When is an autoimmune disease not an autoimmune disease?

What are the enviromental triggers and genetic susceptibilities underlying the development of autoimmune diseases? These and other questions were addressed at a recent meeting in Finland¹.     

Behçet's disease from the aspect of autoinflammatory disease

Beh?et's disease is a systemic inflammatory disease presented with recurrent oral aphtha, cutaneous manifestations, uveitis, and genital ulcer. The etiology of Beh?et's disease is still unknown, but both genetic background and environmental factors are thought to be important in the pathogenesis of Beh?et's disease. Beh?et's disease has long been regarded as a Th1 type autoimmune disease, because of the association with HLA-B51 and hyperreactivity against streptococcal antigen. However, it was recently found that Beh?et's disease and autoinflammatory diseases share several clinical features. Furthermore, increased activity of neutrophils and elevated levels of interleukin-1β are observed in both Beh?et's disease and autoinflammatory diseases. The relationship between Beh?et's disease and autoinflammatory diseases, especially Familial Mediterranean fever, is speculated, because both diseases are prevalent in the Mediterranean basin and treated with colchicine. Genetic researches on Beh?et's disease and FMF suggest that the MEFV gene mutated in Familial Mediterranean fever is a probable susceptibility gene for Beh?et's disease. Although many observations suggest that Beh?et's disease might be autoinflammatory, there is evidence implying autoimmune pathogenesis of Beh?et's disease. For example, some symptoms of Beh?et's disease is treated with T cell suppressing agents. Recent data suggest that a novel subset of T cells, Th17, plays a crucial role in pathogenesis of Beh?et's disease, and genome-wide association researches verified it. IL-17, which is the secreted from of Th17 activates neutrophils. Hence, IL-17 might cause the symptoms resembling autoinflammatory diseases. Recently, Anti-IL-1 treatment proved to be effective and other susceptibility genes are being investigated. These new findings will shed light on the long-sought pathogenesis of Beh?et's disease.     

Can the disease course in Parkinson’s disease be slowed?

Background

The diagnosis of Parkinson’s disease (PD), which is needed for useful symptomatic therapy, is based on clinical criteria. However, it became quite clear in recent years that the same features can occur through different etiopathogenic mechanisms. Even a pathological diagnosis of PD, based on the demonstration of α-synuclein deposits in a typical distribution, can result from different causes and, vice versa, nigral cell loss can occur without α-synuclein deposition.

Discussion

Thus far, attempts to influence the progression of PD have failed. However, since the clinical manifestations of PD can be the result of diverse mechanisms, a single intervention may not be able to slow the course of the disease in all patients. Indeed, targeting the underlying pathogenic processes, which differ among cases, may be more effective. PD may develop as a consequence of mitochondrial damage, which itself may result from a variety of genetic or environmental factors. Correction of the ensuing oxidative stress may theoretically be useful in these PD patients, but will not affect the progression of the disease among other PD patients in whom an identical clinical syndrome derives from defects in other pathways such as the ubiquitin-proteasome system and lysosomal dysfunction, among others.

Summary

Precision medicine can now be used to identify the underlying pathogenic mechanisms in individual patients, paving the way to the development of real disease modification through a pathway-oriented approach, aimed at the underlying biologic processes of disease occurrence and evolution.

     

How many cases of disease in a pedigree imply familial disease?

The ability to perform whole‐exome and, increasingly, whole‐genome sequencing on large numbers of individuals has led to increased efforts to identify rare genetic variants that affect the risk of both common and rare diseases. In such applications, it is important to identify families that are segregating the rare variants of interest. For rare diseases or rare familial forms of common diseases, pedigrees with multiple affected members are clearly harbouring risk variants. For more common diseases, however, it may be unclear whether a family with a few affected members is segregating a familial disease, is the result of multiple sporadic cases, or is a mixture of familial cases and phenocopies. We provide calculations for the probability that a family is harbouring familial disease, presented in general terms that admit working guidelines for selecting families for current sequencing studies. Using examples motivated by our own studies of thyroid cancer and published studies of colorectal cancer, we show that for common diseases, families with exactly two affected first‐degree relatives have only a moderate probability of segregating familial disease, but this probability is higher for families with three or more affected relatives, and those families should therefore be prioritised in sequencing studies.     

Measurement of platelet membrane fluidity in patients with Binswanger's disease or Alzheimer's disease

目的和方法：探讨血小板在Ｂｉｎｓｗａｎｇｅｒ病（ＢＤ）发病中的作用，用荧光探针测定１１例ＢＤ患者、９例Ａｌｚｈｅｉｍｅｒ病（ＡＤ）患者和６例健康对照者血小板膜的流动性（ＰＭＦ），以颈内静脉和肘静脉血ＰＭＦ的差值作为反映脑循环中ＰＭＦ变化的指标。结果：ＢＤ和ＡＤ患者的ＰＭＦ的均值显著低于健康对照组，但只有ＢＤ患者颈内静脉血ＰＭＦ显著低于肘静脉血，ＢＤ患者ＰＭＦ差值与ＨＤＳ积分具有显著相关。结论：ＢＤ病人脑循环中ＰＭＦ降低可能是ＢＤ的发病因素之一。     

Is it Fabry disease?

Fabry disease is caused by mutations in the GLA gene that lower α-galactosidase A activity to less than 25–30% of the mean normal level. Several GLA variants have been identified that are associated with relatively elevated residual α-galactosidase A. The challenge is to determine which GLA variants can cause clinical manifestations related to Fabry disease. Here, we review the various types of GLA variants and recommend that pathogenicity be considered only when associated with elevated globotriaosylceramide in disease-relevant organs and tissues as analyzed by mass spectrometry. This criterion is necessary to ensure that very costly and specific therapy is provided only when appropriate.Genet Med 18 12, 1181–1185.     

Systemic Erdheim–Chester disease

Erdheim–Chester disease is a rare xanthomatosis that may present with characteristic radiologic and histologic features. There have been conflicting reports regarding the nature of this process, including whether it represents a reactive or neoplastic lesion. We present the clinical histories, pathologic findings, and an analysis of clonality using the HUMARA assay in two patients diagnosed with Erdheim–Chester disease. One case has previously been documented in the literature. Histologically, both cases demonstrated sheets of foamy xanthomatous histiocytes with widespread infiltration of the viscera. These regions were punctuated by variable amounts of inflammation, including lymphocytes, plasma cells, and occasional Touton-type giant cells. The histiocytes were immunoreactive for CD68 and CD163; they did not stain with S100 or CD1a. One case was found to be monoclonal; however, the second case had extensive DNA degradation; thus, clonality could not be assessed. In addition to contributing an additional report of this rare disease to the literature, we demonstrate the histiocytes to express CD163, thereby further supporting a monocyte/macrophage basis. Moreover, in confirming clonality, our observations lend additional evidence to the view that Erdheim–Chester disease represents a neoplastic process.     

Micro-invasive vulvar Paget's disease and lymph node metastasis: a same disease?

Vulvar Paget's disease is sub-classified into three types based upon its origin. It might be a primary vulvar disease (type 1) or associated with a non-cutaneous adenocarcinoma-rectal, colonic, cervical (type 2) or linked with an urothelial neoplasia (type 3). Type 1lesions must be considered as potentially invasive. Their immunophenotype is CK7+/CK20-. Classically, in case of depth of invasion below 1mm, nodal metastases are exceptional. We report a case of type 1?Paget's disease in a postmenopausal woman with superficial invasion and multiple inguinal nodal metastases.     

Non-alcoholic fatty liver disease–a chronic disease of the 21st century

Non-alcoholic fatty liver disease (NAFLD) comprises a spectrum of metabolic states ranging from simple steatosis o inflammation with associated fibrosis to cirrhosis. Though accumulation of hepatic fat is not associated with a ignificant increase in mortality rates, hepatic inflammation is, as this augments the risk of terminal liver disease, i.e., cirrhosis, hepatic decompensation (liver failure) and/or hepatocellular carcinoma. Disease progression is usually low, over a decade or more and, for the most part, remains asymptomatic. Recent estimates suggest that the global prevalence of NAFLD is high, about one in four. In most cases, NAFLD overlaps with overweight, obesity, cardiovascular disease and the metabolic syndrome with numerous contributing parameters including a dysregulation of adipose tissue, insulin resistance, type 2 diabetes, changes in the gut microbiome, neuronal and hormonal dysregulation and metabolic stress. NAFLD is diagnosed incidentally, despite its high prevalence. Non-invasive maging techniques have emerged, making it possible to determine degree of steatosis as well asfibrosis. Despite this, he benefit of routine diagnostics remains uncertain. A better understanding of the (molecular) pathogenesis of NAFLD is needed combined with long-term studies where benefits of treatment can be assessed to determine cost benefit ratios. This review summarizes the current state of knowledge and possible areas of treatment.     

Parkinson’s disease and Alzheimer’s disease: a Mendelian randomization study

Background

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the top two common neurodegenerative diseases in elderly. Recent studies found the α-synuclein have a key role in AD. Although many clinical and pathological features between AD and PD are shared, the genetic association between them remains unclear, especially whether α-synuclein in PD genetically alters AD risk.

Results

We did not obtain any significant result (OR?=?0.918, 95% CI: 0.782–1.076, P?=?0.291) in MR analysis between PD and AD risk. In MR between α-synuclein in PD with AD risk, we only extracted rs356182 as the IV through a strict screening process. The result indicated a significant association based on IVW method (OR?=?0.638, 95% CI: 0.485–0.838, P?=?1.20E-03). In order to examine the robustness of the IVW method, we used other three complementary analytical methods and also obtained consistent results.

Conclusion

The overall PD genetic risk factors did not predict AD risk, but the α-synuclein susceptibility genetic variants in PD reduce the AD risk. We believe that our findings may help to understand the association between them, which may be useful for future genetic studies for both diseases.