NT FRZ 基因多态性与SEL 的相关性研究

本研究通过调查中国南方SLE人群和健康对照人群中TNFR2基因两个位点（nt587,nt694）的多态性频率,探讨TNFR2基因多态性是否与中国汉族SLE人群的易感性相关。结果发现128例SLE中,nt587G的等位基因频率为54个（21．1％）;而135例健康人群中nt587G的频率为35个（13．0％）;SLE组明显高于健康对照人群（P〈0．05）,携带nt587G的个体SLE发病危险性大。同时128例SLE中,舶94A的等位基因频率为41个（16．0％）;而健康人群中舶94A的频率为32个（11．9％）;两组比较无显著差异（P=0．149）。提示TNFR2基因nt587的多态性与中国南方SLE人群相关,可能通过影响TNFR2的表达而参与SLE的发病,而nt694（G—A）的多态性与中国南方SLE人群不相关。     

Tau Isoforms Expression in Transgenic Mouse Model of Amyotrophic Lateral Sclerosis

Tau is a protein involved in regulation of microtubule stability, axonal differentiation and transport. Alteration of retrograde transport may lead to motor neuron degeneration. Thus alternative mRNA splicing and expression of tau isoforms were studied in a transgenic mouse model harboring the human SOD1 G93A mutation. The studies were performed on cortex, hippocampus and spinal cord of 64- and 120-day-old animals (presymptomatic and symptomatic stage) and wild type controls. Exon 10 was found in all studied tissues. The 2N isoform containing exons 2 and 3 (+2+3) and the 1N (+2−3) predominated over the 0N (−2−3) in brain regions of the studied mice. The 2N expression was significantly lower in cortex and hippocampus of symptomatic animals compared to analogue control tissues. The decrease in 2N expression resulted in lower levels of total tau mRNA and tau protein. No changes in tau expression were observed in spinal cord of studied animals.     

β-干扰素与多发性硬化症的治疗

多发性硬化症(MS)是一种慢性中枢神经系统疾病,目前在临床上难以治愈。β-干扰素(IFN-β)是一种多功能细胞因子,具有抗病毒、抑制生长、诱导凋亡和免疫调节等作用。近年来IFN-β在缓解MS急性发作和延缓病程方面表现出很好的效果,但IFN-β对MS的作用机制却仍不明了。本文简要综述近年来有关IFN-β治疗MS的作用机理。     

Exposure of Hydrophobic Surfaces Initiates Aggregation of Diverse ALS-Causing Superoxide Dismutase-1 Mutants

The copper-zinc superoxide dismutase-1 (SOD1) is a highly structured protein and, a priori, one of the least likely proteins to be involved in a misfolding disease. However, more than 140, mostly missense, mutations in the SOD1 gene cause aggregation of the affected protein in familial forms of amyotrophic lateral sclerosis (ALS). The remarkable diversity of the effects of these mutations on SOD1 properties has suggested that they promote aggregation by a variety of mechanisms. Experimental assessment of surface hydrophobicity using a sensitive fluorescent-based assay, revealed that diverse ALS-causing mutations provoke SOD1 aggregation by increasing their propensity to expose hydrophobic surfaces. These findings could not be anticipated from analysis of the amino acid sequence. Our results uncover the biochemical nature of the misfolded aggregation-prone intermediate and reconcile the seemingly diverse effects of ALS-causing mutations into a unifying mechanism. Furthermore, the method we describe here will be useful for investigating and interfering with aggregation of various proteins and thereby provide insight into the molecular mechanisms underlying many neurodegenerative diseases.     

Early diagnosis of systemic lupus erythmatosus using ANN models of dsDNA binding antibody sequence data

In this paper a new method based on artificial neural networks (ANN), is introduced for identifying pathogenic antibodies in Systemic Lupus Erythmatosus (SLE). dsDNA binding antibodies have been implicated in the pathogenesis of this autoimmune disease. In order to identify these dsDNA binding antibodies, the protein sequences of 42 dsDNA binding and 608 non-dsDNA binding antibodies were extracted from Kabat database and encoded using a physicochemical property of their amino acids namely Hydrophilicity. Encoded antibodies were used as the training patterns of a general regression neural network (GRNN). Simulation results show that the accuracy of proposed method in recognizing dsDNA binding antibodies is 83.2%. We have also investigated the roles of the light and heavy chains of anti-dsDNA antibodies in binding to DNA. Simulation results concur with the published experimental findings that in binding to DNA, the heavy chain of anti-dsDNA is more important than their light chain.     

Regulatory T cells (CD4CD25FoxP3) expansion in systemic sclerosis correlates with disease activity and severity

Background

The role and function of T regulatory (Treg) cells have not been fully investigated in patients with systemic sclerosis (SSc).

Methods

Ten patients with SSc donated 20 ml of peripheral blood. Activity (Valentini) and severity (Medsger) scores for SSc were calculated for all patients. Healthy volunteers (controls) were matched to each patient by gender and age. CD4⁺ cells were separated using the MACS system. The numbers of Treg cells were estimated by flow cytometry after staining for CD4, CD25, and FoxP3 and calculated as patient-to-control ratio separately for each experiment. Correlations with activity and severity indices of the disease were performed. Twenty-four-hour production of TGF-β and IL-10 by activated CD4⁺ cells was measured by ELISA in culture supernatants.

Results

The numbers of Treg cells, expressed as patient-to-control ratio, correlated significantly with both activity and severity indices (r = 0.71, p = 0.034 and r = 0.67, p = 0.044, respectively). ELISA-measured production of TGF-β and IL-10 by CD4⁺ cells was similar in patients and controls.

Conclusions

Increased numbers of Treg cells are present in patients with SSc, correlating with activity and severity of the disease. This expansion of Treg cells was not accompanied, however, by heightened TGF-β or IL-10 production. Further studies to elaborate the causes and functional significance of Treg cell expansion in SSc are needed.     

Aggregation modulating elements in mutant human superoxide dismutase 1

Mutations in superoxide dismutase 1 (SOD1) cause some forms of familial amyotrophic lateral sclerosis (fALS). Affected tissues of patients and transgenic mouse models of the disease accumulate misfolded and aggregated forms of the mutant protein. In the present study we have identified specific sequences in human SOD1 that modulate the aggregation of fALS mutant proteins. From our study of a panel of mutant proteins, we identify two sequence elements in human SOD1 (residues 42-50 and 109-123) that are critical in modulating the aggregation of the protein. These sequences are components of the 4th and 7th β-strands of the protein, and in the native structure are normally juxtaposed as elements of the core β-barrel. Our data suggest that some type of intermolecular interaction between these elements may occur in promoting mutant SOD1 aggregation.