Mast cells and inflammatory kidney disease

Summary:  Inflammatory kidney disease involves a complex network of interactions between resident kidney and infiltrating hematopoietic cells. Mast cells (MCs) are constitutively found in kidneys in small numbers but increase considerably in various renal diseases. While this increase is usually interpreted as a sign of pathological involvement, recent data using MC-deficient animals show their ability to restore kidney homeostasis. In anti-glomerular basement membrane antibody-induced glomerulonephritis, MCs are protective by initiating repair and remodeling functions counteracting the devastating effects of glomerular injury. Protection may also include immunoregulatory capacities to limit autoreactive T-cell responses. MCs also control tubulointerstitial fibrosis by activating tissue remodeling and neutralizing fibrotic factors. Release of mediators by MCs during inflammation, however, could also promote unwanted responses that ultimately lead to destruction of kidney structure, as exemplified by data showing either protection or aggravation in related renal disease models. Similarly, while the action of proteases may initially be beneficial, the generation of fibrosis-promoting angiotensin II by chymase also shows the limits of adaptive responses to achieve homeostasis. Thus, it is likely the physiological context involving the interaction with other cells and inflammatory mediators that determines the final action of MCs in the development of kidney disease.     

The role of the innate immune response in autoimmune disease

Autoimmune diseases are the clinical correlate of a dysregulation of the immune system, involving multiple steps and multiple components of both the innate and the adaptive immune system. Innate immune cells are sensitive to a very limited repertoire of foreign "patterns" that bind to selective "pattern recognition receptors". In contrast, adaptive auto-reactive T or B cells bear receptors specific for antigens including "self" antigens and are rendered non-reactive by several "quality control" mechanisms. Under special conditions, activation of cells of the innate immune system can break the state of inactivity of auto-reactive cells of the adaptive immune system, thereby provoking autoimmune disease. Here we review examples to illustrate how innate immune activation influences autoimmune disease and point to the implications for the treatment of human autoimmune disease.     

Editorial overview: CD27 and (TNFR) relatives in the immune system: their role in health and disease

Relatives of the tumor necrosis factor receptor family are proving of crucial importance for an effective immune response as well as maintenance of homeostasis. The reviews in this issue summarise accumulating evidence for an emerging intricate interplay between these receptors themselves and with the CD28 pathway. It is hypothesised, that the lesser known CD27 receptor may overlap and synergise with CD40 and other relatives and may regulate the T–cell mediated activation cascade and control lymphocyte expansion by facilitating maturation and cell cycle progression. The diagnostic and prognostic value of the occurrence of these receptors and their soluble forms is becoming increasingly apparent, and recent data may herald new strategies for T cell manipulation via combinations of these receptors to ameliorate or prevent immune disease, coronary heart disease, transplant rejection, graft-versus-host disease, viral infections, and to promote tumor eradication.     

Autosomal recessive polycystic kidney disease

Summary Autosomal recessive polycystic kidney disease is a rare inherited disorder which usually becomes clinically manifest in early childhood, whereas autosomal dominant polycystic kidney disease usually is a disorder of adult onset. With increasing knowledge and improving diagnostic techniques, it becomes evident that the spectrum of both entities is much more variable than generally known. The presentation of autosomal recessive polycystic kidney disease at later ages and survival into adulthood have been reported. The diagnostic criteria, clinical course, genetics and differential diagnosis of autosomal recessive polycystic kidney disease will be presented.Abbreviations ADPKD, ARPKD autosomal dominant/recessive polycystic kidney disease - CHF congenital hepatic fibrosis     

Absence of ULK1 decreases AMPK activity in the kidney,leading to chronic kidney disease progression

AMP-activated protein kinase (AMPK) inactivation in chronic kidney disease (CKD) leads to energy status deterioration in the kidney, constituting the vicious cycle of CKD exacerbation. Unc-51-like kinase 1 (ULK1) is considered a downstream molecule of AMPK; however, it was recently reported that the activity of AMPK could be regulated by ULK1 conversely. We demonstrated that AMPK and ULK1 activities were decreased in the kidneys of CKD mice. However, whether and how ULK1 is involved in the underlying mechanism of CKD exacerbation remains unknown. In this study, we investigated the ULK1 involvement in CKD, using ULK1 knockout mice. The CKD model of Ulk1^−/− mice exhibited significantly exacerbated renal function and worsening renal fibrosis. In the kidneys of the CKD model of Ulk1^−/− mice, reduced AMPK and its downstream β-oxidation could be observed, leading to an energy deficit of increased AMP/ATP ratio. In addition, AMPK signaling in the kidney was reduced in control Ulk1^−/− mice with normal renal function compared to control wild-type mice, suggesting that ULK1 deficiency suppressed AMPK activity in the kidney. This study is the first to present ULK1 as a novel therapeutic target for CKD treatment, which regulates AMPK activity in the kidney.     

The kidney in Fabry's disease

Fabry disease (FD) is an X‐linked disease in which mutations of the GLA gene result in a deficiency of the enzyme α‐galactosidase A and subsequent progressive, intralysosomal deposition of undegraded glycosphingolipid products, primarily globotriaosylceramide, in multiple organs. Progressive nephropathy is one of the main features of FD and is marked by an insidious development, with an overall rate of progression of chronic kidney disease (CKD) very similar to diabetic nephropathy. Untreated patients usually develop end stage renal disease in their 50s. The decline in renal function in FD is adversely affected by male gender, advanced CKD, hypertension and, in particular, severe proteinuria. Enzyme replacement therapy (ERT) has been shown to slow the progression of Fabry nephropathy. The current consensus is that ERT should be started in all men and women with signs of renal involvement.     

The role of atorvastatin in regulating the immune response leading to vascular damage in a model of Kawasaki disease

Superantigens have been implicated in a number of diseases including Kawasaki disease (KD), a multi-system vasculitis resulting in coronary artery aneurysms. We have characterized a murine disease model in which coronary arteritis is induced by a novel superantigen found in Lactobacillus casei cell wall extract (LCWE). Using this animal model of KD, we have identified three pathogenic steps leading to coronary artery aneurysm formation. These steps include T cell activation and proliferation, production of the proinflammatory cytokine tumour necrosis factor (TNF)-α and up-regulation of matrix metalloproteinase 9 (MMP-9), an elastolytic protease. In addition to their cholesterol-lowering effects, 3-hydroxy-3-methylglutaryl (HMG) coenzyme A (CoA) reductase inhibitors (statins) have pleotropic immunomodulatory properties. Thus, we examined the effect of atorvastatin in modulating each of these three critical pathogenic processes leading to aneurysm formation in the disease model. Atorvastatin inhibited lymphocyte proliferation in response to superantigen stimulation in a dose-dependent manner. This inhibition was also observed for production of soluble mediators of inflammation including interleukin (IL)-2 and TNF-α. The inhibitory effect on proliferation was rescued completely by mevalonic acid, confirming that the mechanism responsible for this inhibitory activity on immune activation was inhibition of HMG-CoA reductase. Similarly, TNF-α-induced MMP-9 production was reduced in a dose-dependent manner in response to atorvastatin. Inhibition of extracellular-regulated kinase (ERK) phosphorylation appears to be the mechanism responsible for inhibition of MMP-9 production. In conclusion, atorvastatin is able to inhibit critical steps known to be important in the development of coronary aneurysms, suggesting that statins may have therapeutic benefit in patients with KD.     

临床药师在制定免疫球蛋白制剂治疗原发性免疫缺陷性疾病合理用药方案中的作用

对于接受某些药物治疗久治不愈、欲更换免疫球蛋白治疗方案的原发性免疫缺陷性疾病患者进行用药分析,是临床药师在制定和更换治疗方案中的重要职能.由于临床药师既能分析不同免疫球蛋白给药途径的差异,在治疗方案确立中通过分析患者的病史和用药史、不同剂型的药物特性、患者个体差异、药物剂量控制和因人而异的药物免疫耐受程度、患者的经济条件及患者个人喜好等因素来确立合理用药方案,因而临床药师在完善治疗方案、用药监测和更改治疗方案后的用药指导方面具有重要作用.因为临床药师参与治疗并能使治疗效果显著提升,所以免疫球蛋白的个性化治疗是未来抗体治疗的发展趋势,抗体治疗方案的制定过程离不开专业药学人员的参与.     

The impact of concurrent HIV and type II diabetes on immune maturation,immune regulation and immune activation

Chronic immune activation and inflammation are constant findings in people living with HIV (PLWH) and contribute to the risk of non‐AIDS‐related morbidities, including cardiovascular diseases (CVD). Type 2 diabetes (T2D) is also characterized by immune activation and inflammation. We aimed to investigate the impact of concurrent HIV infection and T2D on T‐cell subsets. The study included PLWH with T2D (HIV+T2D+, N = 25) and without T2D (HIV+T2D?, N = 25) and HIV‐negative controls with T2D (HIV?T2D+, N = 22) and without T2D (HIV?T2D?, N = 28). All PLWH in the study were receiving combination antiretroviral therapy. We examined T‐cell homeostasis by determining T‐cell subsets (immune maturation, immune regulation and immune activation) using flow cytometry. HIV+T2D? had lower proportion of Tc17 cells and higher proportion of apoptotic cells than HIV?T2D?. When comparing HIV+T2D+ and HIV+T2D? a lower proportion of CD4+ recent thymic emigrants (RTE) was found (p = 0.028). Furthermore, HIV+T2D+ had a higher proportion of non‐suppressive CD4+ Tregs compared to HIV+T2D? (p = 0.010). In conclusion, even in the setting of treated HIV infection, distinct immunological alterations are found. In PLWH with concomitant T2D, most alterations in T‐cell subsets were related to HIV and only few differences were found between PLWH with and without diabetes.     

The immune system's role in sepsis progression,resolution, and long-term outcome

Sepsis occurs when an infection exceeds local tissue containment and induces a series of dysregulated physiologic responses that result in organ dysfunction. A subset of patients with sepsis progress to septic shock, defined by profound circulatory, cellular, and metabolic abnormalities, and associated with a greater mortality. Historically, sepsis-induced organ dysfunction and lethality were attributed to the complex interplay between the initial inflammatory and later anti-inflammatory responses. With advances in intensive care medicine and goal-directed interventions, early 30-day sepsis mortality has diminished, only to steadily escalate long after “recovery” from acute events. As so many sepsis survivors succumb later to persistent, recurrent, nosocomial, and secondary infections, many investigators have turned their attention to the long-term sepsis-induced alterations in cellular immune function. Sepsis clearly alters the innate and adaptive immune responses for sustained periods of time after clinical recovery, with immune suppression, chronic inflammation, and persistence of bacterial representing such alterations. Understanding that sepsis-associated immune cell defects correlate with long-term mortality, more investigations have centered on the potential for immune modulatory therapy to improve long-term patient outcomes. These efforts are focused on more clearly defining and effectively reversing the persistent immune cell dysfunction associated with long-term sepsis mortality.     

活性维生素D在慢性肾脏病中的作用研究进展

慢性肾脏病(CKD)可以导致维生素D缺乏,而后者又可通过激活肾素-血管紧张素系统(RAS)等机制导致肾脏损伤的加重.体内外研究证明,活性维生素D及其类似物替代治疗可以延缓肾小球硬化和肾小管间质纤维化,具有肾脏保护作用,从而改善CKD患者预后,降低死亡率.     

Hepatorenal findings in obligate heterozygotes for autosomal recessive polycystic kidney disease

Autosomal recessive polycystic kidney disease (ARPKD), characterized by progressive cystic degeneration of the kidneys and congenital hepatic fibrosis (CHF), is the most common childhood onset ciliopathy, with an estimated frequency of 1 in 20,000 births. It is caused by mutations in PKHD1. The carrier frequency for ARPKD in the general population is estimated at 1 in 70. Given the recessive inheritance pattern, individuals who are heterozygous for PKHD1 mutations are not expected to have clinical findings. We performed ultrasound (USG) evaluations on 110 parents from 64 independent ARPKD families and identified increased medullary echogenicity in 6 (5.5%) and multiple small liver cysts in 10 parents (9%). All ARPKD parents with these abnormal imaging findings were asymptomatic; kidney and liver function tests were unremarkable. Complete sequencing of PKHD1 in the 16 ARPKD parents with abnormal imaging confirmed the mutation transmitted to the proband, but did not reveal any other pathogenic variants. Our data suggest that carrier status for ARPKD is a predisposition to polycystic liver disease and renal involvement associated with increased medullary echogenicity on USG. Whether some of these individuals become symptomatic as they age remains to be determined.     

Maturation of the enteric mucosal innate immune system during the postnatal period

The innate immune system instructs the host on microbial exposure and infection. This information is critical to mount a protective innate and adaptive host response to microbial challenge, but is also involved in homeostatic and adaptive processes that adjust the organism to meet environmental requirements. This is of particular importance for the neonatal host during the transition from the protected fetal life to the intense and dynamic postnatal interaction with commensal and pathogenic microorganisms. Here, we discuss both adaptive and developmental mechanisms of the mucosal innate immune system that prevent inappropriate stimulation and facilitate establishment of a stable homeostatic host–microbial interaction after birth.     

单核苷酸多态性和免疫细胞在糖尿病肾脏疾病中的研究进展

糖尿病肾脏疾病具有很明显的家族聚集性及种族差异,已经确定了一些与糖尿病肾脏疾病易感性有关的单核苷酸多态性(SNPs),尤其是吞噬和细胞运动性1基因(ELMO1)和氯化钠共转运蛋白基因(SLC12A3),与中国人群糖尿病肾脏疾病发展进展有关;同时炎性反应在糖尿病肾脏疾病的发生和发展中起着关键作用,其中细胞和2型固有淋巴细胞(ILC2)分泌炎性因子促进肾脏慢性炎性反应及纤维化。     

The effects of the microbiota on the host immune system

Abstract

The human gastrointestinal track harbors hundreds of species of commensal organisms, collectively known as microbiota. The composition of the intestinal microbiota is changeable by various factors, such as host genotype, diet, antibiotics, pathogen infections, among others. Changes in these factors can cause microbiome disruption known as dysbiosis, leading to the outgrowth of potential pathogenic bacteria or decrease in the number of beneficial bacteria. Dysbiosis has been implicated in numerous inflammatory and autoimmune diseases. This review is focused on host–microbiota interactions, specifically on influence of bacterial-derived signals on immune cell function and the mechanisms by which these signals modulate the development and progression of inflammatory and autoimmune diseases.