review shall focus on the bi-directional effects of scleroderma on fertility and pregnancy as well as on the management of pregnancy and delivery in the scleroderma patient.     

Platelets in renal scleroderma

Electron microscopic findings in a case of suspected scleroderma (progressive systemic sclerosis) showed platelet aggregates within numerous capillary lumens of the kidney. Evidence suggests that platelets may be a factor in the pathogenesis of renal scleroderma.     

A case of bleomycin-induced scleroderma.

The association of exposure to bleomycin with the development of scleroderma-like cutaneous abnormalities has been reported. We experienced a case of scleroderma involving the hands, feet, and forearms after bleomycin chemotherapy. The present report supports the possible causal relation of bleomycin with scleroderma. Regarding the widespread use of bleomycin, this complication is thought to be under appreciated.     

A cross-reactive idiotype in scleroderma

Autoantibodies to centromere proteins (anti-CENPs) and to topoisomerase-I are highly specific for scleroderma. Unlike most autoantibodies in other diseases, these autoantibodies are mutually exclusive. We have analysed the idiotypes (Ids) expressed by anti-CENP-B, antitopoisomerase-I, and IgGs from 20 scleroderma patients. Rabbit anti-Ids were prepared to antitopoisomerase-I from two scleroderma patients, and to anti-CENP-B from four patients. These six anti-Ids were used to study the purified autoantibodies from 20 scleroderma patients: four antitopoisomerase-I, 10 anti-CENP-B, and six purified IgG from scleroderma patients who were negative for both autoantibodies. In addition, we studied sera from 40 normal autoantibody-negative controls, and sera and purified immunoglobulins from 17 systemic lupus erythematosus (SLE) patients containing high titres of anti-double-stranded DNA, and/or autoantibodies to extractable nuclear antigens (ENA). Using direct binding, and competitive inhibition ELISAs and immunoblots, we identified an Id present in the heavy chains of all the affinity-purified antitopoisomerase-I, and anti-CENP-B. Interestingly, this Id was also present in the immunoglobulins of the scleroderma patients who had neither of the two autoantibodies. By contrast, cross-reactive Id-EM was not found in the sera or immunoglobulins from 17 SLE patients, or in the sera from 40 normal subjects. Several samples from two patients showed that this cross-reactive Id-EM was stable over time. The scleroderma disease-specific autoantibodies may be identified through a common structural feature at the variable region of the heavy chain: cross-reactive Id-EM.     

Mononuclear cell-fibroblast interactions in scleroderma

We studied cell proliferation and collagen biosynthesis in cocultures of dermal fibroblasts with peripheral blood mononuclear cells (MNC) from scleroderma patients and from age-matched normal controls. Autologous one-way mixed MNC-fibroblast cultures revealed that fibroblasts do not stimulate MNC proliferation. Conversely, MNC stimulate autologous fibroblasts from scleroderma patients as well as from normal controls. This effect is increased in cells from scleroderma patients in which it seems to be mediated both by cell-to-cell interaction and through the production of soluble factors by MNC. In normal control cell systems we found no proliferative effect of supernatants of unstimulated cells or from those stimulated in autologous mixed-lymphocyte reactions. Coculture of fibroblasts with autologous MNC resulted in increased [14C]proline incorporation into both collagenic and noncollagenic proteins. This effect was mediated mostly by soluble factors that are released into the culture medium. Protein synthesis by MNC-fibroblast cocultures from scleroderma patients was significantly greater than protein synthesis by those from normal controls. Culture supernatants from unstimulated MNC or from autologous mixed-lymphocyte cultures caused a slight decrease in collagenic protein synthesis by cultured fibroblasts from scleroderma patients but not by those from normal controls. This effect of culture supernatants could be reproduced, and magnified, with purified IL-1 on cells from either patients or controls. Our findings indicate abnormal MNC-fibroblast interactions in scleroderma that could play an important role in the pathogenesis of fibrosis, the hallmark of this condition.