Clinical features and management of primary biliary cirrhosis

Primary biliary cirrhosis(PBC),which is characterised by progressive destruction of intrahepatic bile ducts,is not a rare disease since both prevalence and incidence are increasing during the last years mainly due to the improvement of case finding strategies.The prognosis of the disease has improved due to both the recognition of earlier and indolent cases,and to the wide use of ursodeoxycholic acid(UDCA).New indicators of prog-nosis are available that will be useful especially for the growing number of patients with less severe disease.Most patients are asymptomatic at presentation.Pruri-tus may represent the most distressing symptom and,when UDCA is ineffective,cholestyramine represents the mainstay of treatment.Complications of long-standing cholestasis may be clinically relevant only in very ad-vanced stages.Available data on the effects of UDCA on clinically relevant end points clearly indicate that the drug is able to slow but not to halt the progression of the disease while,in advanced stages,the only thera-peutic option remains liver transplantation.

Immune-mediated bile duct injury:The case of primary biliary cirrhosis

Autoimmune cholangitis would be the appropriate name to define the immune-mediated bile duct injury following the breakdown of tolerance to mitochondrial proteins and the appearance of serum autoantibodies and autoreactive T cells.Nevertheless,the conditionis universally named primary biliary cirrhosis(PBC).The disease etiology and pathogenesis remain largely unknown despite the proposed lines of evidence.One twin study and numerous epidemiology reportssuggest that both a susceptible genetic background and environmental factors determine disease onsetwhile a recent genome-wide association study proposed highly significant associations with several commongenetic polymorphisms in subgroups of patients.Specific infectious agents and chemicals may contribute to the disease onset and perpetuation in a geneticallysusceptible host,possibly through molecular mimicry.Importantly,several murine models have been proposed and include strains in which PBC is genetically determined or induced by immunization with chemicals and bacteria.From a pathogenetic standpoint,new exciting data have demonstrated the unique apoptotic features of bile duct cells that allow the mitochondrial autoantigens to be taken up in their intact form within apoptotic blebs.We are convinced that the application of the most recent molecular techniques will soon pro-vide developments in PBC etiology and pathogenesis with likely implications in diagnostics and therapeutics.

2021皮肤红斑狼疮的诊断、治疗和长期管理指南

皮肤红斑狼疮(CLE)是一种炎症性自身免疫性疾病,其分型较多,包括急性、亚急性、慢性和间歇性CLE。其中,慢性CLE可以进一步分为红斑狼疮(LE)的几个亚型,如盘状LE、疣状LE、深在性LE、冻疮样LE和Blaschko线状LE等。为了给皮肤科医生和风湿科医生提供CLE的诊断、治疗和长期管理的实用指导建议,本证据和共识指南根据卫生保健实践指南的报告条目(国际RIGHT工作组)目录编制,并在国际实践指南注册平台注册。在亚洲皮肤科学会(ADA)、亚洲皮肤病性病学会(AADV)以及中华医学会皮肤性病学分会(CSD)红斑狼疮研究中心的共同努力下,来自亚洲、美洲、欧洲等16个国家或地区的25名皮肤科医生、7名风湿科医生、1名红斑狼疮领域专家和2名方法学家参与了本指南的制定。所有建议均取得了32名医生中至少80%的同意。作为共识,CLE的诊断主要基于临床和组织病理学表现的评估,并且通过对全身多系统损伤的评估,排除系统性红斑狼疮(SLE)。外用糖皮质激素和钙调磷酸酶抑制剂是局部CLE的一线治疗。对于泛发或严重的CLE皮损和/或局部耐药的病例,可以合并全身治疗,包括抗疟药和/或短期全身使用糖皮质激素。值得注意的是,抗疟药是所有类型CLE的一线全身治疗药物,同样可用于妊娠期患者和儿童。二线治疗用药包括沙利度胺、类维生素A类药物、氨苯砜和甲氨蝶呤,而霉酚酸酯是三线治疗用药。最后,脉冲染料激光或手术可作为四线治疗,用于局部以及发生在不可修饰部位的慢性、难治性CLE皮损。贝利尤单抗亦可作为四线治疗用药,用于活动性SLE患者的泛发性CLE皮损或糖皮质激素逐渐减量期间复发的急性CLE。对于疾病的管理,患者教育和长期随访是必要的。建议在每次随访时适当评估疾病活动度、皮肤和其他器官损伤、生活质量、合并症及可能发生的不良事件。

The microbiome and autoimmunity: a paradigm from the gut–liver axis

Microbial cells significantly outnumber human cells in the body,and the microbial flora at mucosal sites are shaped by environmental factors and,less intuitively,act on host immune responses,as demonstrated by experimental data in germ-free and gnotobiotic studies.Our understanding of this link stems from the established connection between infectious bacteria and immune tolerance breakdown,as observed in rheumatic fever triggered by Streptococci via molecular mimicry,epitope spread and bystander effects.The availability of high-throughput techniques has significantly advanced our capacity to sequence the microbiome and demonstrated variable degrees of dysbiosis in numerous autoimmune diseases,including rheumatoid arthritis,type 1 diabetes,multiple sclerosis and autoimmune liver disease.It remains unknown whether the observed differences are related to the disease pathogenesis or follow the therapeutic and inflammatory changes and are thus mere epiphenomena.In fact,there are only limited data on the molecular mechanisms linking the microbiota to autoimmunity,and microbial therapeutics is being investigated to prevent or halt autoimmune diseases.As a putative mechanism,it is of particular interest that the apoptosis of intestinal epithelial cells in response to microbial stimuli enables the presentation of self-antigens,giving rise to the differentiation of autoreactive Th17 cells and other T helper cells.This comprehensive review will illustrate the data demonstrating the crosstalk between intestinal microbiome and host innate and adaptive immunity,with an emphasis on how dysbiosis may influence systemic autoimmunity.In particular,a gut–liver axis involving the intestinal microbiome and hepatic autoimmunity is elucidated as a paradigm,considering its anatomic and physiological connections.

Experimental evidence on the immunopathogenesis of primary biliary cirrhosis

Primary biliary cirrhosis(PBC)is a chronic cholestatic liver disease for which an autoimmune pathogenesis is supported by clinical and experimental data,including the presence of autoantibodies and autoreactive T cells.The etiology remains to be determined,yet data suggest that both a susceptible genetic background and unknown environmental factors determine disease onset.Multiple infectious and chemical candidates have been proposed to trigger the disease in a genetically susceptible host,mostly by molecular mimicry.Most recently,several murine models have been reported,including genetically determined models as well as models induced by immunization with xenobiotics and bacteria.

The epigenetics of autoimmunity

The etiology of autoimmune diseases remains largely unknown.Concordance rates in monozygotic twins are lower than 50% while genome-wide association studies propose numerous significant associations representing only a minority of patients.These lines of evidence strongly support other complementary mechanisms involved in the regulation of genes expression ultimately causing overt autoimmunity.Alterations in the post-translational modification of histones and DNA methylation are the two major epigenetic mechanisms that may potentially cause a breakdown of immune tolerance and the perpetuation of autoimmune diseases.In recent years,several studies both in clinical settings and experimental models proposed that the epigenome may hold the key to a better understanding of autoimmunity initiation and perpetuation.More specifically,data support the impact of epigenetic changes in systemic lupus erythematosus,rheumatoid arthritis,multiple sclerosis and other autoimmune diseases,in some cases based on mechanistical observations.We herein discuss what we currently know and what we expect will come in the next future.Ultimately,epigenetic treatments already being used in oncology may soon prove beneficial also in autoimmune diseases.

The effects of Spirulina on anemia and immune function in senior citizens

Anemia and immunological dysfunction(i.e.immunosenescence)are commonly found in older subjects and nutritional approaches are sought to counteract these phenomena.Spirulina is a filamentous and multicellular bule-green alga capable of reducing inflammation and also manifesting antioxidant effects.We hypothesized that Spirulina may ameliorate anemia and immunosenescence in senior citizens with a history of anemia.We enrolled 40 volunteers of both sexes with an age of 50 years or older who had no history of major chronic diseases.Participants took a Spirulina supplementation for 12 weeks and were administered comprehensive dietary questionnaires to determine their nutritional regimen during the study.Complete cell count(CCC)and indoleamine 2,3-dioxygenase(IDO)enzyme activity,as a sign of immune function,were determined at baseline and weeks 6 and 12 of supplementation.Thirty study participants completed the entire study and the data obtained were analyzed.Over the 12-week study period,there was a steady increase in average values of mean corpuscular hemoglobin in subjects of both sexes.In addition,mean corpuscular volume and mean corpuscular hemoglobin concentration also increased in male participants.Older women appeared to benefit more rapidly from Spirulina supplements.Similarly,the majority of subjects manifested increased IDO activity and white blood cell count at 6 and 12 weeks of Spirulina supplementation.Spirulina may ameliorate anemia and immunosenescence in older subjects.We encourage large human studies to determine whether this safe supplement could prove beneficial in randomized clinical trials.

The elegance of a macrophage

In the latest issue of Nature Immunology,Piccolo et al.1 elegantly explored the effect of coexisting interferon-γ(IFN-γ)and interleukin 4(IL-4)antagonistic signals on macrophage transcriptional and epigenetic profiles and,interestingly,identified a plastic cross-talk as opposed to mutually exclusive programs between M1 and M2 polarized macrophages.Their results support the fascinating hypothesis that transcriptional and epigenetic reprogramming overcame genetics to drive the evolution of eukaryotic organisms.A rapid reshaping of chromatin acetylation redirected the expression of hundreds of genes under the control of a few transcription factors in response to two coexisting but opposing signals that indicated inflammation and its resolution simultaneously.

The long and latent road to autoimmunity

Autoimmune diseases affect nearly 5%of the general population,yet etiology remains poorly understood.Genomic factors are clearly necessary but remain insufficient to explain the loss of tolerance;environmental and stochastic factors fill this gap.This paradigm is indicated by the concordance rates(ranging between 4 and 63%)for autoimmune diseases among monozygotic twins,who share an identical genome,compared to the invariably lower rates in dizygotic twins.The term“exposome”cumulatively refers to the non-hereditary(i.e.,environmental)factors that account for the remaining susceptibility and include endogenous factors such as hormones.Accumulating evidence suggests that exposure to infections,drugs,vaccines,and chemicals may contribute to the loss of tolerance.The mechanisms by which environmental factors can shape the immune system to generate autoimmunity include molecular mimicry,self-antigen modification,bystander activation,and immune reactivity modulation.In all cases,we should first consider the prolonged time between an environmental trigger and the appearance of autoreactivity and subsequent clinical disease.In this special issue,several excellent reviews discuss the potential mechanisms linking environmental factors and autoimmunity.