Geoepidemiology, gender and autoimmune disease

Autoimmune diseases include more than 70 different disorders affecting over 5% of the population of the Western countries. They are mainly characterized by female predominance and have great impact on the quality of life of affected subjects. It is generally accepted that ADs are the result of a complex interaction between genetic and environmental factors; however the mechanisms involved in the loss of tolerance remain unknown. Studying the distribution of these conditions across various global regions and ethnic groups by means of geoepidemiology might readily provide epidemiological data and also advance our understanding of their pathogenesis. Indeed, geoepidemiology demonstrates that genetic susceptibility interacts with lifestyle and environmental factors, which include socioeconomic status, infectious agents (triggering or protective agents), environmental pollutants, and vitamin D (dependent on sunlight exposure), in determining the risk of developing autoimmunity and in the understanding of their female prevalence. To properly understand the geoepidemiology of human autoimmunity, it is important to consider the many pleiotropic factors which lead to its initiation. In most studies the focus has been on genetics and environment. However, in this review the focus is primarily on gender. Overall, autoimmune diseases are well known to have female predominance, but there is significant variation in geographic area. Further, the mechanisms that influence female predominance are relatively unknown. Hence the attempt in this review is to focus on these critical issues.     

Autoantibodies in autoimmune liver diseases

Autoimmune hepatitis is a chronic hepatitis of unknown etiology characterized by clinical, histological, and immunological features, generally including circulating autoantibodies and a high total serum and/or gamma globulin. Liver‐related autoantibodies are very significant for the correct diagnosis and classification of autoimmune liver diseases (AILD), namely autoimmune hepatitis types 1 and 2 (AIH‐1 and 2), primary biliary cirrhosis (PBC), and the sclerosing cholangitis types in adults and children. This article intends to review recent studies that investigate autoantibodies in autoimmune liver diseases from a microbiological perspective.     

B cells and autoimmune liver diseases

Autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are the three major autoimmune diseases affecting the liver. They are all characterized by the presence of a variety of autoantibodies, some of which are found in all three diseases, whereas others are restricted to one or two of them or are even specific for the particular disease. In this review we will first provide details of the serological features of these three autoimmune diseases that target the liver. In addition, we will highlight the possible pathogenic roles of autoreactive B cells, focusing on their immunological functions as autoantibody producing cells and as antigen-presenting cells for T cell priming. As well, we will describe the contribution of toll-like receptor (TLR) signaling to the activation of autoimmune B cells and the putative role of defects in regulatory T cell function in the development of autoimmune liver diseases.     

多种自身抗体联合检测对自身免疫性肝病的诊断价值

目的：分析各种肝病患者多种自身抗体的检出率,探讨其对自身免疫性肝病（autoimmune liver diseases,ALD）的诊断价值。方法：根据临床诊断将患者分为ALD组（n=96）、病毒性肝炎组（n=135,包括75例乙型肝炎,65例丙型肝炎）,另取62例健康体检者作为健康对照组（n=62）;其中,ALD组又分为自身免疫性肝炎组（AIH组,n=36）、原发性胆汁性肝硬化组（PBC组,n=58）、原发性硬化性胆管炎组（PSC组,n=2）。用间接免疫荧光法检测上述各组的抗核抗体（antinuclear antibodies,ANA）、抗平滑肌抗体（anti-smooth muscle antibodies,ASMA）、抗线粒体抗体（antimitochondrial ant-ibodies,AMA）;用Western印迹法检测抗肝肾微粒体Ⅰ型抗体（anti liver-kidney microsomal antibody Type 1,LKM-1）和抗线粒体Ⅱ型抗体（subtype of AMA,AMA-M2）、抗可溶性肝抗原/胰抗原抗体（soluble liver antigen/liver pancreas,SLA/LP）、抗肝细胞溶质抗原Ⅰ型抗体（antihepatocyte cytosol antigen Type 1,LC-1）。结果：AIH组ANA阳性率（69.4%）和PBC组ANA阳性率（87.9%）显著高于病毒性肝炎组（37.3%）和健康对照组（4.8%）（均P〈0.01）;AIH组ASMA,LKM-1,SLA/LP,LC-1阳性率（44.4%,11.1%,2.8%,8.3%）显著高于病毒性肝炎组（1.3%,1.7%,0,0）和健康对照组（均P〈0.01）;PBC组AMA-M2阳性率（91.3%）显著高于病毒性肝炎组（1.3%）和健康对照组（0）（均P〈0.01）。结论：联合检测ANA,ASMA,LKM-1,SLA/LP,LC-1和AMA-M2等自身抗体可提高ALD诊断的灵敏性和特异性,且对ALD分型、诊疗具有重要意义。     

In situ mass spectrometry of autoimmune liver diseases

Primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and autoimmune hepatitis (AIH) are the major forms of autoimmune liver diseases each characterized by the destruction of a specific liver cell type and the presence of differing auto-antibodies. We took a proteomic approach utilizing in situ matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS) to obtain profiles directly from liver samples of patients with PBC, PSC, AIH and controls. The ability to precisely localize the region for acquisition of MALDI MS allowed us to obtain profiles from bile ducts, inflammatory infiltrates and hepatocytes from each biopsy sample. Analysis tools developed to identify peaks and compare peaks across diseases and cell types were used to develop models to classify the samples. Using an initial set of testing samples from PBC patients and controls, we identified unique peaks present in bile ducts, inflammatory infiltrates and hepatocytes that could classify samples in a validation cohort with 88-91% accuracy. Interestingly, profiles of PSC and AIH did not differ significantly from PBC. Identification of proteins in these peaks may represent novel autoantigens or effector molecules. These findings illustrate the potential of a proteomic approach to autoimmune diseases with in situ MALDI MS.     

Markers of autoimmune liver diseases in postmenopausal women with osteoporosis

INTRODUCTION:

Osteoporosis is a common complication of chronic liver diseases. However, there is limited information about autoimmune liver diseases as a factor of secondary osteoporosis. Therefore, we aimed to investigate the autoantibodies of autoimmune liver diseases in patients with osteoporosis.

METHODS:

One hundred fifty female patients with postmenopausal osteoporosis were included. Bone mineral density was measured by dual energy X‐ray absorptiometry. We analysized autoantibodies including antinuclear antibodies, liver membrane antibodies, anti‐liver/kidney microsomal autoantibodies1, liver‐specific protein, anti‐smooth muscle antibodies, and anti‐mitochondrial antibodies by indirect immunofluorescence. Serum was assayed for the levels of aminotransferases.

RESULTS:

The mean age of the patients was 63,13±8,6 years. The mean values of L1‐L4 T‐scores and femur total T‐scores were ‐3,08±0,58 and ‐1,53±0,81, respectively. Among the 150 patients with osteoporosis, 14 (9.3%) were antinuclear antibodies, four (2.7%) were liver membrane antibodies, three (2.0%) were anti‐liver/kidney microsomal autoantibodies1, and two (1.3%) were liver‐specific protein positive. None of the patients had anti‐mitochondrial antibodies or smooth muscle antibodies positivity. The mean values of levels of aminotransferases were within normal range.

CONCLUSIONS:

The presence of liver membrane antibodies, liver‐specific protein, and anti‐liver/kidney microsomal autoantibodies1 has permitted us to see that there may be some suspicious clues of autoimmune liver diseases in patients with osteoporosis as a secondary risk factor. On the other hand, there is a need for comprehensive studies with a larger sample size and studies designed to compare the results with a normal population to understand the clinical importance of our findings.     

IL-17 and IL-17-producing cells and liver diseases,with focus on autoimmune liver diseases

The pro-inflammatory cytokine interleukin(IL)-17 and IL-17-producing cells are important players in the pathogenesis of many autoimmune / inflammatory diseases. More recently, they have been associated with liver diseases. This review first describes the general knowledge on IL-17 and IL-17 producing cells. The second part describes the in vitro and in vivo effects of IL-17 on liver cells and the contribution of IL-17 producing cells to liver diseases. IL-17 induces immune cell infiltration and liver damage driving to hepatic inflammation and fibrosis and contributes to autoimmune liver diseases. The circulating levels of IL-17 and the frequency of IL-17-producing cells are elevated in a variety of acute and chronic liver diseases. The last part focuses on the effects of IL-17 deletion or neutralization in various murine models. Some of these observed beneficial effects suggest that targeting the IL-17 axis could be a new therapeutic strategy to prevent chronicity and progression of various liver diseases.     

Anti-Saccharomyces cerevisiae antibodies (ASCA) and autoimmune liver diseases

Antibodies to the baker's yeast Saccharomyces cerevisiae (ASCA), recently proposed as a serological marker of Crohn's disease, have also been detected in other autoimmune disorders. The aim of this study was to determine prevalence and clinical significance of ASCA in autoimmune liver disease. The presence of IgG and IgA ASCA was evaluated using a commercially available immunoassay in 215 patients with autoimmune liver disease (primary biliary cirrhosis, PBC, 123 cases; autoimmune hepatitis, AIH, 67 cases; primary sclerosing cholangitis, PSC, 25 cases), 48 with inflammatory bowel disease and 19 healthy blood donors. Anti neutrophil cytoplasmic antibodies with the perinuclear pattern (p-ANCA) were assessed by indirect immunofluorescence in PSC patients. The main clinical and biochemical parameters between ASCA-positive and negative patients were analysed and compared. ASCA are predominant in Crohn's disease (70%); among liver patients, PSC and AMA-negative PBC show the highest ASCA prevalence (53% and 44%). In PBC ASCA correlate with higher levels of circulating IgA (P < 0.05). In PSC the detection of either ASCA or p-ANCA is neither associated with any clinical or biochemical feature, nor with an underlying inflammatory bowel disease. ASCA can not be considered an additional serological marker of autoimmune liver disease, but the possibility of detecting such a reactivity in autoimmune liver disorders should be considered; their correlation with elevated IgA in PBC suggests that ASCA may be an indirect sign of enhanced mucosal immunity; in PSC patients neither ASCA nor p-ANCA predict the occurrence of a concomitant inflammatory bowel disease.     

161例自身免疫性肝病患者相关自身抗体检测的临床研究

目的探讨自身抗体检测对自身免疫性肝病(AILD)诊断的临床意义。方法 161例自身免疫性肝病[其中自身免疫性肝炎(AIH)68例、原发性胆汁性肝硬化(PBC)41例和原发性硬化性胆管炎(PSC)52例]、276例病毒性肝炎患者和50例健康体检者采用间接免疫荧光法(IIF)检测抗核抗体(ANA)、抗中性粒细胞胞浆抗体(ANCA)、抗平滑肌抗体(SMA)和抗线粒体抗体(AMA)等自身抗体,采用酶联免疫吸附法(ELISA)检测抗MPO抗体,并对其结果进行回顾性分析。结果 161例AILD检测ANA、ANCA、SMA、抗MPO抗体及AMA结果显示其阳性率分别为42.9%、46.6%、29.2%、30.1%、42.2%,与病毒性肝炎及对照组比较,均P<0.01。各种肝病对自身抗体的检测结果显示AIH较高;AIH中ANCA及p-ANCA检出率与其他肝病组及对照组相比,除PSC外P<0.01,有非常显著意义。结论肝病相关自身抗体的联合检测对自身免疫性肝病的检出、诊断、鉴别诊断、临床分型有重要临床价值,对提高自身免疫性肝病在临床上同病毒性肝炎鉴别诊断和指导治疗有着非常重要的意义。     

肝抗原自身抗体在自身免疫性肝病诊断中的意义

目的 探讨肝抗原自身抗体在自身免疫性肝病患者血清中的阳性率。方法 将患者分为3组：①自身免疫性肝病组，包括自身免疫性肝炎(AIH)、原发性胆汁性肝硬化(PBC)，原发性硬化性胆管炎(PSC)。②各类病毒性肝炎组；③不明原因肝损伤组。分别用间接免疫荧光法、免疫印迹法检测肝抗原(SAL/LP、LKM-1、LC-1、AMA-M2)自身抗体。结果 抗SLP／LP抗体在AIH患者血清中阳性率为46．4％，明显高于LKM-1(13．3％)、LC-1(0．O％)及AMA-M2(13．3％)抗体，并且在病毒性肝炎患者血清中呈阴性反应。抗AMA-M2抗体在PBC患者血清中阳性率达95．0％。不明原因肝损伤组患者中有10．0％的AMA-M2抗体阳性。结论 抗SLA/LP抗体对AIH具有特异性，肝抗原自身抗体的检测将有助于自身免疫性肝病患者的诊断及治疗。     

Decreased serum DNase1-activity in patients with autoimmune liver diseases

Deoxyribonuclease1 (DNase1) is involved in chromatin degradation of apoptotic cells. Its deficiency results in accumulation of self-DNA, which in turn may induce inflammation and autoimmunity. We assessed for the first time serum DNase1-activity in a large consecutive cohort of treatment-naïve patients with autoimmune liver diseases (ALD). DNase1-activity was determined by single radial enzyme-diffusion (SRED) at diagnosis of 224 patients with autoimmune hepatitis (AIH), 249 with primary biliary cirrhosis (PBC) and 36 with primary sclerosing cholangitis (PSC). Sera from 146 patients with chronic hepatitis B or C, 140 with nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NAFLD/NASH) and 114 healthy individuals served as disease and healthy controls. Available serum samples during remission from 50 AIH and 39 PBC patients were also investigated by paired analyzes. DNase1-activity was significantly lower in AIH, PBC and PSC compared to viral hepatitis (p?p?p?=?0.03), NAFLD/NASH (p?p?p?p?1400?mg/dl; p?p?p?p?=?0.008). In PSC, DNase1-activity was inversely associated with alkaline phosphatase (ALP) (p?p?p?相似文献   

Novel insights into autoimmune liver diseases provided by genome-wide association studies

Autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are complex disorders, resulting from the interaction of genetic and environmental factors. For many years, investigators have attempted to delineate the genetic architecture of these conditions, aiming to elucidate disease pathogenesis and identify molecular targets for pharmacotherapy. Early genetic studies consisted of HLA association studies and non-HLA candidate gene association studies, designed to identify association with selected HLA or non-HLA loci. HLA association studies identified HLA risk loci that are now well-established. Non-HLA candidate gene studies were less fruitful because they were mostly underpowered to detect modest effects and were frequently designed to investigate one or two functional polymorphisms, meaning that gene coverage was poor. Furthermore, weak associations detected in one small cohort were often never validated. If replication studies were undertaken, the results were often conflicting. More recently, a series of genome-wide association studies (GWAS) and related study designs have evaluated the impact of common genetic variants (frequency >5% in the general population) across the entire genome. These studies have identified several non-HLA risk loci for autoimmune liver disease. The majority of risk loci detected are similar to those of non-hepatic immune-mediated diseases, suggesting that outcomes from GWAS and related genetic studies reflect broad phenotypic themes rather than traditional clinical conditions. The specific genetic basis of these PBC and PSC associated inflammatory themes as determined by GWAS is described and discussed in the context of interacting genetic and non-genetic (including environmental) factors.     

自身抗体测定在临床自身免疫性肝病中的作用和诊断意义

自身抗体的检测对自身免疫性肝病分型、诊断、鉴别诊断、治疗、预后及提高其检出率均具重要价值。但实践应用中应结合受检者的临床表现及其它诊疗程序等进行综合分析和判断。     

Immunoregulation of autoimmune diseases

Since the discovery of human leukocyte antigen (HLA) as a genetic system, the search for the biological function of HLA molecules has been a very intense and attractive area of immunological research. It has been a major factor in the development of our understanding of the role of T cells in the initiation and regulation of autoimmune diseases. The currently increasing incidences of chronic inflammatory diseases, such as allergies but also several autoimmune diseases, possibly due to our Westernized modern life-style, are asking for novel intervention or prevention strategies. Heat shock proteins (or stress proteins) can be an example of relevant microbial antigens with an intrinsic capacity to trigger anti-inflammatory T cell regulation. Heat shock proteins may be part of an ancient system, which includes several stress-induced self-antigens, seen by a self-protective immune system. Peptide-based intervention, including clinical trials with HSP60 and HSP70 peptides, is now an area of intensive clinical research.     

Presence of high avidity anticardiolipin antibodies in patients with autoimmune cholestatic liver diseases

We studied the prevalence and clinical significance of anticardiolipin antibodies (aCL) in primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) as similar data are missing. Ninety-nine PBC patients, 41 PSC, 228 HCV, 50 HBV, 111 with other non-viral and non-autoimmune liver disorders and 267 healthy were investigated. In order to evaluate the avidity of aCL, urea 2 M was used. IgG and/or IgM aCL were detected in 40% of PBC and PSC patients, in 26.2% of disease controls (P < 0.05) and 2.25% of healthy (P < 0.05). In PBC, IgG aCL associated with presence of cirrhosis, increased Mayo risk score and thrombocytopenia, while in PSC with longer disease duration and biochemical activity. Anti-beta2-GPI was detected in only three patients. Both in PBC and PSC, resistance of aCL to urea was high, similar to that observed in antiphospholipid syndrome (APS). We demonstrated a significantly higher prevalence of aCL in PBC and PSC compared to other liver diseases and healthy. aCL were associated with more severe disease in PBC and biochemical activity in PSC, but they rather seem to be "non-pathogenic" (co-factor-independent). However, their avidity was comparable with that of APS, indicating the need for prospective studies in order to address whether aCL in PBC and PSC may contribute to APS development or the progression of hepatic disease.     

Geoepidemiology of COPD and idiopathic pulmonary fibrosis

Progress in improving patient outcomes and advancing therapeutics in chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) is hampered by phenotypic heterogeneity and variable responsiveness to clinical interventions that are not fully explained by currently held disease paradigms for COPD and IPF. Although these chronic lung diseases differ in their geoepidemiology and immunopathogenesis, emerging evidence suggest that organ-specific autoimmunity may underlie subphenotypes of COPD and IPF. In particular, the links to tobacco smoking, diet, gender, and environment are explored in this review. We also highlight potential mechanisms that could guide future investigations in both laboratory and clinical settings. A paradigm shift is needed in how we think about COPD and IPF, based on geoepidemiology and a broader understanding of disease pathogenesis that may ultimately lead to new therapies and improved patient outcomes.