共查询到20条相似文献,搜索用时 0 毫秒
1.
Benjamin J. Cooze Matthew Dickerson Rukshikah Loganathan Lewis M. Watkins Ethan Grounds Ben R. Pearson Ryan Jack Bevan B. Paul Morgan Roberta Magliozzi Richard Reynolds James W. Neal Owain W. Howell 《Brain pathology (Zurich, Switzerland)》2022,32(5)
The extent of grey matter demyelination and neurodegeneration in the progressive multiple sclerosis (PMS) brains at post‐mortem associates with more severe disease. Regional tissue atrophy, especially affecting the cortical and deep grey matter, including the thalamus, is prognostic for poor outcomes. Microglial and complement activation are important in the pathogenesis and contribute to damaging processes that underlie tissue atrophy in PMS. We investigated the extent of pathology and innate immune activation in the thalamus in comparison to cortical grey and white matter in blocks from 21 cases of PMS and 10 matched controls. Using a digital pathology workflow, we show that the thalamus is invariably affected by demyelination and had a far higher proportion of active inflammatory lesions than forebrain cortical tissue blocks from the same cases. Lesions were larger and more frequent in the medial nuclei near the ventricular margin, whilst neuronal loss was greatest in the lateral thalamic nuclei. The extent of thalamic neuron loss was not associated with thalamic demyelination but correlated with the burden of white matter pathology in other forebrain areas (Spearman r = 0.79, p < 0.0001). Only thalamic neuronal loss, and not that seen in other forebrain cortical areas, correlated with disease duration (Spearman r = −0.58, p = 0.009) and age of death (Spearman r = −0.47, p = 0.045). Immunoreactivity for the complement pattern recognition molecule C1q, and products of complement activation (C4d, Bb and C3b) were elevated in thalamic lesions with an active inflammatory pathology. Complement regulatory protein, C1 inhibitor, was unchanged in expression. We conclude that active inflammatory demyelination, neuronal loss and local complement synthesis and activation in the thalamus, are important to the pathological and clinical disease outcomes of PMS. 相似文献
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《European journal of human genetics : EJHG》2009,17(10):1309-1313
In a recent genome-wide association study (GWAS) based on 12 374 non-synonymous single nucleotide polymorphisms we identified a number of candidate multiple sclerosis susceptibility genes. Here, we describe the extended analysis of 17 of these loci undertaken using an additional 4234 patients, 2983 controls and 2053 trio families. In the final analysis combining all available data, we found that evidence for association was substantially increased for one of the 17 loci, rs34536443 from the tyrosine kinase 2 (TYK2) gene (P=2.7 × 10−6, odds ratio=1.32 (1.17–1.47)). This single nucleotide polymorphism results in an amino acid substitution (proline to alanine) in the kinase domain of TYK2, which is predicted to influence the levels of phosphorylation and therefore activity of the protein and so is likely to have a functional role in multiple sclerosis. 相似文献
3.
G. Ingram S. Hakobyan N. P. Robertson B. P. Morgan 《Clinical and experimental immunology》2009,155(2):128-139
Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system with a poorly defined and complex immunopathogenesis. Although initiated by reactive T cells, persistent inflammation is evident throughout the disease course. A contribution from complement has long been suspected, based on the results of pathological and functional studies which have demonstrated complement activation products in MS brain and biological fluids. However, the extent and nature of complement activation and its contribution to disease phenotype and long‐term outcome remain unclear. Furthermore, functional polymorphisms in components and regulators of the complement system which cause dysregulation, and are known to contribute to other autoimmune inflammatory disorders, have not been investigated to date in MS in any detail. In this paper we review evidence from pathological, animal model and human functional and genetic studies, implicating activation of complement in MS. We also evaluate the potential of complement components and regulators and their polymorphic variants as biomarkers of disease, and suggest appropriate directions for future research. 相似文献
4.
Tissue microarray analysis of neuroendocrine differentiation and its prognostic significance in breast cancer 总被引:4,自引:0,他引:4
The aim of this study was to detect neuroendocrine differentiation (NE), to determine its association with major clinicopathological parameters of breast cancer, and to study the prognostic significance of NE differentiation in a group of breast carcinomas by using tissue microarray (TMA) methodology. NE differentiation was studied by using 3 markers, synaptophysin (Syn), chromogranin A (ChA), and neuron-specific enolase (NSE) in a group of 334 patients with breast carcinoma. TMA blocks were made by using duplicate 0.6-mm-diameter tissue cores from each paraffin block. Results of immunostaining were scored on a 4-point scale, that is, as negative, weak, intermediate, and strong immunoreactivity. Positive staining of breast cancers for any of the 3 NE markers was detected in 19.5% of cases. Expression of a single marker was present in 16.2% of cases, and expression of 2 or 3 markers in combination was detected in 3.3% of cases. There was no statistically significant correlation of NE phenotype with tumor morphology, except mucinous carcinoma (3 of 6 cases positive), estrogen receptor, progesterone receptor, or nodal status. A weak correlation was noted between synaptophysin staining and higher tumor grade (P = 0.029). Analysis of disease-specific and overall survival based on up to 20 years of follow-up data showed a correlation between NSE expression and improved disease-specific (P = 0.043) and overall survival (P = 0.03) in univariate but not in multivariate analysis. The expression of Syn and ChA, as well as coexpression of multiple NE markers, had no prognostic significance. 相似文献
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Matthew K. Siggins Kate Davies Rosie Fellows Ryan S. Thwaites J. Kenneth Baillie Malcolm G. Semple Peter J. M. Openshaw Wioleta M. Zelek Claire L. Harris B. Paul Morgan the ISARICC Investigators 《Immunology》2023,168(3):473-492
Complement, a critical defence against pathogens, has been implicated as a driver of pathology in COVID-19. Complement activation products are detected in plasma and tissues and complement blockade is considered for therapy. To delineate roles of complement in immunopathogenesis, we undertook the largest comprehensive study of complement in COVID-19 to date, comprehensive profiling of 16 complement biomarkers, including key components, regulators and activation products, in 966 plasma samples from 682 hospitalized COVID-19 patients collected across the hospitalization period as part of the UK ISARIC4C (International Acute Respiratory and Emerging Infection Consortium) study. Unsupervised clustering of complement biomarkers mapped to disease severity and supervised machine learning identified marker sets in early samples that predicted peak severity. Compared to healthy controls, complement proteins and activation products (Ba, iC3b, terminal complement complex) were significantly altered in COVID-19 admission samples in all severity groups. Elevated alternative pathway activation markers (Ba and iC3b) and decreased alternative pathway regulator (properdin) in admission samples were associated with more severe disease and risk of death. Levels of most complement biomarkers were reduced in severe disease, consistent with consumption and tissue deposition. Latent class mixed modelling and cumulative incidence analysis identified the trajectory of increase of Ba to be a strong predictor of peak COVID-19 disease severity and death. The data demonstrate that early-onset, uncontrolled activation of complement, driven by sustained and progressive amplification through the alternative pathway amplification loop is a ubiquitous feature of COVID-19, further exacerbated in severe disease. These findings provide novel insights into COVID-19 immunopathogenesis and inform strategies for therapeutic intervention. 相似文献
8.
Marina Saresella Federica Piancone Paola Tortorella Ivana Marventano Andrea Gatti Domenico Caputo Christian Lunetta Massimo Corbo Marco Rovaris Mario Clerici 《Clinical immunology (Orlando, Fla.)》2013,148(1):79-88
MS (multiple sclerosis) and ALS (amyotrophic lateral sclerosis) differ in important respects, but common pathogenic features seem to be shared in these two diseases. To shed light on such features, immunophenotypic and functional analysis were performed in peripheral monocytes and T lymphocytes of ALS and primary progressive (PP) MS patients and healthy controls (HC). Results showed that TH1-, TH17-, and IL-6-driven inflammation characterize both diseases; this is unsuccessfully hampered by TH2 activation and, possibly, BDNF secretion. Results herein clarify the pathogenic similarities between ALS and PP-MS and could be helpful for the design of novel diagnostic and therapeutic approaches to ALS. 相似文献
9.
Masaaki Niino Toshiyuki Fukazawa Naoya Minami Itaru Amino Jun Tashiro Naoto Fujiki Shizuki Doi Seiji Kikuchi 《Neuroscience letters》2012
Previous studies have demonstrated that CD5+ B cells produce more interleukin (IL)-10 than CD5− B cells and that CD5+ B cells confer significant protection against experimental autoimmune encephalomyelitis (EAE). The objective of the present study was to determine whether CD5-positive B cell populations are associated with secondary progressive multiple sclerosis (SPMS) and to explore which subsets on CD5+ B cells are associated with SPMS. A total of 26 patients with SPMS, of whom 11 were treated with IFNβ (IFN-SPMS) and 15 were not treated (non-IFN-SPMS), and 19 healthy control (HC) subjects were included in the study. Expression levels of CD11a, CD23, CD25, CD38, CD49d, CD80, CD86, CD138, CCR5, and CXCR5 on CD5+ B cells in blood samples were examined by flow cytometry. The percentage of CD5+ B cells in the SPMS group was significantly lower than in the HC group. Within the subsets of CD5+ B cells, the expression of CD11a in the non-IFN-SPMS group was significantly decreased compared to the HC subjects. Patients with SPMS showed lower CCR5, CD25, and CD138 positivity on CD5+ B cells than HC subjects. Our results indicate that CD5+ B cell subsets might be associated with pathogenesis of SPMS. 相似文献
10.
Tissue microarray analysis of multiple gene expression in intestinal metaplasia, dysplasia and carcinoma of the stomach 总被引:7,自引:0,他引:7
AIMS: To study multiple gene expression patterns and their roles in the process of gastric carcinogenesis. METHODS AND RESULTS: Using a high-throughput tissue microarray technique, 169 specimens from gastric carcinomas, precursor lesions and normal mucosa were immunostained on a series of tissue chips for p53, p21(WAF1/CIP1) cyclin E, Bcl-2, c-met and mucin 5AC expression. The overexpression of p53 was observed in 10.7% of low-grade dysplasia (LGD), 38.1% of high-grade dysplasia (HGD) and 39.6% of intestinal type gastric carcinoma (IGC). Expression of p21(WAF1/CIP1) was found in 47.6% of incomplete intestinal metaplasia (IM), 36.7% of dysplasia (Dys) and 29.5% of IGC. The overexpression of cyclin E was more frequently present in carcinomas than in Dys (P < 0.05); moreover, high-level expression (> 25% in extent) of cyclin E was observed only among IGC. Abnormal Bcl-2 expression was present in 81.0% of incomplete IM, 69.4% of Dys and 22.9% of IGC. Along with progression of the lesion, the expression of c-met increased; in contrast, mucin 5AC decreased gradually. CONCLUSIONS: The specific expression pattern in incomplete IM was mucin 5AC+/Bcl-2+/p53-/cyclin E-, while mucin 5AC-/cyclin E+ was specific for IGC. p53 was useful for distinguishing LGD from HGD. High-level expression of cyclin E might be an indicator for malignant transformation of dysplasia. 相似文献
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Mi Jung Kwon Eun Sook Nam Seong Jin Cho Hye Rim Park Hyung Sik Shin Jun Ho Park Chan Heun Park Won Jae Lee 《Pathology international》2009,59(12):851-856
The aim of the present study was to compare the efficiency of tissue microarray (TMA) results using immunohistochemistry markers applied to a variety of core sizes and full sections of gastrointestinal stromal tumors (GIST) using performance measures such as core loss rate and concordance rate. Six primary antibody markers (c‐Kit, CD34, smooth muscle actin (SMA), S‐100, p53, and Ki‐67) were used with the TMA technique to analyze 0.6 mm, 2 mm, and 3 mm punch cores of GIST samples from 67 patients. No statistical association was found between core size and loss rate (P= 0.512). TMA results for the 0.6 mm, 2 mm, and 3 mm core showed that all core sizes could statistically significantly reflect full sections with regard to c‐Kit, SMA, and S‐100 antibodies, but that the 3 mm core section was the most representative except for CD34. With regard to p53 and Ki‐67 staining, the 0.6 mm core section was not representative, but the 2 mm and 3 mm core sections could statistically significantly represent full section results. Among them, the 3 mm core section was more accurate than the 2 mm core section. Use of a single 3 mm core size in TMA is suitable for evaluating large numbers of protein and nuclear stains with regard to immunohistochemistry for GIST. 相似文献
12.
Galina V. Seledtsova Irina P. Ivanova Alexey A. Shishkov 《Journal of immunotoxicology》2016,13(6):879-884
The overall objective of disease management in autoimmune diseases is to suppress chronic inflammation and prevent organ damage. Therapies often revolve around five drug classes: non-steroidal anti-inflammatory drugs (NSAIDS), anti-malarials, steroids, immunosuppressants, and bio-therapies. However, none of these is a ‘cure’ and each displays a potential for adverse events. In particular, while all of them suppress harmful autoimmune responses, they also impact on useful protective immune responses. T-Cell receptor (TCR) immunogenicity provides a rationale for T-cell vaccinations to induce anti-idiotypic immune responses with the purpose of down-regulating functionality of idiotype-bearing self-reactive T-cells. To explore this, in this study, 39 patients with progressive (chronic) multiple sclerosis (MS) were multiply immunized with autological polyclonal T-cell vaccines (TCVs). None of the TCV-treated patients experienced any significant side-effects during the entire follow-up period (2 years). T-Cell vaccination had no significant effects on T-cell sub-population contents in the blood of MS patients after 2 years of immunotherapy initiation. However, a substantial reduction in the frequency of CD4+?and CD8+?memory T-cells able to produce interferon (IFN)-γ following activation were noted in the blood of TCV-treated patients. Moreover, significant and sustained reduction in plasma IFNγ levels and concomitant increases in interleukin (IL)-4 levels were documented in these samples. The TCV-treated subjects, however, exhibited no significant changes in plasma IL-17 and IL-18. More importantly was a significant decline in proliferative T-cell responses to myelin antigens in the TCV-treated patients, indicating attenuation of myelin-specific T-cell activity. Collectively, the results suggest that polyclonal T-cell vaccination is safe to use, able to induce measurable, long-lasting, anti-inflammatory immune effects in patients with advanced MS. 相似文献
13.
Goverman JM 《Immunological reviews》2011,241(1):228-240
Multiple sclerosis is believed to be mediated by T cells specific for myelin antigens that circulate harmlessly in the periphery of healthy individuals until they are erroneously activated by an environmental stimulus. Upon activation, the T cells enter the central nervous system and orchestrate an immune response against myelin. To understand the initial steps in the pathogenesis of multiple sclerosis, it is important to identify the mechanisms that maintain T-cell tolerance to myelin antigens and to understand how some myelin-specific T cells escape tolerance and what conditions lead to their activation. Central tolerance strongly shapes the peripheral repertoire of myelin-specific T cells, as most myelin-specific T cells are eliminated by clonal deletion in the thymus. Self-reactive T cells that escape central tolerance are generally capable only of low-avidity interactions with antigen-presenting cells. Despite the low avidity of these interactions, peripheral tolerance mechanisms are required to prevent spontaneous autoimmunity. Multiple peripheral tolerance mechanisms for myelin-specific T cells have been identified, the most important of which appears to be regulatory T cells. While most studies have focused on CD4(+) myelin-specific T cells, interesting differences in tolerance mechanisms and the conditions that abrogate these mechanisms have recently been described for CD8(+) myelin-specific T cells. 相似文献
14.
We report here an analysis of measures of the intensification of lipid peroxidation and the state of the non-enzymatic and
enzymatic components of the antioxidant defense system in different clinical forms and stages of multiple sclerosis. The data
obtained support the role of oxidant stress in the development of the pathological process in multiple sclerosis.
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Translated from Zhurnal Nevrologii i Psikhiatrii imeni S. S. Korsakova, Multiple Sclerosis, Supplement, No. 3, pp. 26–30,
2006. 相似文献
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《Expert Review of Clinical Immunology》2013,9(1):73-83
There has been longstanding interest in how B-cell responses may contribute to the pathology of neurological diseases. Traditionally, the premise has been that any such contribution relates to the potential of B cells to produce autopathogenic antibodies. Targeting autoantibodies continues to be an important therapeutic approach, particularly in disorders where the role of antibodies is relatively well established, such as in certain inflammatory disorders of peripheral nerves or the neuromuscular junction. In other conditions, such as multiple sclerosis, the role of circulating antibodies targeting the CNS has been less clear, although pathologic studies continue to implicate CNS-reactive antibodies, as well as B cells within the CNS compartment. Recently, new insights into fundamental properties of B cells have suggested that these cells may contribute in an antibody-independent fashion, both to normal immune responses, and in the context of immune mediated diseases. Here, we will consider the potential roles of antibody-dependent as well as antibody-independent B-cell involvement in multiple sclerosis. The topic is of particular interest at a time that B-cell-directed therapies are being evaluated for this and other autoimmune diseases. 相似文献
16.
目的观察PBK/TOPK在人体正常组织和常见恶性肿瘤组织的分布和表达,探讨作为肿瘤标志物的可能性。方法应用免疫组织化学EnV ision法,在含有人体19种正常组织的组织芯片和含有19种恶性肿瘤组织的组织芯片上进行PBK/TOPK染色,检测PBK/TOPK蛋白的表达。结果在19种正常组织中,只有头皮的汗腺、睾丸的精原细胞、肝脏的胆管上皮、食管黏膜下腺体、胰腺外分泌部的导管上皮、前列腺的基底细胞和肾脏的远曲小管8种组织有不同数量细胞明确阳性表达。在19种恶性肿瘤组织中,乳腺癌、子宫颈癌、甲状腺癌等多种肿瘤组织中存在PBK/TOPK的大量、强阳性表达。结论PBK/TOPK在少数正常组织特定细胞中的明确表达及其在多种恶性肿瘤细胞的强阳性表达,为其成为研究肿瘤起源与发生的标志物提供了依据。 相似文献
17.
多发性硬化(MS)是中枢神经系统(CNS)自身免疫性疾病的代表.本文对多发性硬化的免疫发病机制和免疫干预治疗的研究进展作一概述. 相似文献
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Varga L Széplaki G Laki J Kocsis A Kristóf K Gál P Bajtay Z Wieslander J Daha MR Garred P Madsen HO Füst G Farkas H 《Clinical and experimental immunology》2008,153(1):68-74
The possibility of simultaneous measurement of the classical pathway (CP), mannan-binding lectin (MBL)--lectin pathway (LP) and alternative pathway (AP) of complement activation by the recently developed Wielisa method allowed us to investigate the in vivo significance of the C1-inhibitor (C1INH) in three complement activation pathways. Functional activity of the CP, LP and AP were measured in the sera of 68 adult patients with hereditary angioedema (HAE) and 64 healthy controls. In addition, the level of C1q, MBL, MBL-associated serine protease-2 (MASP-2), C4-, C3- and C1INH was measured by standard laboratory methods. MBL-2 genotypes were determined by polymerase chain reaction. Besides the complement alterations (low CP and C1INH activity, low C4-, C1INH concentrations), which characterize HAE, the level of MASP-2 was also lower (P = 0.0001) in patients compared with controls. Depressed LP activity was found in patients compared with controls (P = 0.0008) in homozygous carriers of the normal MBL genotype (A/A), but not in carriers of variant genotypes (A/O, O/O). Activity of CP correlated with LP in patients (Spearman's r = 0.64; P < 0.0001), but no significant correlation was found in the control group and no correlation with AP was observed. In contrast, the activity of CP and AP correlated (Spearman's r = 0.47; P < 0.0001) in healthy controls, but there was no significant correlation in the HAE patients. We conclude that the activation of LP might also occur in subjects with C1INH deficiency, which is reflected by the low MASP-2 and C4 levels. 相似文献
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病毒感染在多发性硬化的病因及发病机制中起主要作用。近年研究证实,EB病毒、人类疱疹病毒6型(HHV-6)是触发带有易感基因个体发生多发性硬化的主要病因。此外,麻疹、水痘等病毒也可能与多发性硬化的发病密切相关。 相似文献