Current cases in which epitope mimicry is considered as a component cause of autoimmune disease: immune-mediated (type 1) diabetes

Autoimmune diseases result from a combination of genetic, immunologic, hormonal, and environmental factors. Infectious agents may induce the breakdown of immunological tolerance and the appearance of autoreactivity. However, the specific relationship between infection and autoimmunity is still unclear. One of the mechanisms responsible could be molecular mimicry between the infectious agent and self. The concept of molecular mimicry is a viable hypothesis in the investigation of the etiology, pathogenesis, treatment, and prevention of autoimmune disorders. Immune-mediated (type 1) diabetes in humans and in non-obese diabetic (NOD) mice is polygenic and characterized by autoimmune destruction of insulin-producing pancreatic beta cells in islets of Langerhans. In NOD mice, a T-helper 1 (Th1)-based autoimmune response arises spontaneously against glutamate decarboxylase (GAD) concurrently with the onset of insulitis. Subsequently. this Th1-type autoreactivity spreads intra- and intermolecularly to other beta cell autoantigens, suggesting that a Th1-type response is responsible for the progression of the disease, whereas Th2 responses when experimentally induced are protective. In humans, a homology between GAD and the P2-C protein of Coxsackie B make a cause-and-effect molecular mimicry an attractive hypothesis. Evidence to support the concept of molecular mimicry in diabetes is reviewed.     

Peptides as DNA mimics: cross-reactivity and mimicry in systemic autoimmune diseases

No Abstract. Received 21 February 2002; received after revision 16 May 2002; accepted 14 June 2002     

Evidence for mimicry by viral antigens in animal models of autoimmune disease including myocarditis

Molecular mimicry of viral antigens with self determinants has been proposed as one of the pathogenic mechanisms in autoimmune disease. Evidence of viral mimicry in animal models of autoimmunity is accumulating. Murine adenovirus, Semliki forest virus, lactate dehydrogenase-elevating virus, herpes simplex virus type-1, hepatitis B virus, encephalomyocarditis virus, Theiler's murine encephalomyelitis virus, Coxsackievirus and cytomegalovirus have been found to mimic physiologically important host proteins. However, epitope homology of a viral and self determinant is not in itself strong evidence for mimicry as a pathogenic mechanism. The mimicking determinant must also be capable of inducing disease in the absence of replicative virus. Animal models provide evaluation of the viral trigger, and development and therapy for autoimmune diseases. Identification of host proteins that can induce disease together with the knowledge of immune system dysregulation, genetic association and environmental factors may lead to improved immunotherapeutic strategies for human autoimmune diseases.     

Introduction: lipids as regulators of cell function

It is becoming increasingly clear that lipids are key regulators of cellular function and that these effects are quite diverse. First, the lipid environment in the cellular membrane bilayer is important in maintaining the normal function of receptors, enzymes, transporters and so on that are localized in the membrane. Phosphoinositides are important regulators of signalling molecules. Lipid metabolites formed by a number of enzymes including the cyclooxygenases, lipoxygenases and P450s also mediate important cellular functions. Fatty acids and lipid metabolites can also activate the nuclear peroxisome proliferator-activated receptors. Finally, a wide variety of lipid molecules are generated nonenzymatically by free-radical mechanisms that also exert potent biological effects in a wide variety of organs. Presented are a series of eight reviews that broadly cover all of these topics in some detail.     

Molecular mimicry: a critical look at exemplary instances in human diseases

Molecular mimicry, the concept that antigenic determinants of microorganisms resemble antigenic determinants of the host, is frequently cited as a plausible mechanism to account for the association of infection and autoimmune disease. Based on analogous sequences of amino acids or on cross-reactions of monoclonal antibodies, numerous examples of such mimicry have been reported. There are, however, no clear examples of a human disease caused by molecular mimicry.     

Ultrastructural observation of lysosomal activation as a possible cause of incisor malformation in cyclophosphamide-treated rat

Zusammenfassung In vorläufigen Untersuchungen akuter Effekte von Cyklophosphamid wurden in der Rattenzahnpulpa elektronenoptisch autophagische Vakuolen gefunden, was auf eine Aktivierung der Lysosomen hinweist.     

CHFR: a key checkpoint component implicated in a wide range of cancers

CHFR (Checkpoint with Forkhead-associated and RING finger domains) has been implicated in a checkpoint regulating entry into mitosis. However, the details underlying its roles and regulation are unclear due to conflicting lines of evidence supporting different notions of its functions. We provide here an overview of how CHFR is thought to contribute towards regulating mitotic entry and present possible explanations for contradictory observations published on the functions and regulation of CHFR. Furthermore, we survey key data showing correlations between promoter hypermethylation or down-regulation of CHFR and cancers, with a view on the likely reasons why different extents of correlations have been reported. Lastly, we explore the possibilities of exploiting CHFR promoter hypermethylation status in diagnostics and therapeutics for cancer patients. With keen interest currently focused on the association between hypermethylation of CHFR and cancers, details of how CHFR functions require further study to reveal how its absence might possibly contribute to tumorigenesis.     

Tris as a blocking agent of the proton-sensitive component of the sodium efflux in barnacle muscle fibers

Zusammenfassung Studien über den Natriumtransport in den Muskeln vonBalanus sp. haben bewiesen, dassTris den protonempfindlichen Anteil der Natrium-Pumpe verlangsamt und dasTris hauptsächlich an der Aussenseite des Sarkolemms aktiv ist.

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Acknowledgments. This work was supported in part by grants from the Wisconsin Heart Association, the Medical School Research Committee, the Graduate School Research Committee and the Office of Naval Research. Our thanks are due to Mr.Geoffrey Chambers for technical assistance. E.Y.T. is a Postdoctoral Fellow of the Wisconsin Heart Association. B.G.D. is a Visiting Scientist of the American Heart Association.     

Total replacement of blood by an emulsion of fluorocarbon in the rat-water extravasation as a cause of failure

Summary After exchange transfusion by an emulsion of fluorocarbons (Fluosol 43) in rats, an increase in fluorocarbons and¹³¹I-labelled albumin was observed. These changes suggest a transfer of water from vascular to interstitial space possibly owing to the inability of the emulsion to reproduce the oncotic pressure of normal blood.     

Crosstalk between metabolism and epigenetic modifications in autoimmune diseases: a comprehensive overview

Little information is available regarding mechanistic links between epigenetic modifications and autoimmune diseases. It seems plausible to surmise that aberrant gene expression and energy metabolism would disrupt immune tolerance, which could ultimately result in autoimmune responses. Metaboloepigenetics is an emerging paradigm that defines the interrelationships between metabolism and epigenetics. Epigenetic modifications, such as the methylation/demethylation of DNA and histone proteins and histone acetylation/deacetylation can be dynamically produced and eliminated by a group of enzymes that consume several metabolites derived from various physiological pathways. Recent insights into cellular metabolism have demonstrated that environmental stimuli such as dietary exposure and nutritional status act through the variation in concentration of metabolites to affect epigenetic regulation and breakdown biochemical homeostasis. Metabolites, including S-adenosylmethionine, acetyl-CoA, nicotinamide adenine dinucleotide, α-ketoglutarate, and ATP serve as cofactors for chromatin-modifying enzymes, such as methyltransferases, deacetylases and kinases, which are responsible for chromatin remodelling. The concentration of crucial nutrients, such as glucose, glutamine, and oxygen, spatially and temporally modulate epigenetic modifications to regulate gene expression and the reaction to stressful microenvironments in disease pathology. In this review, we focus on the interaction between metabolic intermediates and epigenetic modifications, integrating environmental signals with programmes through modification of the epigenome–metabolome to speculate as to how this may influence autoimmune diseases.