Transfection "Junk" DNA - a link to the pathogenesis of Alzheimer's disease?

A transfection product incorporates in one molecule of human DNA, an inserted segment of DNA from another species. This communication addresses the hypothesis that a novel variation of the theme of transfection, namely "junk transfection" for which no protein product and no RNA is transcribed, might offer insights into the pathogenesis of Alzheimer's disease. It is hypothesized that spirochetal DNA gains access to the intracellular compartment of nerve cells during the subclinical latency phase of neuroborreliosis and chemically combines with human DNA. A previously reported Molecular interrogation of Alzheimer's disease autopsy tissues has yielded novel DNA sequences containing the 11 q human chromosome and a short piece of the Borrelia burgdorferi Flagellin B DNA. Although the usually encountered transfection product bundles an entire nonhuman gene within it, this model proposes that shorter inserts into the human genome constitute "junk transfection" because no protein is derived from them. Junk transfections would offer an important new cognitive model for the detection of occult infections as the root causes for the Tauopathies, which are degenerative neurological disorders, including Alzheimer's disease.     

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.     

HIV diversity, recombination and disease progression: how does fitness "fit" into the puzzle?

HIV appears to have diverged into several lineages upon multiple zoonotic introductions from the nonhuman primates. The HIV-2 and HIV-1 groups M, N, and O likely represent different cross-species transmission events. The radial evolution of group M in multiple clades or subtypes is likely due to adaptation and expansions in the human hosts. It is not well understood why HIV strains such as HIV-1 subtype C in particular or group M in general have spread disproportionately as compared to other subtypes, groups, or types, which often remained geographically constrained to local epidemics. Host genetic effects, transmission bottlenecks, social/behavioral and environmental limitations, founder effect and other viral factors could have contributed to variable spread through the human population. Even after transmission, viruses evolve at different rates during disease progression. Recent studies have explored phenotypic differences between HIV types, groups, and subtypes in attempts to explain or understand this radial evolution and expansion. This review explores some of the important aspects relating to fitness during disease progression, during global distribution of different HIV subtypes, and related to circulation of recombinant forms in the epidemic.     

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.     

Vascular consequences of passive Abeta immunization for Alzheimer's disease. Is avoidance of "malactivation" of microglia enough?

The role of inflammation in Alzheimer's disease (AD) has been controversial since its first consideration. As with most instances of neuroinflammation, the possibility must be considered that activation of glia and cytokine networks in AD arises merely as a reaction to neurodegeneration. Active, healthy neurons produce signals that suppress inflammatory events, and dying neurons activate phagocytic responses in microglia at the very least. But simultaneous with the arrival of a more complex view of microglia, evidence that inflammation plays a causal or exacerbating role in AD etiology has been boosted by genetic, physiological, and epidemiological studies. In the end, it may be that the semantics of "inflammation" and glial "activation" must be regarded as too simplistic for the advancement of our understanding in this regard. It is clear that elaboration of the entire repertoire of activated microglia - a phenomenon that may be termed "malactivation" - must be prevented for healthy brain structure and function. Nevertheless, recent studies have suggested that phagocytosis of Abeta by microglia plays an important role in clearance of amyloid plaques, a process boosted by immunization paradigms. To the extent that this clearance might produce clinical improvements (still an open question), this relationship thus obligates a more nuanced consideration of the factors that indicate and control the various activities of microglia and other components of neuroinflammation.     

Regulation of T:B cell interactions by the inducible costimulator molecule: does ICOS "induce" disease?

The Inducible Costimulator molecule (ICOS), a member of the CD28 family of costimulatory molecules, was identified in 1999 as a molecule expressed primarily on activated human T cells. Induced upon activation, ICOS appears to be an ideal target for modifying T-cell-mediated immune responses. ICOS was also found to be highly expressed on germinal center T cells, suggesting that ICOS was involved in T:B cell interactions. While ICOS has subsequently been shown to be important for both Th1 and Th2 cell activation and effector function, a central role for ICOS in the generation and maintenance of humoral immunity is emerging. In this review, we summarize the evidence that the level of ICOS expression regulates T-cell-dependent B cell responses and propose a model for the role of ICOS in diseases characterized by dysregulated humoral immunity.     

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。     

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.     

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.