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At least 19 recordsLinked to original sources
PubMed1998

HLA allele distribution distinguishes sporadic inclusion body myositis from hereditary inclusion body myopathies.

We studied the HLA class II associations in patients with sporadic inclusion body myositis (s-IBM) and hereditary inclusion body myopathies (h-IBM) and attempted to distinguish these myopathies on the basis of HLA allele assignments. Forty-five patients, 30 with s-IBM and 15 with h-IBM, underwent HLA class II allele-specific typing using polymerase chain reaction sequence-specific primers for 71 alleles contained in the DRbeta1, DRbeta3-5, and DQbeta1 loci. In s-IBM, we found a high (up to 77%) frequency of DRbeta1*0301, DRbeta3*0101 (or DRbeta3*0202) and DQbeta1*0201 alleles. No significant association with alleles in the DR and DQ haplotypes was found among the 15 h-IBM patients. The strong association of prominent alleles with s-IBM, but not h-IBM, suggests that s-IBM is a distinct disorder with an immunogenetic background that differs from h-IBM.

Aged↗
PubMed1996

Difference in expression of phosphorylated tau epitopes between sporadic inclusion-body myositis and hereditary inclusion-body myopathies.

Sporadic inclusion-body myositis (s-IBM) and the hereditary inclusion-body myopathies (h-IBMs) are severe and progressive muscle diseases, characterized pathologically by vacuolated muscle fibers containing paired-helical filaments (PHFs). An interesting feature of the s- and h-IBM muscle phenotype is its striking similarity to Alzheimer-disease (AD) brain. We immunostained muscle biopsies of 9 s-IBM patients, 9 autosomal-recessive h-IBM patients, 1 autosomal-dominant h-IBM patients, and 18 normal and disease-controls with several antibodies known to react with the hyperphosphorylated tau of AD-PHFs. Those included SMI-31, SMI-310, PHF-1, and AT8. In both s- and h-IBM, virtually all vacuolated muscle fibers had strongly immunoreactive inclusions with SMI-31, and by immuno-electronmicroscopy SMI-31 was exclusively localized to PHFs. Approximately 40 to 50% of both s- and h-IBM vacuolated muscle fibers were also immunoreactive with AT8 antibody. To the contrary, in h-IBM, there was no immunoreactivity with SMI-310 and PHF-1 antibodies, whereas in s-IBM the vacuolated muscle fibers had strong immunoreactivity with those two antibodies. By immunoelectronmicorscopy, SMI-310 and PHF-1 also were localized to PHFs. Within s-IBM muscle fibers, the structures immunoreactive with SMI-310 were congophilic, whereas h-IBM muscle fibers did not have congophilia. Our studies: (a) demonstrate a distinct difference between s-IBM and the h-IBMs in regard to expression of immunoreactive phosphorylated tau and congophilia; (b) demonstrate a new "diagnostic duo" combination of SMI-31 and SMI-310 antibodies for identifying and distinguishing s-IBM and the h-IBMs; and (c) provide another close similarity of pathologic phenotypes between s-IBM muscle and AD brain, suggesting that similar cellular pathogenic mechanisms may be active in both diseases.

Adult↗
PubMed1994

Abnormal accumulation of prion protein mRNA in muscle fibers of patients with sporadic inclusion-body myositis and hereditary inclusion-body myopathy.

Sporadic inclusion-body myositis is the most common progressive muscle disease of older patients. The muscle biopsy demonstrates mononuclear cell inflammation and vacuolated muscle fibers containing paired helical filaments and 6 to 10-nm fibrils, both resembling those of Alzheimer brain, and Congo-red positivity. Hereditary inclusion-body myopathy designates patients cytopathologically similar but without inflammation. In both muscle diseases, prion, and several proteins characteristic of Alzheimer brain--eg, beta-amyloid protein and hyperphosphorylated tau (which normally are expressed mainly in neurons), and apolipoprotein E--are abnormally accumulated in vacuolated muscle fibers, by unknown mechanisms. We now demonstrate in both muscle diseases that prion mRNA is strongly expressed in the vacuolated muscle fibers, which suggests that their accumulated prion protein results, at least partly, from increased gene expression. This, to our knowledge, is the first demonstration of abnormally increased prion mRNA in human disease. Another novel finding is the increased prion mRNA in human muscle macrophages, and both increased prion protein and prion mRNA in regenerating muscle fibers. The latter indicates that prion may play a role in human muscle development.

Adult↗
PubMed1995

New advances in the understanding of sporadic inclusion-body myositis and hereditary inclusion-body myopathies.

This review emphasizes new advances in seeking the pathogenic mechanisms of sporadic inclusion-body myositis and hereditary inclusion-body myopathy syndromes. Clinical and pathologic similarities and differences between sporadic and hereditary forms are described. Hypotheses are presented regarding the possible causes and consequences of abnormally accumulated intramyofiber beta-amyloid precursor protein (beta APP) (including beta-amyloid protein and C- and N-terminal epitopes), hyperphosphorylated tau, alpha 1-antichymotrypsin, apolipoprotein E, prion protein, ubiquitin, nicotinic acetylcholine receptor and its 43-kD associated protein, fibroblast growth factor, and transforming growth factor-beta. Also increased are beta APP mRNA and prion protein mRNA. Striking similarities between the pathology of muscle specimens from sporadic inclusion-body myositis and samples from the brains of patients with Alzheimer's disease in regard to Congo red positivity and accumulations of several proteins are discussed. Because most of the proteins that pathologically accumulate throughout the abnormal muscle fibers also accumulate focally at normal human neuromuscular junctions, the possible "junctionalization" of nonjunctional nuclei as a pathogenic mechanism in the muscle fiber is discussed.

Diagnosis, Differential↗
PubMed1998

Sporadic inclusion-body myositis and hereditary inclusion-body myopathies: current concepts of diagnosis and pathogenesis.

We discuss the pathologic diagnostic criteria and review the major new advances related to seeking the pathogenic mechanism of sporadic inclusion-body myositis (s-IBM) and hereditary inclusion-body myopathy (h-IBM). A classification of the various h-IBM syndromes is also presented. The several forms of the h-IBMs have different genetic transmissions and probably different genetic defects. In neither s-IBM nor the h-IBMs are the sequential steps of the pathogenic cascade understood. Because s-IBM and the h-IBMs have a number of characteristic pathologic features in common, we postulate that their different causes trigger the same upstream aberration leading to a similar downstream cascade of pathologic events, which are ultimately responsible for the characteristic muscle-fiber degeneration. Muscle-biopsy and experimental evidence is given supporting our hypothesis that overexpression of beta-amyloid precursor protein within abnormal muscle fibers is an early upstream event causing the pathogenic cascade. We also present evidence supporting our concept that muscle aging and oxidative stress are important factors contributing to the s-IBM-specific muscle fiber destruction. Additionally, the intriguing parallels between the pathologic phenotype of IBM muscle fibers and Alzheimer's disease brain are summarized.

Aging↗
PubMed1998

Light and electron microscopic immunolocalization of presenilin 1 in abnormal muscle fibers of patients with sporadic inclusion-body myositis and autosomal-recessive inclusion-body myopathy.

Sporadic inclusion-body myositis (s-IBM) is the most common progressive muscle disease of older persons. The muscle biopsy demonstrates mononuclear cell inflammation and vacuolated muscle fibers containing paired helical filaments and 6- to 10-nm fibrils, both resembling those of Alzheimer disease brain and Congo red positivity. The term hereditary inclusion-body myopathies (h-IBMs) designates autosomal-recessive or autosomal-dominant disorders with muscle biopsies cytopathologically similar to s-IBM but without inflammation. Vacuolated muscle fibers of both s-IBM and the h-IBMs contain accumulations of several "Alzheimer-characteristic proteins" including beta-amyloid protein and beta-amyloid precursor protein, and their paired helical filaments are composed of phosphorylated tau. We used six well characterized antibodies against several residues of presenilin 1 (PS1) to immunostain muscle biopsies of 12 patients with s-IBM, 5 patients with autosomal-recessive inclusion-body myopathy, and 16 normal and disease controls. Seventy to eighty percent of the vacuolated muscle fibers of both s-IBM and autosomal-recessive inclusion-body myopathy had inclusions that were strongly PS1-immunoreactive, which by immunoelectron microscopy localized mainly to paired helical filaments and 6- to 10-nm filaments. None of the control biopsies had PS1-positive inclusions characteristic of the s- and h-IBM abnormal muscle fibers. Mutations of the newly discovered PS1 gene are responsible for early-onset familial Alzheimer disease (AD), and PS1 is abnormally accumulated in sporadic and familial AD brain. Our study provides the first demonstration of PS1 abnormality in non-neural tissue and in diseases other than AD and suggests that the cytopathogenesis in AD brain and IBM muscle may share similarities.

Adult↗
PubMed2005

Solubilization and refolding of bacterial inclusion body proteins.

Inclusion bodies produced in Escherichia coli are composed of densely packed denatured protein molecules in the form of particles. Refolding of inclusion body proteins into bioactive forms is cumbersome, results in poor recovery and accounts for the major cost in production of recombinant proteins from E. coli. With new information available on the structure and function of protein aggregates in bacterial inclusion bodies, it has been possible to develop improved solubilization and refolding procedures for higher recovery of bioactive protein. Inclusion bodies are formed from partially folded protein intermediates and are composed of aggregates of mostly single types of polypeptide. This helps to isolate and purify the protein aggregates to homogeneity before solubilization and refolding. Proteins inside inclusion body aggregates have native-like secondary structures. It is assumed that restoration of this native-like secondary structure using mild solubilization conditions will help in improved recovery of bioactive protein in comparison to solubilization using a high concentration of chaotropic agent. Analysis of the dominant forces causing aggregation during inclusion body formation provides information to develop suitable mild solubilization procedures for inclusion body proteins. Refolding from such solubilized protein will be very high due to restoration of native-like secondary structure. Human growth hormone inclusion bodies were purified to homogeneity from E. coli cells before solubilization and refolding. Pure inclusion bodies were solubilized at alkaline pH in the presence of 2 M urea solution. The solubilized proteins were refolded using a pulsatile renaturation process and subsequently purified using chromatographic procedures. More than 40% of the inclusion body proteins could be refolded back to the bioactive native conformation. Mild solubilization is thus the key for high recovery of bioactive protein from inclusion bodies.

Cell Fractionation↗
PubMed1978

[Structure of inclusion bodies and electron microscopic virus detection in naturally occurring inclusion body hepatitis in chickens].

Electron microscopy was used to examine the liver of chickens with spontaneous inclusion body hepatitis. Eosinophilic inclusion bodies only were established from two flocks, mainly amphophilic from one flock, and primarily basophilic from another two flocks. Eosinophilic inclusion bodies were predominant in broiler chickens with dystrophic fatty degeneration of the liver, while basophile inclusion bodies were recorded primarily from parental or laying-hen chickens with reduced metabolic stress of the liver and more focal necrosis. The eosinophilic inclusion bodies consitsed of a filamentous matrix, with virus particles not safely detectable. The amphophilic inclusion bodies contained parvovirus particles, most likely adenoassociated virus, while the basophilic inclusion bodies inclused parvoviruses or adenoviruses (in flock NO. IV) or adenoviruses only (in flock No. V) in an amorphous chromatin matrix. The presence of parvoviruses in field material was taken to suggest a possible role of those pathogens in inclusion body hepatitis.

Adenoviridae↗
PubMed1997

Ubiquitin immunostaining and inclusion body myositis: study of 30 patients with inclusion body myositis.

Distinction of inclusion body myositis (IBM) from other forms of inflammatory myopathy is significant from prognostic and therapeutic standpoints. This study retrospectively examines ubiquitin expression by paraffin immunohistochemistry in muscle biopsy material from 30 patients with IBM. Patients included 19 men and 11 women (ages 29 to 80 years; mean, 64 years). All biopsies were characterized by endomysial chronic inflammation, muscle fiber degeneration and regeneration, rimmed vacuoles, and angular atrophic esterase-positive muscle fibers. Ragged red fibers were identified in biopsies of five patients and a partial cytochrome C-oxidase deficiency by enzyme histochemistry in biopsies of 10 patients. Evidence of intranuclear or cytoplasmic tubulofilamentous structures confirming a diagnosis of IBM was observed in all 30 cases. Paracrystalline mitochondrial inclusions were noted in five patients. Discrete myocyte intranuclear ubiquitin-positive inclusions were noted in 14 patients (47%). Discrete intracytoplasmic ubiquitin-positive inclusions were noted in 24 (80%) patients. Positive staining of rimmed vacuoles by ubiquitin was observed in 25 (83%) patients. Diffuse staining of scattered muscle fibers was observed in 21 (70%) patients. In a control group including patients with polymyositis (n = 3), dermatomyositis (n = 3), necrotizing vasculitis (n = 1), and granulomatous myositis (n = 1), discrete intranuclear or cytoplasmic ubiquitin-positive inclusions were not observed. Rimmed vacuoles were not seen either by light microscopy or ubiquitin immunostaining in any of the eight cases. Occasional myofibers from all eight cases showed diffuse, positive muscle fiber staining. Although not present in all cases, evidence of ubiquitin-positive myocytic intranuclear or cytoplasmic inclusions or positive-staining rimmed vacuoles in the setting of an inflammatory myopathy may be suggestive of a diagnosis of inclusion body myositis. Use of ubiquitin immunohistochemistry may be useful in cases in which frozen tissue or tissue processed for electron microscopy is not available, and IBM is suspected. Light or electron microscopic evidence of mitochondrial abnormalities were noted in a significant subset of patients (13 of 30; 43%) of patients with IBM.

Adult↗
PubMed2006

Inclusion body anatomy and functioning of chaperone-mediated in vivo inclusion body disassembly during high-level recombinant protein production in Escherichia coli.

During production in recombinant Escherichia coli, the human basic fibroblast growth factor (hFGF-2) partly aggregates into stable cytoplasmic inclusion bodies. These inclusion bodies additionally contain significant amounts of the heat-shock chaperone DnaK, and putative DnaK substrates such as the elongation factor Tu (ET-Tu) and the metabolic enzymes dihydrolipoamide dehydrogenase (LpdA), tryptophanase (TnaA), and d-tagatose-1,6-bisphosphate aldolase (GatY). Guanidinium hydrochloride induced disaggregation studies carried out in vitro on artificial aggregates generated through thermal aggregation of purified hFGF-2 revealed identical disaggregation profiles as hFGF-2 inclusion bodies indicating that the heterogenic composition of inclusion bodies did not influence the strength of interactions of hFGF-2 in aggregates formed in vivo as inclusion bodies compared to those generated in vitro from native and pure hFGF-2 through thermal aggregation. Compared to unfolding of native hFGF-2, higher concentrations of denaturant were required to dissolve hFGF-2 aggregates showing that more energy is required for disruption of interactions in both types of protein aggregates compared to the unfolding of the native protein. In vivo dissolution of hFGF-2 inclusion bodies was studied through coexpression of chaperones of the DnaK and GroEL family and ClpB and combinations thereof. None of the chaperone combinations was able to completely prevent the initial formation of inclusion bodies, but upon prolonged incubation mediated disaggregation of otherwise stable inclusion bodies. The GroEL system was particularly efficient in inclusion body dissolution but did not lead to a corresponding increase in soluble hFGF-2 rather was promoting the proteolysis of the recombinant growth factor. Coproduction of the disaggregating DnaK system and ClpB in conjunction with small amounts of the chaperonins GroELS was most efficient in disaggregation with concomitant formation of soluble hFGF-2. Thus, fine-balanced coproduction of chaperone combinations can play an important role in the production of soluble recombinant proteins with a high aggregation propensity not through prevention of aggregation but predominantly through their disaggregating properties.

Chaperonin 10↗
PubMed1992

Management of dysphagia in inclusion body myositis.

Inclusion body myositis is an inflammatory myopathy in which dysphagia has been considered a rare finding. However, recent literature finds dysphagia an increasingly common symptom as more cases of inclusion body myositis are identified. Unlike some inflammatory myopathic disorders, inclusion body myositis is resistant to treatment with corticosteroids, and therefore, the otolaryngologist may be consulted regarding surgical options for relief of dysphagia. A patient is described in whom severe progressive dysphagia associated with inclusion body myositis developed. Impaired pharyngeal wall motion and cricopharyngeal achalasia were demonstrated by videofluoroscopic evaluation, and the patient was successfully treated by cricopharyngeal myotomy. The pathophysiologic nature of inclusion body myositis and the mechanisms of cervical dysphagia in the inflammatory myopathies are reviewed.

Aged↗
PubMed2006

Localization of functional polypeptides in bacterial inclusion bodies.

Bacterial inclusion bodies, while showing intriguing amyloid-like features, such as a beta-sheet-based intermolecular organization, binding to amyloid-tropic dyes, and origin in a sequence-selective deposition process, hold an important amount of native-like secondary structure and significant amounts of functional polypeptides. The aggregation mechanics supporting the occurrence of both misfolded and properly folded protein is controversial. Single polypeptide chains might contain both misfolded stretches driving aggregation and properly folded protein domains that, if embracing the active site, would account for the biological activities displayed by inclusion bodies. Alternatively, soluble, functional polypeptides could be surface adsorbed by interactions weaker than those driving the formation of the intermolecular beta-sheet architecture. To explore whether the fraction of properly folded active protein is a natural component or rather a mere contaminant of these aggregates, we have explored their localization by image analysis of inclusion bodies formed by green fluorescent protein. Since the fluorescence distribution is not homogeneous and the core of inclusion bodies is particularly rich in active protein forms, such protein species cannot be passively trapped components and their occurrence might be linked to the reconstruction dynamics steadily endured in vivo by such bacterial aggregates. Intriguingly, even functional protein species in inclusion bodies are not excluded from the interface with the solvent, probably because of the porous structure of these particular protein aggregates.

Capsid Proteins↗
PubMed1998

Amyloid-beta deposition in skeletal muscle of transgenic mice: possible model of inclusion body myopathy.

Inclusion body myopathy is a progressive muscle disorder characterized by nuclear and cytoplasmic inclusions and vacuolation of muscle fibers. Affected muscle fibers contain deposits of congophilic amyloid, amyloid-beta immunoreactive filaments, and paired helical filaments, all of which are pathological hallmarks of Alzheimer's disease in brain. Accumulations of amyloid-beta and its precursor are thought to play important roles in the pathogenesis of both inclusion body myopathy and Alzheimer's disease. Overexpression of mutant forms of beta protein precursor in transgenic mice by neuron-specific promoters has been reported to cause amyloid deposits in the brain. Here we report that overexpression in transgenic mice of the signal plus 99-amino acid carboxyl-terminal sequences of beta protein precursor, under the control of a cytomegalovirus enhancer/beta-actin promoter, resulted in vacuolation and increasing accumulation of the 4-kd amyloid-beta and the carboxyl-terminus in skeletal muscle fibers during aging. These deposits in transgenic muscle only rarely showed Congo red birefringence. Thus, overexpression of part of beta protein precursor in transgenic mice led to development of some of the characteristic features of inclusion body myopathy. These mice may be a useful model of inclusion body myopathy, which shares a number of pathological markers with Alzheimer's disease.

Age Factors↗
PubMed2005

Amyloid-like properties of bacterial inclusion bodies.

Bacterial inclusion bodies are major bottlenecks in protein production, narrowing the spectrum of relevant polypeptides obtained by recombinant DNA. While regarded as amorphous deposits formed by passive and rather unspecific precipitation of unfolded chains, we prove here that they are instead organized aggregates sharing important structural and biological features with amyloids. By using an Escherichia coli beta-galactosidase variant, we show that aggregation does not necessarily require unfolded polypeptide chains but rather depends on specific interactions between solvent-exposed hydrophobic stretches in partially structured species. In addition, purified inclusion bodies are efficient and highly selective nucleation seeds, promoting deposition of soluble homologous but not heterologous polypeptides in a dose-dependent manner. Finally, inclusion bodies bind amyloid-diagnostic dyes, which, jointly with Fourier transform infra red spectroscopy data, indicates a high level of organized intermolecular beta-sheet structure. The evidences of amyloid-like structure of bacterial inclusion bodies, irrespective of potential applications in bioprocess engineering, prompts the use of bacterial models to explore the molecular determinants of protein aggregation by means of simple biological systems.

Amyloid↗
PubMedDate not supplied

Intranuclear inclusion bodies in an elderly demented woman: a form of intranuclear inclusion body disease.

Intranuclear inclusion body disease (INIBD) is a rare neuropathological entity characterized by eosinophilic intranuclear bodies in neurons and/or glia. While this disease generally occurs in children, in whom it presents as a multiple systems degeneration, a few adult cases are also described. Only 4 previously reported adult cases have had an associated dementia and all of these patients had additional significant neurological abnormalities. We report a 72-year-old woman with primary degenerative dementia in whom intranuclear inclusion bodies (INIB) were a major neuropathologic finding. The INIB were most easily found in astrocytes of Alzheimer II type, which had proliferated in the cortex and white matter. Occasional neurons were affected. The inclusions consisted of 13 nm diameter filaments associated with amorphous electron-dense material, arranged in a random pattern without lattice formation. They did not stain with antibodies against all 3 neurofilament subunits, glial fibrillary acidic protein, tau-1 protein, vimentin, keratin or actin. We conclude that INIBD is a rare substrate of primary degenerative dementia in elderly patients.

Aged↗
PubMed1996

[Inclusion body myositis].

Inclusion body myositis has been recently recognized as a clinical entity although its exact definition remains uncertain. Initially considered to be an inflammatory dermatomyositis, inclusion body myositis can actually take on three specific forms: disseminated muscle atrophy and weakness, pseudopolymyositis, or pseudo-degenerative disease. Inclusion body myositis is different from non-inflammatory neuromuscular diseases with vacuoles. Abnormal deposits are seen within the muscle fiber may contain amyloid substance, beta-amyloid precursor, ubiquitin, antichymotrypsin, protein tau, apolipoprotein E and even prions. The signification of these deposits is unknown. Deletions in mitochondrial DNA have been demonstrated but do not appear to play a causal role. More and more hereditary forms are being recognized and certain may be related to an abnormality in chromosome 9.

Amyloid beta-Peptides↗