Diabetes, Renal and Cardiovascular Disease in p47 phox−/− Chronic Granulomatous Disease

Chronic granulomatous disease is a rare immunodeficiency due to defects in the phagocyte NADPH oxidase. The X-linked form (gp91 ^phox deficiency) accounts for about 70 % of cases; autosomal recessive p47 ^phox deficiency accounts for about 25 % of cases. We identified a 10 % incidence of diabetes in p47 ^phox deficient CGD, but none in X-linked CGD. Renal and cardiovascular diseases were also higher in p47 ^phox deficiency. p47 ^phox deficient CGD has non-infectious morbidities distinct from those in X-linked CGD.     

Chemokines and Chemokine Receptors： Their Manifold Roles in Homeostasis and Disease

Chemokines are a superfamily of small proteins that bind to G protein-coupled receptors on target cells and were originally discovered as mediators of directional migration of immune cells to sites of inflammation and injury. In recent years, it has become clear that the function of chemokines extends well beyond the role in leukocyte chemotaxis. They participate in organ development, angiogenesis/angiostasis, leukocyte trafficking and homing, tumorigenesis and metastasis, as well as in immune responses to microbial infection. Therefore, chemokines and their receptors are important targets for modulation of host responses in pathophysiological conditions and for therapeutic intervention of human diseases.     

Vesicular Acetylcholine Transporter Density and Alzheimer’s Disease

We have evaluated the vesamicol analogue meta-[¹²⁵I]iodobenzyltrozamicol {(+)-[¹²⁵I]MIBT} as a probe to assess cholinergic terminal integrity in the human temporal cortex. Saturation binding analysis, using 5-aminobenzovesamicol (ABV) to define nonspecific binding, revealed a high-affinity binding site with a K_d value of 4.3 ± 1.2 nM in the temporal cortex of the young control subjects. Similar affinity values were observed for (+)-[¹²⁵I]MIBT binding in aged control subjects (K_d = 3.4 ± 0.5 nM) and AD patients (K_d = 3.0 ± 0.8 nM). In contrast, Bmax values for young subjects, aged controls and AD patients were 31.2 ± 6.3, 17.0 ± 2.0 and 9.4 ± 1.6 pmol/g, respectively, clearly reflecting significant reductions in (+)-[¹²⁵I]MIBT binding site density with aging and age-related neuropathology. Moreover, the decrease in (+)-[¹²⁵I]MIBT binding was correlated with choline acetyltransferase activities (r = 0.72) in the AD temporal cortex. These results suggest that when selective ligands are used, the vesicular acetylcholine transporter can be a useful marker protein for assessing the loss of cholinergic projections in AD and related disorders.     

The “Atypical” Mycobacteria: Recognition and Disease Association

Abstract

Current advances in the understanding of the pathogenicity of the agents of diarrheal infections, Vibrio cholerae, diarrheagenic E. coli, Shigella, Salmonella, and enteropathogenic Yersinia, have, to a great extent, become possible due to morphological studies of host-pathogen interactions in natural and experimental infections. Despite a multigenic nature and a diversity of pathogenic features in the bacterial species and even in serogroups of the same species, it is now possible to delineate four major patterns of interaction of enteric pathogens with their cellular targets, the enterocytes, and with the immune apparatus of the gut. These patterns, epicellular cytotonic, epicellular restructuring cytotonic, invasive intraepithelial cytotonic and cytotoxic, and invasive transcellular cytotonic and cytotoxic bacteremic, underlie early pathogenesis and clinical manifestations in the respective diarrheal diseases. In this review, the results of the morphological analyses of these patterns over the last 3 decades as well as some methodological problems encountered in the interpretation of morphological observations are discussed.     

Pott's Disease? AIDS-Associated Mycobacterium heckeshornense Spinal Osteomyelitis and Diskitis

Acid-fast bacillus (AFB) spinal osteomyelitis in a patient with AIDS is often presumed to be caused by reactivated Mycobacterium tuberculosis. However, other AFB pathogens can mimic M. tuberculosis and, to ensure appropriate and adequate therapy, should be considered by clinicians. We present a case of aggressive spinal osteomyelitis caused by Mycobacterium heckeshornense in an AIDS patient; a review of the literature is also included.     

Epigenetic Programming and Risk: The Birthplace of Cardiovascular Disease?

Epigenetics, through control of gene expression circuitries, plays important roles in various physiological processes such as stem cell differentiation and self renewal. This occurs during embryonic development, in different tissues, and in response to environmental stimuli. The language of epigenetic program is based on specific covalent modifications of DNA and chromatin. Thus, in addition to the individual identity, encoded by sequence of the four bases of the DNA, there is a cell type identity characterized by its positioning in the epigenetic “landscape”. Aberrant changes in epigenetic marks induced by environmental cues may contribute to the development of abnormal phenotypes associated with different human diseases such as cancer, neurological disorders and inflammation. Most of the epigenetic studies have focused on embryonic development and cancer biology, while little has been done to explore the role of epigenetic mechanisms in the pathogenesis of cardiovascular disease. This review highlights our current knowledge of epigenetic gene regulation and the evidence that chromatin remodeling and histone modifications play key roles in the pathogenesis of cardiovascular disease through (re)programming of cardiovascular (stem) cells commitment, identity and function.     

Legionella and Legionnaires’ Disease: Time to Explore in India

Legionella pneumophila was first recognised as a fatal cause of pneumonia more than four decades ago, during the 1976-American Legion convention in Philadelphia, USA. Legionella spp. continue to cause disease outbreaks of public health significance, and at present, Legionnaires’ disease (LD) has emerged as an important cause of community and hospital-acquired pneumonia. Parallel to this, the understanding of LD has also increased exponentially. However, the disease is likely to be underreported in many countries because of the dearth of common definitions, diagnostic tests and active surveillance systems. In this review, we outline the basic concepts of Legionella including clinical presentations, epidemiology, laboratory diagnosis and the status of LD in India. This article also summarises the progress of research related to Legionella in this country, identifying the research gaps and discussing priorities to explore this unexplored pathogen in India.     

Immunology, Autoimmunity, and Autoantibodies in Parkinson’s Disease

Recent revelations of immune alterations in Parkinson??s disease have led to the convergence that an autoimmune mechanism may play a role in the etiopathogenesis of this neurodegenerative disease. In the current study, 77 Parkinson??s disease patients and 77 matched healthy controls were analyzed for the presence of seven autoantibodies previously found to be associated with central nervous system manifestations namely: antineuronal-cells, anti-brain lysate, anti-dsDNA, anti-phosphatidylserine, anti-cardiolipin, anti-serotonin, and anti-melanocytes antibodies. Patients underwent systematic assessments of demographics, clinical, and biochemical manifestations. Three autoantibodies were found to be more prevalent among Parkinson??s disease patients (antineuronal cells10.3% vs. 1.3%, p?=?0.017; anti-brain lysate 9.1% vs. 1.3%, p?=?0.032; anti-dsDNA 10.3% vs. 2.6%, p?=?0.049). Clinical manifestations of Parkinson??s disease, particularly dyskinesia and depression, were found to be associated with the presence of these autoantibodies.     

Dysbiosis of gut microbiota and microbial metabolites in Parkinson’s Disease

Gut microbial dysbiosis and alteration of microbial metabolites in Parkinson’s disease (PD) have been increasingly reported. Dysbiosis in the composition and abundance of gut microbiota can affect both the enteric nervous system and the central nervous system (CNS), indicating the existence of a microbiota-gut-brain axis and thereby causing CNS diseases. Disturbance of the microbiota-gut-brain axis has been linked to specific microbial products that are related to gut inflammation and neuroinflammation. Future directions should therefore focus on the exploration of specific gut microbes or microbial metabolites that contribute to the development of PD. Microbiota-targeted interventions, such as antibiotics, probiotics and fecal microbiota transplantation, have been shown to favorably affect host health. In this review, recent findings regarding alterations and the role of gut microbiota and microbial metabolites in PD are summarized, and potential molecular mechanisms and microbiota-targeted interventions in PD are discussed.     

Self-Reactive CD4+ T Cells and B Cells in the Blood in Health and Autoimmune Disease: Increased Frequency of Thyroglobulin-Reactive Cells in Graves’ Disease

The mechanisms underlying activation of potentially self-reactive circulating B cells and T cells remain unclear. We measured the uptake of a self-antigen, thyroglobulin, by antigen presenting cells, and the subsequent proliferation of CD4⁺ T cells and B cells from healthy controls and patients with autoimmune thyroiditis. In Hashimoto's thyroiditis, B cells bound increased amounts of thyroglobulin in a complement- and autoantibody-dependent manner, and the thyroglobulin-elicited proliferation of CD4⁺ T cells and B cells was complement dependent. Increased proportions of Tg-responsive CD4⁺ T cells and B cells were found in patients with Graves’ disease. Notably, both patient groups and healthy controls exhibited higher proliferative responses to thyroglobulin than to a foreign recall antigen, tetanus toxoid. Our results suggest that self-tolerance can be broken by exposure of circulating lymphocytes to high local concentrations of self-antigen, and that complement plays a role in the maintenance of autoimmune processes, at least in Hashimoto's thyroiditis.     

A 21st Century Appraisal of Whipple’s Disease and Tropheryma whipplei

Whipple’s disease was formally described more than 100 years ago; nonetheless, only recently have investigators identified, cultivated, and characterized the causative agent, Tropheryma whipplei, and deciphered some of its complex associations with human hosts. The acquisition of knowledge about T. whipplei, a Gram-positive bacterium in the class Actinobacteria, accelerated at an extraordinarily rapid pace during the first two decades of the 21st century, to include the recognition of asymptomatic carriage, localized disease, and acute infections caused by this peculiar bacterium. This review discusses current knowledge of the microbiology and epidemiology of T. whipplei, the expanding clinical spectrum of disease caused by the pathogen, its treatment, and historical and diagnostic assays that facilitate the diagnosis of the various diseases caused by this enigmatic bacterium.The findings and conclusions in this article are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.