Inherited Neurodegenerative Disorders Caused by CAG/Polyglutamine Tract Expansions: Symposium Introduction

At the beginning of this decade, the American Association of Neurology decided that the 1990's should be labelled "the decade of the brain" for expected advances in our understanding of neurological disorders and neuroscience. By the end of this decade, clinicians and researchers who work in the field of inherited neurological disorders might well remember the 1990's as "the decade of the trinucleotide repeat". At the time of writing this introduction, eleven inherited neurological disorders have been found to be caused by expansions of trinucleotide repeats, and a twelfth trinucleotide repeat expansion mutation has been identified (6), although the gene containing this mutant triplet repeat has not been cloned to our knowledge (Table 1).     

The Neuropathology of CAG Repeat Diseases: Review and Update of Genetic and Molecular Features

Classification of inherited neurodegenerative diseases is increasingly based on their genetic features, which supplement, clarify, and sometimes replace the older clinical and pathologic schemata. This change has been particularly rapid and impressive for the CAG repeat disorders. In Huntington's disease, X-linked spinobulbar muscular atrophy, dentatorubropallidoluysian atrophy, and a series of autosomal dominant cerebellar atrophies, genetic advances have resolved many nosologic issues, and opened new avenues for exploration of pathogenesis. In this review, we summarize classic and current concepts in neuropathology of these CAG repeat diseases.     

Molecular Pathogenesis of Primary Gastrointestinal Tract Lymphomas

Primary gastrointestinal lymphomas are rare though the incidence is significantly increased among adult patients in recent years. The majority of the patients present with symptoms overlapping with other gastrointestinal disorders and imaging findings are not specific. Therefore, histologic examination is necessary to establish the diagnosis. Insight into etiologies, molecular pathogenesis and critical signaling pathways in lymphomas including gastrointestinal lymphomas has significantly expanded within the last 3 decades. Given the increasing demand for incorporation of genetic data, the appropriate handling and processing of small endoscopic gastrointestinal biopsy samples of suspected lymphoma is becoming extremely crucial and at times challenging. The use of next generation sequencing with analysis of genes relevant to diagnosis, prognosis, and therapeutic targets continues to have a significant promising impact on management of patients in lymphoid malignancies. In particular, the identification of constitutively activated pathways and the emergence of novel targeted medications predict that more effective therapies will be identified for these disorders in the coming years.     

The Elements Steering Pathogenesis in IgG-Mediated Alloimmune Diseases

Alloimmune diseases can occur in pregnancy and after blood transfusions, where antibodies are formed, targeting foreign cells and tissues for destruction by myeloid cells through IgG Fc-receptors (FcγR). In pregnancy, antibodies against human blood group or platelet antigens (e.g. HPA1-a) cause life-threatening anemia or thrombocytopenia in the developing fetus or newborn. Here we discuss how both the induction of those IgG antibodies as well as the proinflammatory status of the fetus affects the effector functions through FcγR. Recent studies have found IgG-glycosylation to be important with low IgG-Fc-core fucosylation resulting in increased affinity to FcγRIIIa and FcγRIIIb and enhanced antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis. The importance of these and other features, including oxidative stress and acute phase responses (C-reactive protein, CRP), will be discussed and how these features may collectively synergize resulting in elevated disease pathology in these allo-, but also autoimmune mediated diseases.     

常染色体显性视神经萎缩的分子遗传学研究进展

常染色体显性视神经萎缩 (Autosomal Dominant Optic Atrophy , ADOA), 亦称Kjer型，是一种常见的遗传性视神经病变。该病常在儿童期发病（平均发病年龄为7岁），发病率约1:10 000-1:50 000，表现为隐匿性渐进性视力减退，双颞侧视盘苍白，中心或旁中心暗点，色觉障碍(常表现为蓝黄色盲)。组织病理学表现为：视网膜神经节细胞退行性变。 OPA1编码一种保守的动力相关GTPase，OPA1突变是ADOA发病的主要原因，目前已发现117个ADOA相关OPA1突变，包括：31.6%缺失和插入突变， 16.2%无义突变，25.6%错义突变和28.8%剪接突变。这些突变分布于OPA1基因编码区，但多数位于GTPase区。另外，本病还与OPA3 (19q13.2-q13.3)、OPA4 (18q12.2-12.3)及OPA5 (22q12.1-q13.1)基因突变有关。个体间的表型差异表明：其他遗传因素，个人因素以及环境因素可能与ADOA发病有关。     

Listeria Pathogenesis and Molecular Virulence Determinants

The gram-positive bacterium Listeria monocytogenes is the causative agent of listeriosis, a highly fatal opportunistic foodborne infection. Pregnant women, neonates, the elderly, and debilitated or immunocompromised patients in general are predominantly affected, although the disease can also develop in normal individuals. Clinical manifestations of invasive listeriosis are usually severe and include abortion, sepsis, and meningoencephalitis. Listeriosis can also manifest as a febrile gastroenteritis syndrome. In addition to humans, L. monocytogenes affects many vertebrate species, including birds. Listeria ivanovii, a second pathogenic species of the genus, is specific for ruminants. Our current view of the pathophysiology of listeriosis derives largely from studies with the mouse infection model. Pathogenic listeriae enter the host primarily through the intestine. The liver is thought to be their first target organ after intestinal translocation. In the liver, listeriae actively multiply until the infection is controlled by a cell-mediated immune response. This initial, subclinical step of listeriosis is thought to be common due to the frequent presence of pathogenic L. monocytogenes in food. In normal individuals, the continual exposure to listerial antigens probably contributes to the maintenance of anti-Listeria memory T cells. However, in debilitated and immunocompromised patients, the unrestricted proliferation of listeriae in the liver may result in prolonged low-level bacteremia, leading to invasion of the preferred secondary target organs (the brain and the gravid uterus) and to overt clinical disease. L. monocytogenes and L. ivanovii are facultative intracellular parasites able to survive in macrophages and to invade a variety of normally nonphagocytic cells, such as epithelial cells, hepatocytes, and endothelial cells. In all these cell types, pathogenic listeriae go through an intracellular life cycle involving early escape from the phagocytic vacuole, rapid intracytoplasmic multiplication, bacterially induced actin-based motility, and direct spread to neighboring cells, in which they reinitiate the cycle. In this way, listeriae disseminate in host tissues sheltered from the humoral arm of the immune system. Over the last 15 years, a number of virulence factors involved in key steps of this intracellular life cycle have been identified. This review describes in detail the molecular determinants of Listeria virulence and their mechanism of action and summarizes the current knowledge on the pathophysiology of listeriosis and the cell biology and host cell responses to Listeria infection. This article provides an updated perspective of the development of our understanding of Listeria pathogenesis from the first molecular genetic analyses of virulence mechanisms reported in 1985 until the start of the genomic era of Listeria research.     

The Association of MHC with Autoimmune Diseases: Understanding the Pathogenesis of Autoimmune Diabetes

The current paradigm of MHC and disease association is efficient binding of autoantigens by disease-associated MHC molecules leading to a T cell-mediated immune response and resultant autoimmune sequelae. Data presented here offer a different model for this association of MHC with autoimmune diabetes. This new explanation suggests that the association of MHC with autoimmunity results from “altered” thymic selection in which high-affinity self-reactive (potentially autoreactive) T cells escape negative selection. This model offers an explanation for the requirement of homozygous MHC class II expression in NOD mice (and in man) in susceptibility to IDDM.     

Microorganisms in the Female Genital Tract during Pregnancy: Tolerance versus Pathogenesis

Microorganisms in the pregnant female genital tract are not always associated with pathology. The factors that influence the maternal response to microorganisms remain ill defined. We review the state of knowledge of microbe–host interactions in gestational tissues and highlight mechanisms that promote tolerance or pathogenesis. Tolerance to microorganisms is promoted during pregnancy by several mechanisms including upregulation of anti‐inflammatory mediators, induction of endotoxin tolerance, and possibly by regulation of autophagy. Conversely, an altered vaginal microbiota or a pre‐existing viral presence may result in induction of excessive inflammation and preterm labor. Although infections play a prevalent role in preterm birth, microbes are present in gestational tissues of women with healthy outcomes and may provide beneficial functions. The complex interactions between different microbial species and the maternal immune system during gestation remain incompletely elucidated.     

Gene Regulation and Inflammatory Diseases

Inflammation Research -     

Immunogold-Silver Staining and the Pathogenesis of Bacterial Infectious Diseases

Abstract

The revolutionary concept of antigen detection by immunogold-silver staining (IGSS) has been evaluated for its applicability in the field of microbiology. We have successfully applied the method to identify various microorganisms (including Neisseria gonorrhoeae and Helicobacter pylori), to demonstrate phase- and antigen-variation of cell surface components, to discriminate adherence and entry of the bacteria into host cells, and to screen for isogenic variants (colony-immunoblotting). The method has proved to be a simple, valuable technique with a high sensitivity and with a broad spectrum of use. It is a powerful alternative to the conventional enzymatic and radioactive antigen detection methods. (The J Histotechnology 16:271, 1993)