Immunological tolerance and autoimmunity

Immunological tolerance is a complex series of mechanisms that impair the immune system to mount responses against self antigens. Central tolerance occurs when immature lymphocytes encounter self antigens in the primary lymphoid organs, and consequently they die or become unreactive. Peripheral tolerance occurs when mature lymphocytes, escaped from negative selection during ontogeny, encounter self antigens in secondary lymphoid organs and undergo anergy, deletion or suppression. A heterogeneous family of T regulatory cells has recently been identified, which have been found to play an important role in suppressing immune responses against self. Failure or breakdown of immunological tolerance results in autoimmunity and autoimmune diseases. Such events are related to both genetic and environmental factors, the latter being mainly represented by infections. Infectious agents can indeed promote autoimmune responses either by inducing tissue inflammation and therefore an unintended bystander activation of autoreactive T cells, or by promoting T cell responses to microbial epitopes that cross react against self peptides.     

Helicobacter pylori infection and other bacteria in pancreatic cancer and autoimmune pancreatitis

Helicobacter pylori (H. pylori) is an infectious agent influencing as much as 50% of the world’s population. It is the causative agent for several diseases, most especially gastric and duodenal peptic ulcer, gastric adenocarcinoma and mucosa-associated lymphoid tissue lymphoma of the stomach. A number of other, extragastric manifestations also are associated with H. pylori infection. These include neurological disorders, such as Alzheimer’s disease, demyelinating multiple sclerosis and Parkinson’s disease. There is also evidence for a relationship between H. pylori infection and such dermatological diseases as psoriasis and rosacea as well as a connection with infection and open-angle glaucoma. Generally little is known about the relationship between H. pylori infection and diseases of the pancreas. Most evidence about H. pylori and its potential role in the development of pancreatic diseases concerns pancreatic adenocarcinoma and autoimmune forms of chronic pancreatitis. There is data (albeit not fully consistent) indicating modestly increased pancreatic cancer risk in H. pylori-positive patients. The pathogenetic mechanism of this increase is not yet fully elucidated, but several theories have been proposed. Reduction of antral D-cells in H. pylori-positive patients causes a suppression of somatostatin secretion that, in turn, stimulates increased secretin secretion. That stimulates pancreatic growth and thus increases the risk of carcinogenesis. Alternatively, H. pylori, as a part of microbiome dysbiosis and the so-called oncobiome, is proven to be associated with pancreatic adenocarcinoma development via the promotion of cellular proliferation. The role of H. pylori in the inflammation characteristic of autoimmune pancreatitis seems to be explained by a mechanism of molecular mimicry among several proteins (mostly enzymes) of H. pylori and pancreatic tissue. Patients with autoimmune pancreatitis often show positivity for antibodies against H. pylori proteins. H. pylori, as a part of microbiome dysbiosis, also is viewed as a potential trigger of autoimmune inflammation of the pancreas. It is precisely these relationships (and associated equivocal conclusions) that constitute a center of attention among pancreatologists, immunologists and pathologists. In order to obtain clear and valid results, more studies on sufficiently large cohorts of patients are needed. The topic is itself sufficiently significant to draw the interest of clinicians and inspire further systematic research. Next-generation sequencing could play an important role in investigating the microbiome as a potential diagnostic and prognostic biomarker for pancreatic cancer.     

Guillain-Barré syndrome following hepatitis E

preceding bacterial or viral infection. Occasionally, it has been observed in association with acute hepatitis A, B and C, and three cases have been previously described in India in which GBS was associated with acute hepatitis E. A molecular mimicry mechanism is supposed to be involved in the pathogenesis of GBS triggered by infectious agents, although the nature of the shared epitopes has not been characterized in most instances, including that in the case of hepatotropic viruses. We report a case of GBS following acute hepatitis E in a European individual. The presence of antiganglioside GM2 antibodies in this patient suggested molecular mimicry involving ganglioside GM2 in the pathogenesis of GBS associated with hepatitis E.     

99th Dahlem Conference on Infection,Inflammation and Chronic Inflammatory Disorders: Triggering of autoimmune diseases by infections

Human autoimmune diseases, such as multiple sclerosis, type 1 diabetes, rheumatoid arthritis and systemic lupus erythematosus (SLE), are linked genetically to distinct major histocompatibility complex (MHC) class II molecules and other immune modulators. However, genetic predisposition is only one risk factor for the development of these diseases, and low concordance rates in monozygotic twins as well as geographical distribution of disease risk suggest a critical role for environmental factors in the triggering of these autoimmune diseases. Among potential environmental factors, infections have been implicated in the onset and/or promotion of autoimmunity. This review will discuss human autoimmune diseases with a potential viral cause, and outline potential mechanisms by which pathogens can trigger autoimmune disease as discerned from various animal models of infection‐induced autoimmune disease.     

Abnormal Intestinal Permeability in Primary Biliary Cirrhosis

Antimitochondrial antibodies (AMAs) found in patients with primary biliary cirrhosis (PBC) cross-react with bacterial proteins and hence molecular mimicry has been proposed as a mechanism for AMA development. Alterations in gastrointestinal permeability would provide a potential route for increased exposure of gut flora to the immune system. In this study we aimed to compare the measured gastrointestinal permeability in patients with PBC to that in patients with liver disease (hepatitis C) and healthy control populations. Subjects drank a mixture of sucrose, lactulose, and mannitol dissolved in water. Eight-hour urinary excretion of the sugars was measured to assess intestinal permeability. Antiendomysial antibody testing was performed to exclude subclinical celiac disease. Eighty-six patients with PBC were evaluated and compared to 69 hepatitis C patients and 155 healthy controls. The mean urinary excretion of sucrose in the PBC patients (133.89 ± 72.56 mg) was significantly higher than that in hepatitis C patients (101.07±63.35) or healthy controls (89.46±41.76) (P=0.0001), suggesting abnormal gastric or proximal small intestinal permeability. Sucrose excretion was not increased among patients with hepatitis C compared to healthy controls. The ratio of lactulose:mannitol excretion, reflecting small bowel permeability, was also elevated in the PBC group (0.017±0.012) compared to healthy controls (0.012±0.007) (P=0.0001) but was equal to that found among patients with hepatitis C (0.016±0.011) (P=NS). We conclude that the permeability of both the stomach and the small bowel is increased in patients with PBC, however, it is unclear if it is a cause, consequence, or manifestation of the disease.     

Reactive arthritis following BCG immunotherapy for urinary bladder carcinoma: a systematic review

Intravesical instillation of Bacillus Calmette-Guerin (BCG) is used with efficacy and safety in the treatment of patients with intermediate and high-risk superficial bladder carcinoma. Arthralgia and/or arthritis is one of the rare severe complications following intravesical BCG immunotherapy. We searched MEDLINE in order to analyze the frequency of this clinical complication, its pathogenesis and outcome. The electronic search was conducted using the following key words: “BCG immunotherapy” and “Arthritis, arthralgias and BCG immunotherapy”. At the end of a process of abstract analysis, 48 papers were included in the systematic review. All the selected papers, except one that was a clinical review, described at least one case of arthritis after BCG therapy. The BCG immunotherapy resulted to be safe and efficacious in the treatment of bladder cancer; the development of reactive arthritis is rare and can evolve in a chronic process. The review of the literature highlighted that reactive arthritis following BCG intravesical instillation is a complication usually well controlled with the discontinuation of the immunotherapy and nonsteroidal anti-inflammatory drugs (NSAIDs) treatment. Only a small portion of patients with a particular genetic background will develop a chronic process.     

膀胱尿路上皮癌中CD133、CD82/KAI1的表达及其与血管生成拟态的关系

目的研究膀胱尿路上皮癌中CD133、CD82/KAI1蛋白与膀胱尿路上皮癌患者各临床病理因素之间的关系。方法采用免疫组织化学ElivisionTMplus法和特殊组织化学法检测90例膀胱尿路上皮癌和20例正常膀胱粘膜中CD133、CD82/KAI1的表达和血管生成拟态(VM)的形成情况。结果在正常膀胱粘膜组织中CD133、CD82/KAI1蛋白的表达阳性率和VM检出率分别为0%、90.0%和0%,在尿路上皮癌组织中三者表达分别为65.6%、31.1%和31.1%,差异均有显著性(P<0.01)。膀胱尿路上皮癌中,CD133、CD82/KAI1蛋白阳性表达以及VM的形成与患者的性别、年龄、肿瘤的数量均无相关性(P>0.05);而与肿瘤分化程度、临床病理分期以及复发与否具有相关性(P<0.01)。癌组织中,CD82/KAI1的表达与VM的形成及CD133的表达成负相关性(r=-0.452,-0.776,P<0.01-0.05),CD133的表达与VM的形成呈正相关(r=0.487,P<0.05)。结论 CD133、CD82/KAI1参与膀胱尿路上皮癌中VM形成,并且CD133、CD82/KAI1以及VM共同参与尿路上皮癌的侵袭及复发。     

PDGFRβ and FGFR2 mediate endothelial cell differentiation capability of triple negative breast carcinoma cells

Triple negative breast cancer (TNBC) is a very aggressive subgroup of breast carcinoma, still lacking specific markers for an effective targeted therapy and with a poorer prognosis compared to other breast cancer subtypes.In this study we investigated the possibility that TNBC cells contribute to the establishment of tumor vascular network by the process known as vasculogenic mimicry, through endothelial cell differentiation.Vascular‐like functional properties of breast cancer cell lines were investigated in vitro by tube formation assay and in vivo by confocal microscopy, immunofluorescence or immunohistochemistry on frozen tumor sections. TNBCs express endothelial markers and acquire the ability to form vascular‐like channels in vitro and in vivo, both in xenograft models and in human specimens, generating blood lacunae surrounded by tumor cells. Notably this feature is significantly associated with reduced disease free survival. The impairment of the main pathways involved in vessel formation, by treatment with inhibitors (i.e. Sunitinib and Bevacizumab) or by siRNA‐mediating silencing, allowed the identification of PDGFRβ and FGFR2 as relevant players in this phenomenon. Inhibition of these tyrosine kinase receptors negatively affects vascular lacunae formation and significantly inhibits TNBC growth in vivo.In summary, we demonstrated that TNBCs have the ability to form vascular‐like channels in vitro and to generate blood lacunae lined by tumor cells in vivo. Moreover, this feature is associated with poor outcome, probably contributing to the aggressiveness of this breast cancer subgroup. Finally, PDGFRβ and FGFR2‐mediated pathways, identified as relevant in mediating this characteristic, potentially represent valid targets for a specific therapy of this breast cancer subgroup.     

血管生成拟态在恶性肿瘤的研究进展

血管生成拟态(VM)一种存在于恶性肿瘤的血液供应模式,乳腺恶性肿瘤VM的形成机制十分复杂.肿瘤细胞的可塑性和多种分子的调节在VM形成机制中起重要作用,同时缺氧微环境及微小RNA(miRNA)与VM的发生和发展具有相关性.缺氧微环境及miRNA与乳腺恶性肿瘤VM关系尤为密切,将有望成为乳腺癌临床研究中重要的诊断及判断预后的指标.