狼疮性肾炎患者肾组织中胎源性微嵌合体的表达及其临床意义

目的：探讨胎源性微嵌合体（FMc）与狼疮性肾炎（LN）的相关性。方法：收集生育过男胎的24例LN和24例肾小球轻微病变（GML）的女性患者肾活检组织,采用荧光原位杂交技术（FISH）检测细胞中的Y染色体,并收集患者孕育史、临床和实验室资料进行分析。结果：在9例LN和3例GML的肾组织中发现Y染色体阳性嵌合细胞,两组发生率的差异有统计学意义（P<0.05）,但在LN组,嵌合细胞的出现与蛋白尿、血清肌酐、抗双链DNA抗体、抗核抗体、补体C3、C4水平及SLEDAI评分等之间均无相关（P>0.05）。结论：FMc在女性LN患者肾组织中的发生频率高于对照组GML患者,但FMc的存在很可能与LN的发病、疾病活动性和进展性无关。     

Clinical and immunological factors associated with lupus nephritis in patients from northwestern Colombia

A cross-sectional and multicenter study was undertaken to analyze the clinical and immunological characteristics at diagnosis associated with nephritis in northwestern Colombian patients with systemic lupus erythematosus (SLE). Thirty-nine patients with lupus nephritis were included and were compared to 100 SLE patients without nephritis. A multivariate analysis was performed. The patients who developed nephritis had a higher frequency of oral ulcers (41% vs. 21%, OR = 3.1, 95% CI: 1.3-7.5 p = 0.01) and malar erythema (77% vs. 45%, OR = 4.4, 95% CI: 1.8-10.8 p = 0.001). Lupus nephritis was observed in 77% of cases during the first year of the disease. The frequency of anti-DNA antibodies was higher in patients with nephritis, however, differences were not statistically significant (83% vs 64%, OR = 2.6, 95% CI: 1.03-6.41, p = 0.06). The presence of other autoantibodies (anti-Ro, anti-La, anti-RNP, anti-Sm and anticardiolipin) at diagnosis was similar in both groups. This autoantibody profile remained unchanged throughout the evolution of the disease. Patients with lupus nephritis had a higher prevalence of arterial hypertension (60% vs 10%, OR = 13.7, 95% IC: 5-37, p = 0.00001) and hyperlipidemia (30% vs 7%, OR = 8.1, 95% IC: 2.5-27, p = 0.0006) at onset. Finally, patients with lupus nephritis required more hospitalizations (> 1) over the course of disease (89% vs 60%, OR = 7.8, 95% CI: 2.1-29, p = 0.002). In conclusion, lupus nephritis appears early during the course of SLE. Malar erythema, oral ulcers, hypertension and hyperlipidemia at onset of disease are associated factors. Lupus nephritis is a major risk factor leading to repeated hospitalizations. This study may help to assist in public health policies in our population in order to improve patient outcomes while simultaneously reducing disease costs.     

The synergistic effects of clopidogrel with montelukast may be beneficial for asthma treatment

Platelets modulate asthma pathogenesis by forming the platelet‐eosinophil aggregation (PEA), which facilitates the activation of eosinophils. Platelets exhibit the purinergic receptor (P2Y12R), which responds to cysteinyl leukotriene E4 (LTE₄). We have suggested that the combination of an antiplatelet drug (clopidogrel, [Clo]) and montelukast (Mon) would synergistically suppress asthma. BALB/c mice were intraperitoneally sensitized with ovalbumin (OVA) on days 0 and 14 and subsequently challenged on days 28‐30 and 42‐44. Mice were administered with Clo (10 mg/kg), Mon (10 mg/kg) or both drugs (Clo/Mon) orally 30 minutes before the OVA (1%) challenge on days 42‐44. Mice were assayed for airway hyper‐responsiveness (AHR) to methacholine and airway inflammation. Clopidogrel and montelukast attenuated the increased AHR; the combined treatment was more effective than a single treatment for total and eosinophil counts (all P < 0.05). Levels of interleukin (IL)‐4, IL‐5, IL‐13, platelet factor 4, eosinophil peroxidase and LTE₄ increased in the bronchoalveolar lavage fluid of asthmatic mice, but these levels decreased in mice treated with Clo/Mon (all P < 0.05). Goblet cell hyperplasia decreased in response to Clo/Mon. Mouse platelets and eosinophils were isolated and co‐cultured for an in vitro assay with 10 µmol/L adenosine diphosphate (ADP), LTE₄ (200 nmol/L), Mon (1 µmol/L), Clo (1 µmol/L) and Clo/Mon (1 µmol/L). Flow cytometry revealed that the increased formation of the PEA (%) was fully mediated by ADP and partly mediated by LTE₄. Clo/Mon reduced ADP‐induced PEA formation and P‐selectin expression (P < 0.05). In conclusion, Clo/Mon synergistically relieved asthma by inhibiting ADP‐mediated PEA formation.     

Levels of anti-cytokine antibodies may be elevated in patients with pulmonary disease associated with non-tuberculous mycobacteria

Pulmonary disease due to non-tuberculous mycobacteria (NTM) is caused by several species (particularly Mycobacterium avium, Mycobacterium intracellulare) that are abundant in the environment. Th1 cytokines such as interferon (IFN)-γ are important in the control of mycobacteria, but in vitro production of IFN-γ is not deficient in adult patients with pulmonary NTM disease. Antibodies reactive with IFN-γ have been described in patients with disseminated NTM disease, but it is not clear whether they are common in pulmonary disease. Here we show that patients with pulmonary NTM have a higher level of anti-IFN-γ and anti-GM-CSF antibodies than healthy controls, although some controls also have high levels. Levels of anti-IFN-γ antibodies did not correlate with levels of total immunoglobulin. Longitudinal studies are required to determine whether anti-cytokine autoantibodies are consequence rather than a cause of pulmonary NTM disease.     

Drought may be beneficial to the competitive advantage of Amaranthus spinosus

干旱利于刺苋的竞争优势 干旱可以影响入侵植物的生长和土壤酶活性。因此,非常有必要评估干旱背景下入侵植物的竞争优势以及入侵植物和干旱对土壤酶活性的影响。本研究旨在分析干旱背景下起源于热带美洲的入侵植物刺苋(Amaranthus spinosus)与本地植物苋菜(Amaranthus tricolor)共存时的竞争优势和土壤酶活性。通过栽植实验进行刺苋与苋菜的竞争共栽培,并进行不同水平的干旱处理,即：(i)对照;(ii)轻度干旱;(iii)重度干旱。实验结束后测定两种苋属植物的功能性状、渗透调节、抗氧化酶活性以及土壤pH、电导率、土壤微生物生物量碳含量和土壤酶活性。干旱背景下,刺苋的相对竞争强度和相对优势度均高于苋菜。因此,干旱利于刺苋的竞争优势。干旱背景下,刺苋的土壤水溶性盐含量和蔗糖水解能力均大于苋菜。而较高的土壤水溶性盐含量和蔗糖水解能力利于刺苋对养分的获取和利用。     

Treatment with a laminin-derived peptide suppresses lupus nephritis

The role of DNA as the target for pathogenic lupus autoantibodies in systemic lupus erythematosus is equivocal and renal damage may be due to cross-reactivity of lupus Abs with glomerular components. We have previously shown that lupus autoantibodies bind to the laminin component of the extracellular matrix. In the present work, we have analyzed the fine specificity of the interaction of pathogenic murine lupus autoantibodies with this molecule and the effect of inhibiting their binding to laminin during the course of the disease. We have found that pathogenic murine lupus autoantibodies react with a 21-mer peptide located in the globular part of the alpha-chain of laminin. Immunization of young lupus-prone mice with this peptide accelerated renal disease. Analysis of transgenic, congenic, and RAG-1(-/-) mice confirmed the importance of this epitope in the pathogenesis of lupus renal disease. We have synthesized a panel of peptides that cross-react with the anti-laminin Abs and have found that the binding of lupus autoantibodies to the extracellular matrix could be inhibited in vitro by some of these competitive peptides. Treatment of MRL/lpr/lpr mice with these peptides prevented Ab deposition in the kidneys, ameliorated renal disease, and prolonged survival of the peptide-treated mice. We suggest that laminin components can serve as the target for lupus Abs. The interaction with these Ags can explain both the tissue distribution and the immunopathological findings in lupus. Moreover, inhibition of autoantibody binding to the extracellular matrix can lead to suppression of disease.     

Serum protein pattern associated with organ damage and lupus nephritis in systemic lupus erythematosus revealed by PEA immunoassay

Background

Systemic lupus erythematosus (SLE) is a remarkably heterogeneous autoimmune disease. Despite tremendous efforts, our knowledge of serum protein patterns in severe SLE phenotypes is still limited. We investigated the serum protein pattern of SLE, with special emphasis on irreversible organ damage and active lupus nephritis (LN) as assessed by renal Systemic Lupus Erythematosus Disease Activity Index.

Methods

We used proximity extension immunoassay (PEA, Proseek Multiplex, Olink) to assess the serum levels of ninety-two inflammation-related proteins in Czech patients with SLE (n = 75) and age-matched healthy control subjects (n = 23). Subgroup analysis was carried out on the basis of organ damage (with/without, 42/33) and biopsy-proven LN (with/without, 27/48; active LN, n = 13; inactive LN, n = 14).

Results

Of thirty deregulated proteins between SLE and the healthy controls (P _corr  < 0.05), the top upregulated proteins in SLE were sirtuin 2, interleukin 18 (IL18), and caspase 8 (P _corr  < 0.0006). Of these, sirtuin 2 and caspase 8 had not yet been reported with SLE. Elevated levels of IL8, CCL2/MCP1, CCL11, and MMP10 (P _corr  < 0.05) were detected in patients with organ damage for which the serum levels of CCL11 and MMP10 were particularly informative in organ damage prediction. Comparing patients based on LN, elevated levels of CSF1, sIL15RA, sCD40, sCX3CL1, caspase 8, sIL18R1, bNGF, and GDNF (P _corr  < 0.05) were detected in active LN. Except GDNF, all LN-associated markers showed usefulness in prediction of active renal disease.

Conclusions

This highly sensitive PEA analysis identified the serum pattern of SLE, organ damage, and active LN, with many novel candidate proteins detected. Their exact role and suitability as biomarkers in SLE deserve further investigation.

     

Behavioral states may be associated with distinct spatial patterns in electrocorticogram

To determine if behavioral states are associated with unique spatial electrocorticographic (ECoG) patterns, we obtained recordings with a microgrid electrode array applied to the cortical surface of a human subject. The array was constructed with the intent of extracting maximal spatial information by optimizing interelectrode distances. A 34-year-old patient with intractable epilepsy underwent intracranial ECoG monitoring after standard methods failed to reveal localization of seizures. During the 8-day period of invasive recording, in addition to standard clinical electrodes a square 1 × 1 cm microgrid array with 64 electrodes (1.25 mm separation) was placed on the right inferior temporal gyrus. Careful review of video recordings identified four extended naturalistic behaviors: reading, conversing on the telephone, looking at photographs, and face-to-face interactions. ECoG activity recorded with the microgrid that corresponded to these behaviors was collected and ECoG spatial patterns were analyzed. During periods of ECoG selected for analysis, no electrographic seizures or epileptiform patterns were present. Moments of maximal spatial variance are shown to cluster by behavior. Comparisons between conditions using a permutation test reveal significantly different spatial patterns for each behavior. We conclude that ECoG recordings obtained on the cortical surface with optimal high spatial frequency resolution reveal distinct local spatial patterns that reflect different behavioral states, and we predict that similar patterns will be found in many if not most cortical areas on which a microgrid is placed.     

Evidence that the ancestral haplotype in Australian hemochromatosis patients may be associated with a common mutation in the gene.

Hemochromatosis (HC) is a common inherited disorder of iron metabolism for which neither the gene nor biochemical defect have yet been identified. The aim of this study was to look for clinical evidence that the predominant ancestral haplotype in Australian patients is associated with a common mutation in the gene. We compared indices of iron metabolism and storage in three groups of HC patients categorized according to the presence of the ancestral haplotype (i.e., patients with two copies, one copy, and no copies of the ancestral haplotype). We also examined iron indices in two groups of HC heterozygotes (those with the ancestral haplotype and those without) and in age-matched controls. These analyses indicate that (i) HC patients with two copies of the ancestral haplotype show significantly more severe expression of the disorder than those with one copy or those without, (ii) HC heterozygotes have partial clinical expression, which may be influenced by the presence of the ancestral haplotype in females but not in males, and (iii) the high population frequency of the HC gene may be the result of the selective advantage conferred by protecting heterozygotes against iron deficiency.     

吗替麦考治疗狼疮性肾炎的疗效分析

目的探讨吗替麦考治疗狼疮性肾炎的疗效。方法选取我院接受治疗的狼疮性肾炎患者54例,根据患者入院时间分为对照组和研究组,对照组给予环磷酞胺治疗,研究组应用吗替麦考治疗,观察比较两组患者的治疗效果、不良反应发生情况。结果研究组的临床疗效为96.30%,显著高于对照组的77.78%,差异有统计学意义(P0.05);两组不良反应发生率比较,研究组为3.70%明显低于对照组18.52%,差异有统计学意义(P0.05)。结论吗替麦考治疗狼疮性肾炎的效果较好,不良反应少,值得临床推广应用。     

A conserved anti-DNA antibody idiotype associated with nephritis in murine and human systemic lupus erythematosus

In order to identify unique structural features of pathogenic autoantibodies to DNA in SLE, a murine anti-anti-DNA (anti-Id) mAb (mAb 1C7) was produced in response to immunization of lupus mice with a syngeneic anti-DNA mAb (mAb 3E10). Immunization of lupus mice with mAb 3E10 inhibited production of native anti-DNA antibodies, suppressed development of lupus kidney disease (nephritis), and induced production of anti-anti-DNA (anti-Id) antibodies. mAb 1C7 bound F(ab')2 fragments of mAb 3E10, and it bound other murine anti-DNA mAb, but not murine mAb or polyclonal serum antibodies unreactive with DNA. Moreover, binding of mAb 1C7 anti-Id to mAb 3E10 was inhibited by DNA, suggesting anti-Id binding within or near the binding site for DNA. Furthermore, mAb 1C7 bound serum IgG immunoglobulins from 9/12 patients with lupus nephritis and serum anti-DNA antibodies compared to only 3/12 SLE patients with comparable serum levels of anti-DNA antibodies, but without nephritis (p = 0.04), and only 1/53 SLE patients without serum anti-DNA antibodies, 0/49 patients with rheumatoid arthritis, and 1/47 healthy subjects (p less than 0.001). These results provide evidence that mAb 1C7 identifies a conserved Id associated with anti-DNA antibodies in murine and human SLE and may be useful as a structural probe to characterize pathogenic anti-DNA antibodies in SLE.