An unusual pattern of peritubular capillary injury involving apoptosis in a renal transplant patient

Microvascular injury is an important factor in renal allograft survival. Repeated episodes of endothelial injury from chronic antibody-mediated rejection typically manifest at the ultrastructural level as circumferential multilayering of remodeled glomerular basement membrane material and peritubular capillary basal lamina. In contrast to this typical pattern of microvascular injury, a renal transplantation case is presented in which focally dilated and multilayered segments of peritubular capillary basal lamina bearing lipid droplets were interspersed with ultrastructurally normal unilayered segments of basal lamina devoid of lipid droplets. Glomerular basement membranes were not affected by this process. The peak incidence of lipid droplets within the peritubular capillary walls coincided with a peak in apoptotic activity within the allograft. Lesser amounts of the same lipidic material were identified in the mesangial matrix and an arteriolar wall. Mesangial electron-dense deposits were detected at two weeks posttransplantation and their appearance coincided with elevated immunological activity in the glomeruli, as determined by immunofluorescence microscopy. The unusual ultrastructure and immunological activity observed in this case may reflect a process of impaired apoptotic clearance within the allograft. The six biopsies from a single patient are discussed in the setting of a highly sensitized renal transplant recipient who received prophylactic terminal complement blockade by eculizumab. The findings may be relevant to the study of apoptosis, efferocytosis, microvascular injury, eculizumab, rejection, lupus, and drug-related disease.     

HLA-C1 ligands are associated with increased susceptibility to systemic lupus erythematosus

Recently, the role of killer cell immunoglobulin-like receptor (KIR) in autoimmune diseases has received increasing attention. The present study was undertaken to determine the association of KIR genes and the human leukocytes antigen (HLA) ligands with Systemic Lupus Erythematosus (SLE) and accompanying oxidative stress. Presence or absence of 17 KIR and 5 HLA loci was performed using the polymerase chain reaction-sequence specific primer (PCR-SSP) method by case-control study. A total of 45 SLE patients, and 60 healthy controls, all of Sicilian descent, were enrolled. Plasma values of the anti-oxidant molecule Taurine were determined in all subjects by capillary electrophoresis UV detection. The carrier frequency of the KIR2DS2 gene was significantly increased in SLE patients compared to healthy controls (73.3 versus 45.0%; OR?=?3.36; 95% CI?=?1.46–7.74; p?=?.005) suggesting a role of KIR2DS2 gene in the susceptibility to disease. We also observed a strong positive association between the presence of HLA-C1 ligands group and the disease (82.2% in SLE patients versus 41.7% in controls; OR?=?6.47, 95% CI?=?2.58–16.26; p?<?.0001). Stepwise logistic regression analysis supported the effect of the HLA-C1 ligands in SLE patients (OR?=?7.06, 95% CI?=?0.07–2.19; p?=?.002), while the KIR genes were no longer significant. Interestingly, we found that SLE patients HLA-C1 positive showed significantly decreased plasma levels of antioxidant activity marker Taurine (69.38?±?28.49?μmol/L) compared to SLE patients HLA-C1 negative (108.37?±?86.09?μmol/L) (p?=?.03). In conclusion, HLA-C1 ligands group was significantly associated with an increased risk of SLE as well as an increased oxidative stress status overall in SLE patients.     

Lupus: The microbiome angle

Microbiota consists of more than 10¹⁴ microorganisms that inhabit different areas of the body including the gastrointestinal tract, mainly the mouth and gut. It includes viruses, fungi, protozoa, archaea and bacteria. The microbiota interacts closely with host leading to a dynamic relationship that results in the biological effects observed. Its diverse genetic material (microbiome) interacts closely with the host immune system and cells, and therefore is closely associated with inflammation, immune tolerance, adaptive immunity and autoimmune diseases. Bacterial microbiota, which is the mostly studied lives in harmony with the host and maintains a symbiotic relationship. Therefore it plays an important role in immunological, metabolic, and neurological aspects and thereby the well-being of the host. Alteration of the homeostatic environment or the dynamic balance of microorganisms can result in dysbiosis or disease. However, does dysbiosis cause disease, aggravate disease or is the result of the disease remains to be defined, it could be a bit of all three factors. More recently, a number of studies demonstrate that these microorganisms could contribute to disease. Alteration of the tightly balanced composition of bacterial microbiota (dysbiosis) leads to exacerbation, rapid progression and worsening of disease states. It is important to identify the ‘healthy’ microbes that maintain a healthy environment, the ‘sensitive’ microbes that go awry with disease, the ‘bad’ microbes that cause disease and the ‘therapeutic’ microbes that can help rectify the changes. Increased relative abundance of certain bacterial species has been linked to triggering autoimmune diseases. Despite the burgeoning literature in the field, the molecular mechanisms by which the microbiota impacts the body in health and disease remain largely unknown. In this review, we will discuss recent advancements in our understanding of the gut bacterial microbiota associated with inflammatory and immunological processes and the role they play in the autoimmune disease, systemic lupus erythematosus.     

Protective effects of quercetin treatment in a pristane-induced mouse model of lupus nephritis

Introduction: Lupus nephritis (LN) is one of the most severe complications of systemic lupus erythematosus. As murine models of LN are valuable tools to better understand its pathophysiology and to search for new effective treatments, we investigated the effects of the bioflavonoid quercetin on pristane-induced LN mice through histomorphological analyses.

Methods: Immunofluorescence and biochemical assays were used to evaluate the expression of markers of inflammation (interleukin-6, IL-6; tumour necrosis factor-α, TNF-α), oxidative stress (catalase, CAT; superoxide dismutase 1, SOD1; thiobarbituric acid reactive substances, TBARS), apoptosis (Bax), and fibrosis (transforming growth factor-β1, TGF-β1). Glomerular and tubular ultrastructure was analysed, and tissue messenger RNA of podocin, podoplanin and α3β1-integrin were quantified using the real-time polymerase chain reaction.

Results: Pristane-induced LN mice showed severe kidney injury, characterized by increased proteinuria, glomerular mesangial expansion and inflammation, high expression of the pro-fibrotic, apoptotic and prooxidant markers and reduction of antioxidants. In the kidney ultrastructure, foot process (FP) effacement, apoptotic mesangial cells and abnormal mitochondria with disrupted cristae were observed, along with suppressed tissue mRNA of podocin, podoplanin and α3β1-integrin. Treatment with quercetin in the pristane-induced LN mice model was nephroprotective, decreasing proteinuria levels and significantly lowering tissue expression of IL-6, TNF-α, TGF-β1, Bax and TBARS. Simultaneously, quercetin significantly increased CAT and SOD1 expressions in these mice. In addition, it was observed improvement of the kidney ultrastructure, and tissue mRNA of podocin, but not podoplanin and α3β1-integrin, was restored to the levels found in the control mice.

Conclusion: In conclusion, these findings provide experimental evidence of the renoprotective effects of quercetin in the pristane-induced LN mice model. We suggest that quercetin effectively ameliorates the kidney damage caused by pristane, a bioflavonoid to be further evaluated as a new therapeutic strategy in this disease.     

Breastfeeding and autoimmunity: Programing health from the beginning

Breast milk is not only a completely adapted nutrition source for the newborn but also an impressive array of immune‐active molecules that afford protection against infections and shape mucosal immune responses. Decisive imprinting events might be modulated during the first months of life with potential health long‐term effects, enhancing the importance of breastfeeding as a major influence on the immune system correct development and modifying disease susceptibility. The aim of this review was to clarify the link between breastfeeding and autoimmune diseases, inquiring the related mechanisms, based on data available in the literature. Being breastfed was associated with a lower incidence of diabetes, celiac disease, multiple sclerosis and asthma, explained by the protection against early infections, anti‐inflammatory properties, antigen‐specific tolerance induction, and regulation of infant's microbiome. The protective role of human milk in idiopathic juvenile arthritis, rheumatoid arthritis, and inflammatory bowel diseases remains controversial. On the other hand, the breastfeeding mother faces a health‐challenging period in life. High levels of prolactin may lead either to the development of autoimmune diseases in susceptible mothers or exacerbations of current immune‐mediated disorders. These features raise the question if mothers with autoimmune diseases, mainly systemic lupus erythematosus, should avoid breastfeeding.     

Tuftsin–phosphorylcholine (TPC) equally effective to methylprednisolone in ameliorating lupus nephritis in a mice model

The role of helminth treatment in autoimmune diseases is growing constantly. Systemic lupus erythematosus (SLE) is a multi‐system autoimmune disease with challenging treatment options. Tuftsin–phosphorylcholine (TPC) is a novel helminth‐based compound that modulates the host immune network. This study was conducted to evaluate the potential value of TPC in ameliorating lupus nephritis in a murine model and specifically to compare the efficacy of TPC to the existing first‐line therapy for SLE: corticosteroids (methylprednisolone). Lupus‐prone NZBxW/F₁mice were treated with TPC (5 µg/mouse), methylprednisolone (MP; 5 mg/body weight) or phosphate‐buffered saline (PBS) (control) three times per week once glomerulonephritis, defined as proteinuria of grade > 100 mg/dl, was established. Levels of anti‐dsDNA autoantibodies were evaluated by enzyme‐linked immunosorbent assay (ELISA), splenic cytokines were measured in vitro and the kidney microscopy was analysed following staining. TPC and MP treatments improved lupus nephritis significantly and prolonged survival in NZBxW/F₁ mice. TPC‐treated mice showed a significantly decreased level of proteinuria (P < 0·001) and anti‐dsDNA antibodies (P < 0·001) compared to PBS‐treated mice. Moreover, TPC and MP inhibited the production of the proinflammatory cytokines interferon IFN‐γ, interleukin IL‐1β and IL‐6 (P < 0·001) and enhanced expression of the anti‐inflammatory cytokine IL‐10 (P < 0·001). Finally, microscopy analysis of the kidneys demonstrated that TPC‐treated mice maintained normal structure equally to MP‐treated mice. These data indicate that the small molecule named TPC hinders lupus development in genetically lupus‐prone mice equally to methylprednisolone in most of the cases. Hence, TCP may be employed as a therapeutic potential for lupus nephritis.     

Alteration of Connexin43 expression in a rat model of obesity-related glomerulopathy

It is accepted that alteration of connexin43 (Cx43) expression in glomeruli is a common pathological response in several forms of kidney diseases. To date, however the change of the Cx43 expression in obesity-related glomerulopathy (ORG) has not been reported. In this study, the alteration of Cx43 expression in the glomeruli of rat with ORG was defined. Five-week-old rats were fed with high-fat diet for 18 weeks to establish the ORG model, then the histological change of glomeruli, the foot process effacement of podocyte, the markers for podocyte injury (nephrin,podocin and WT1) and Cx43 expression in glomeruli were examined respectively. The results demonstrated metabolic disorder, hyperinsulinemia, systemic inflammation and microalbuminuria in ORG rats. There was significant hypertrophy, glomerular expansion and inflammatory cell infiltration in the kidney of ORG rats compared to the control group. Significant foot process effacement of the podocyte in the glomeruli, nephrin loss and density reduction were shown in the ORG rats, and Cx43 expression was significant upregulated in glomeruli of ORG rats compared to the control group. The results indicate the correlation of overexpressed Cx43 with the obesity related renal inflammation and suggest that Cx43 might be a potential target in the development of obesity related glomerulopathy.     

提高系统性红斑狼疮患者的生活质量初探

系统性红斑狼疮是一种典型的自身免疫性疾病，目前无根治的方法。笔认为，在对患的全面教育中，要教育患认识疾病，消除恐惧,保持乐观心情。在饮食起居中，劳逸结合、生活规律及饮食调节，外出避免紫外线直接照射。用药指导中，做好坚持长期用药的思想准备，不能随意减少药量及停药。利用家庭与社会的理解和支持，使患有一个良好的养病和生活环境。成立狼疮病友会，使患之间能相互交流治疗信息，相互安慰和鼓励。     

狼疮抗凝物阳性患者临床数据横断面研究

目的对狼疮抗凝物阳性患者进行临床数据横断面研究。方法采用稀释的蝰蛇毒时间(dilute Russell viper venom time,dRVVT)和硅土凝固时间(silica clot time,SCT)进行血浆狼疮抗凝物检测。对患者的年龄、性别、疾病类型、抗磷脂抗体数据和抗凝用药情况进行分析。结果 LA阳性患者总体年龄为35(14～88)岁,其中男性为53(17～69)岁,女性为34(14～88)岁,两组间差异有统计学意义(U=5 658.5,P=0.002)。401例患者中包括结缔组织病182例(45.4%),病理妊娠及不孕症115例(28.7%),抗磷脂综合征44例(11.0%),静脉血栓栓塞症27例(6.7%),心脑血管疾病19例(4.7%),免疫性血小板减少症或全血细胞减少14例(3.5%);在341例结缔组织病、病理妊娠及不孕症和结缔组织病患者中,男性7例,女性334例;在46例静脉血栓栓塞症和心脑血管疾病患者中,男性37例,女性9例。401例患者中,dRVVT和SCT均呈阳性者166例(41.4%),仅dRVVT阳性者149例(37.2%),仅SCT阳性者86例(21.4%);结缔组织病在上述3组每组中的所占比例率均为最高(分别为49.4%、39.6%和47.7%)。双阳性组、dRVVT(+)组和SCT(+)组的各项抗磷脂抗体阳性率间差异均无统计学意义(P均0.05)。结论 LA阳性患者之间存在明显的年龄、性别和疾病类型特征差异,检测前应充分评估患者是否符合检测适应证,且应同时检测dRVVT和SCT以避免漏诊,此外,还要充分了解患者的用药情况,必要时选择适合的采血时间进行复检。