.

2002.
Book on IBM:
The Official Patient's Sourcebook on Inclusion Body Myositis: A Revised and Updated Directory for the Internet Age by Icon Health Publications 2002, ISBN: 0597830738
-Book Description
-This book has been created for patients who have decided to make education and research an integral part of the treatment process. Although it also gives information useful to doctors, caregivers and other health professionals, it tells patients where and how to look for information covering virtually all topics related to inclusion body myositis (also Idiopathic inflammatory myopathy), from the essentials to the most advanced areas of research. The title of this book includes the word official. This reflects the fact that the sourcebook draws from public, academic, government, and peer-reviewed research. Selected readings from various agencies are reproduced to give you some of the latest official information available to date on inclusion body myositis. Given patients' increasing sophistication in using the Internet, abundant references to reliable Internet-based resources are provided throughout this sourcebook. Where possible, guidance is provided on how to obtain free-of-charge, primary research results as well as more detailed information via the Internet. E-book and electronic versions of this sourcebook are fully interactive with each of the Internet sites mentioned (clicking on a hyperlink automatically opens your browser to the site indicated). Hard-copy users of this sourcebook can type cited Web addresses directly into their browsers to obtain access to the corresponding sites. In addition to extensive references accessible via the Internet, chapters include glossaries of technical or uncommon terms.
A review by Bill: Review

Molecular profiles of inflammatory myopathies.
Greenberg SA, Sanoudou D, Haslett JN, Kohane IS, Kunkel LM, Beggs AH, Amato AA.
Neurology 2002 Oct 22;59(8):1170-82
This work uses new techniques of computer analysis of DNA to study the genes associated with PM, DM, and IBM. This is done to try to get a better, more clear diagnosis between these conditions and to also shed light on the causes of the disorders. Researchers looked at which genes are most active (gene expression) in patients with different disorders. It is shown that the different types of disorders have unique gene profiles. One thing that shocks me is how many different genes and different types of genes are over-expressed - how complex can IBM be? For IBM, examples include genes related to: cytokines (10 genes), major histocompatibility complex class I molecules (3 genes) and class II molecules (7 genes), immunoglobulins (8 genes), other lymphocyte markers (9 genes), actin cytoskeleton (5 genes), alpha-interferon induced transcription factors (2 genes), other interferon induced (8 genes), proteases (2 genes), protease inhibitors (2 genes), adhesion molecules (6 genes and other (4 genes).
Abstract of article: OBJECTIVE: To describe the use of large-scale gene expression profiles to distinguish broad categories of myopathy and subtypes of inflammatory myopathies (IM) and to provide insight into the pathogenesis of inclusion body myositis (IBM), polymyositis, and dermatomyositis. METHODS: Using Affymetrix GeneChip microarrays, the authors measured the simultaneous expression of approximately 10,000 genes in muscle specimens from 45 patients in four major disease categories (dystrophy, congenital myopathy, inflammatory myopathy, and normal). The authors separately analyzed gene expression in 14 patients limited to the three major subtypes of IM. Bioinformatics techniques were used to classify specimens with similar expression profiles based on global patterns of gene expression and to identify genes with significant differential gene expression compared with normal. RESULTS: Ten of 11 patients with IM, all normals and nemaline myopathies, and 10 of 12 patients with Duchenne muscular dystrophy were correctly classified by this approach. The various subtypes of inflammatory myopathies have distinct gene expression signatures. Specific sets of immune-related genes allow for molecular classification of patients with IBM, polymyositis, and dermatomyositis. Analysis of differential gene expression identifies as relevant to disease pathogenesis previously reported cytokines, major histocompatibility complex class I and II molecules, granzymes, and adhesion molecules, as well as newly identified members of these categories. Increased expression of actin cytoskeleton
genes is also identified. CONCLUSIONS: The molecular profiles of muscle tissue in patients with inflammatory myopathies are distinct and represent molecular signatures from which diagnostic insight may follow. Large numbers of differentially expressed genes are rapidly identified.

[I think this theme is interesting: chlamydia pneumoniae]

1: Chlamydia pneumoniae infection of the central nervous system.
Yucesan C, Sriram S. Multiple Sclerosis Research Center, Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
Curr Opin Neurol 2001 Jun;14(3):355-9
Chlamydia pneumoniae is a common respiratory pathogen that is now being implicated in a number of chronic diseases. That the organism can infect vascular endothelium, macrophages and smooth muscle cells suggests that it may play a role in many systemic diseases. The present review focuses on the possibility that the central nervous system can also be a target of this agent. The tropism of C. pneumoniae to the neural tissue suggests it may play a role in diverse neurologic diseases, including Alzheimer's disease, multiple sclerosis and giant-cell arteritis.

2. Role of infection in Alzheimer's disease.
Balin BJ, Appelt DM. Department of Pathology/Microbiology, Philadelphia College of Osteopathic Medicine, Pennsylvania 19131, USA. brianba@pcom.edu
J Am Osteopath Assoc 2001 Dec;101(12 Suppl Pt 1):S1-6
Alzheimer's disease (AD) is a chronic condition in which inflammation has been shown to contribute to neurodegeneration. Current thinking suggests that deposition of beta-amyloid in the brain promotes inflammation resulting in neuronal damage/death. Alternatively, our data suggest that chronic inflammation observed in late-onset sporadic AD may be stimulated by infection with the obligate, intracellular bacterium, Chlamydia pneumoniae. Our results indicate that C. pneumoniae is found in high frequency in glial cells in areas of neuropathology within the brains of patients with AD. Based on our evidence, nervous system infection with C. pneumoniae should be considered a risk factor for sporadic AD.

3: Infectious link to Alzheimer's disease
30 October 2002 17:00 EST
by Martina Habeck
Taken from: http://news.bmn.com/news/story?day=021031&story=2 (link now closed)
Infecting normal mice intranasally with the respiratory pathogen Chlamydia pneumoniae promotes plaque development consistent with Alzheimer's disease, US researchers will report next month at the Society for Neuroscience meeting in Orlando. The finding provides the Alzheimer's world with a long-needed experimental model for sporadic, late-onset Alzheimer's disease (AD) - and, possibly, with a culprit for the disease. Human AD can be attributed to a genetic defect in only 5% of cases. "The question in my mind has always been: How do you take a disease that is this prevalent and explain its presence in a genetically heterogeneous population such as human beings?" said Karl Herrup, professor of neurosciences at Case Western Reserve University.
     Infection with C. pneumoniae is a possible answer. A cousin of the more widely known sexually-transmitted C. trachomatis, C. pneumoniae is a common respiratory pathogen that causes acute and chronic conditions such as pneumonia, sinusitis and chronic obstructive pulmonary disease. A small bacterium, it can survive inside host cells for years and cause inflammatory responses.
     C. pneumoniae made the news in the early 1990s, when it was found living in atherosclerotic plaques. Since then, C. pneumoniae infection has been implicated in the development of atherosclerosis. Curious to see whether it can also infect the nervous system, Brian Balin, Denah Appelt (now at Philadelphia College of Osteopathic Medicine), and Alan Hudson of Wayne State University analyzed post-mortem brains of 38 AD patients and controls.    
     A majority of AD patients had the bacterium in brain regions affected by the disease, while only one control was PCR-positive. The researchers even succeeded in culturing the bacterium isolated from AD brains.
     A few negative reports followed, but chlamydiologist James Mahony of McMaster University believes these were due to sampling errors, because cutting serial sections within a paraffin block is "hit and miss." There is "no question in my mind that [chlamydia] is in the brain," says Mahony, who has corroborated Balin's findings. But the question remains whether it plays a causal role in AD.
     Four years on, Balin and Appelt presented new data that caught the attention of virtually every delegate at the International Alzheimer's meeting in Sweden in July this year. Scott Little, a post-doc in Appelt's and Balin's lab, had infected non-transgenic BALB/c mice with a strain of C. pneumoniae isolated from an AD patient or vehicle alone.
     Within 1-3 months, the researchers found plaques immunoreactive for A-beta 1-42 in the mouse brains. According to Appelt, the plaque load in infected animals rose over time and did not clear a year after infection. Control animals did not develop comparable plaques.
      Herrup, who attended the meeting in Sweden, said the study was "well done" and "rigorously analyzed," which demanded that Alzheimer's researchers take serious note. For a start, someone else must confirm the results. Meanwhile, Balin and Appelt have already done their own control experiments, and have infected BALB/c mice with a respiratory strain of C. pneumoniae. Preliminary evidence indicates this strain also promotes plaque development in the BALB/c brain, they will report at the Society for Neuroscience meeting in Orlando this month.
     The jury is still out as to whether the infected mice also develop the second pathogenic hallmark of AD, neurofibrillary tangles. Appelt and Balin are investigating this, and are also gearing up to do some behavioral studies.
     "I think the most stunning implication is that the mouse nervous system is capable of producing Alzheimer-like plaques without the use of genetic trickery," said Herrup. Having a non-genetic model of AD would enhance the field and "make our drug- and therapy-testing much more apprehensive."
     Mahony agrees: "It will be very interesting to play with the model and see if you can block the formation of plaques by intervening at some point in whatever pathway of events you think occurs." He suggests blocking the action of cytokines, to see whether chlamydia contributes to inflammation that may play a key role in AD.
     Balin and Appelt have already found another clue to chlamydia's role in AD. Having infected cultured monocytes and endothelial cells with C. pneumoniae, they observed that it actually upregulates the production and processing of the amyloid protein. "We think that there is a direct effect of the organism on amyloid, and that is how we think it will play into the Alzheimer problem," Balin said.
      Time and more research will tell whether and how C. pneumoniae is involved the development of AD. "My prediction would be that we are not looking at the cause of all AD," said Herrup, "but that we might actually be getting insight into the kinds of insults that lead to the development of the sporadic form. We already think that vascular factors predispose. To have another route to disease can only help the field."
     Balin now wants to set up clinical trials testing the effect of antibiotics used against C. pneumoniae in patients with late-onset AD. "Right now, we are thinking that combining antibiotics and anti-inflammatory drugs might be instrumental in treating AD," he added. Antibiotics alone might offer hope to people with sporadic AD who show signs of chlamydia infections, he says, but it remains uncertain whether antibiotics can ever eradicate the organism permanently.

Clinical and serological characteristics of 125 Dutch myositis patients. Myositis specific autoantibodies aid in the differential diagnosis of the idiopathic inflammatory myopathies.
-Hengstman GJ, Brouwer R, Egberts WT, Seelig HP, Jongen PJ, van Venrooij WJ, van Engelen BG. Neuromuscular Centre Nijmegen, Institute of Neurology, University Medical Centre Nijmegen, The Netherlands. g.hengstman@czzoneu.azn.nl
J Neurol. 2002 Jan;249(1):69-75.
The idiopathic inflammatory myopathies (IIM) are a heterogeneous group of systemic diseases that include the familiar disease entities of dermatomyositis (DM), polymyositis (PM), and inclusion body myositis (IBM). A subset of patients has unique autoantibodies which are specific for IIM (myositis specific autoantibodies; MSAs). We studied the clinical and serological characteristics of IIM in 125 Dutch patients. Sera were analysed by immunoblotting, enzyme-linked immunosorbent assay, and immunoprecipitation. The most frequently encountered MSA was the anti-Jo-1 autoantibody (20%), followed by anti-tRNAHis (6%), anti-Mi-2 (6%), and anti-SRP (4%). The presence of certain MSAs was clearly associated with specific clinical characteristics. Anti-Jo-1 and anti-tRNAHis were associated with the anti-synthetase syndrome, anti-SRP with PM with severe myalgia and arthralgia and a moderate response to immunosuppressive treatment. A novel finding was the presence of anti-Mi-2, not only in DM, but also in PM. MSAs were frequently present in DM/PM sera, but were hardly ever detected in the sera of IBM patients. The few IBM patients with MSAs demonstrated a significant response to immunosuppressive treatment. It can be concluded that MSAs define specific clinical syndromes within the spectrum of IIM and that they can assist in the differential diagnosis and treatment plan of these enigmatic disorders by virtually excluding IBM by their presence, and by potentially identifying a subgroup of steroid-responsive IBM patients.

[An important mouse model of IBM has been created. This model will speed research and testing of possible new treatments. This research also shows that a "mismetabolism" of amyloid-beta precursor protein may be an integral component in the development of IBM.]
Reference:
Inclusion body myositis-like phenotype induced by transgenic overexpression of beta APP in skeletal muscle.
Sugarman MC, Yamasaki TR, Oddo S, Echegoyen JC, Murphy MP, Golde TE, Jannatipour M, Leissring MA, LaFerla FM.
Proc Natl Acad Sci U S A 2002 Apr 30;99(9):6334-9
Abstract: Inclusion body myositis (IBM), the most common age-related muscle disease in the elderly population, is an incurable disorder leading to severe disability. Sporadic IBM has an unknown etiology, although affected muscle fibers are characterized by many of the pathobiochemical alterations traditionally associated with neurodegenerative brain disorders such as Alzheimer's disease. Accumulation of the amyloid-beta peptide, which is derived from proteolysis of the larger amyloid-beta precursor protein (betaAPP), seems to be an early pathological event in Alzheimer's disease and also in IBM, where in the latter, it predominantly occurs intracellularly within affected myofibers. To elucidate the possible role of betaAPP mismetabolism in the pathogenesis of IBM, transgenic mice were derived in which we selectively targeted betaAPP overexpression to skeletal muscle by using the muscle creatine kinase promoter. Here we report that older (>10 months) transgenic mice exhibit intracellular immunoreactivity to betaAPP and its proteolytic derivatives in skeletal muscle. In this transgenic model, selective overexpression of betaAPP leads to the development of a subset of other histopathological and clinical features characteristic of IBM, including centric nuclei, inflammation, and deficiencies in motor performance. These results are consistent with a pathogenic role for betaAPP mismetabolism in human IBM.

Differential expression of chemokines in inflammatory myopathies.
De Bleecker JL, De Paepe B, Vanwalleghem IE, Schroder JM.
Neurology 2002 Jun 25;58(12):1779-85
[Basic idea: some problem in the muscle fibre causes the muscle cell to display a "flag" that signals our immune system that the muscle cell is defective, this sets off an immune response aimed at muscle fibers - our body sends its immune defenders into muscle fibers and this kills them. What causes this flagging to happen in the first place remains unknown (maybe a virus in the muscle cell causes the initial reaction).This study suggests that IBM and PM share a similar cause and chain but that DM is different.]
-BACKGROUND: Chemokines represent a family of small-molecular-weight cytokines that recruit and activate inflammatory cells in response to inflammation. Invasion of cytotoxic memory T cells and macrophages in nonnecrotic muscle fibers characterizes polymyositis and sporadic inclusion body myositis. Dermatomyositis is a complement-mediated endotheliopathy. Elucidation of the mechanisms guiding lymphocyte diapedesis and trafficking could lead to selective therapeutic interventions. METHODS: Immunoblots and multistep immunofluorescence studies with non-cross-reactive antibodies recognizing interleukin-8, monocyte hemoattractant protein-1 (MCP-1), MCP-3, TARC (thymus and activation regulated cytokine), and RANTES (regulated upon activation, normal T-cell expressed and secreted), using appropriate positive and negative controls. In situ hybridization was used to localize MCP-1 mRNA. RESULTS: MCP-1 protein was strongly expressed on T cells and a subset of macrophages actively invading a proportion of the nonnecrotic muscle fibers in polymyositis and inclusion body myositis alike. Capillaries and arterioles in the vicinity of endomysial inflammatory foci were immunoreactive for MCP-1, with faint or no expression in unaffected parts of the tissue. By contrast, widespread and strong endothelial MCP-1 expression occurred on perifascicular and perimysial endothelia in dermatomyositis, also at sites remote from inflammatory infiltrates. In some control specimens, a subset of capillaries also expressed MCP-1, possibly reflecting a role of this chemokine in normal immune surveillance. MCP-1 mRNA was detected in scattered macrophages in each inflammatory myopathy. All other chemokines were absent. CONCLUSION: Chemokines are differentially expressed in the symptomatic stage of inflammatory myopathies. MCP-1 plays a major role in the myocytotoxicity in polymyositis and inclusion body myositis. MCP-1 may be induced by membranolytic attack complex binding to endothelial cells in dermatomyositis.

Misunderstandings, misperceptions, and mistakes in the management of the inflammatory myopathies.
Kissel JT.
Semin Neurol 2002 Mar;22(1):41-51
Many misconceptions persist concerning fundamental issues related to the idiopathic [means we don't know why they occur or what causes them] inflammatory myopathies. Such misconceptions can lead to frank mistakes in the diagnosis and management of these disorders. In some cases, these misperceptions have resulted from overreliance on out-of-date information and "classic" articles that are no longer classic! In other instances, misperceptions persist because of the many voids in our understanding of these diseases. This review uses case presentations to highlight important caveats [points and reservations we need to know about] in diagnosing and managing the common idiopathic inflammatory myopathies.

Rimmed vacuoles and the added value of SMI-31 staining in diagnosing sporadic inclusion body myositis.
van der Meulen MF, Hoogendijk JE, Moons KG, Veldman H, Badrising UA, Wokke JH.Department of Neurology, G 03.228, Division of Neuromuscular Disorders, University Medical Centre Utrecht, Heidelberglaan 100, 3584 CX, The, Utrecht, Netherlands. m.f.g.vdmeulen@neuro.azu.nl
Neuromuscul Disord. 2001 Jul;11(5):447-51.
Problems in diagnosing sporadic inclusion body myositis may arise if all clinical features fit a diagnosis of polymyositis, but the muscle biopsy shows some rimmed vacuoles. Recently, immunohistochemistry with an antibody directed against phosphorylated neurofilament (SMI-31) has been advocated as a diagnostic test for sporadic inclusion body myositis. The aims of the present study were to define a quantitative criterion to differentiate sporadic inclusion body myositis from polymyositis based on the detection of rimmed vacuoles in the haematoxylin-eosin staining and to evaluate the additional diagnostic value of the SMI-31 staining. Based on clinical criteria and creatine kinase levels in patients with endomysial infiltrates, 18 patients complied with the diagnosis of sporadic inclusion body myositis, and 17 with the diagnosis of polymyositis. A blinded observer counted the abnormal fibres in haematoxylin-eosin-stained sections and in SMI-31-stained sections. The optimal cut-off in the haematoxylin-eosin test was 0.3% vacuolated fibres. Adding the SMI-31 staining significantly increased the positive predictive value from 87 to 100%, but increased the negative predictive value only to small extent. We conclude that (1) patients with clinical and laboratory features of polymyositis, including response to treatment, may show rimmed vacuoles in their muscle biopsy and that (2) adding the SMI-31 stain can be helpful in differentiating patients who respond to treatment from patients who do not.

Peripheral neuropathy associated with hereditary and sporadic inclusion body myositis: confirmation by electron microscopy and morphometry.
Hermanns B, Molnar M, Schroder JM. Institut fur Neuropathologie, Universitatsklinikum der Rheinisch-Westfalischen Technischen Hochschule Aachen, Pauwelsstrasse 30, D-52074, Aachen, Germany.
J Neurol Sci. 2000 Oct 1;179(S 1-2):92-102.
Inclusion body myositis (IBM) is a disabling myopathy affecting proximal and distal muscle groups. The involvement of peripheral nerves in IBM is still a controversial matter. In a previous morphometric study at the light microscopic level only, we described a peripheral neuropathy in sural nerve biopsies of eight patients with sporadic IBM (s-IBM). Here we present a larger series of 14 cases in which a combined muscle and nerve biopsy was available for additional electron microscopic investigation. In two of the new cases, the IBM had a hereditary background (h-IBM). The presence of neuropathy was confirmed in all 14 cases studied. Morphometry using an optic-electronic, digital evaluation system showed large variation of severity presumably due to age and coincidal factors such as diabetes mellitus or lymphoma. Ultrastructural analysis revealed a variety of changes considered to be non-specific. Signs of axonal damage predominated. In addition, there were numerous changes in Schwann cells and myelin sheaths. Neither inflammatory changes nor tubulofilamentous inclusions were detectable in the sural nerves. Peripheral neuropathy, although occasionally without apparent clinical manifestation, appears to be a common and aggravating feature in IBM; its pathogenesis, however, remains elusive.

The Role of Cytotoxic Effector Molecules and Cytokines in Inflammatory Myopathies
Norbert Goebels, Marco DeRossi and Reinhard Hohlfeld
Basic Appl. Myol. 8 (5): 389-397, 1998
Abstract: The inflammatory myopathies include dermatomyositis (DM), polymyositis (PM) and inclusion body myositis (IBM). In DM, muscle fiber injury is secondary to an antibody- or immune-complex-mediated immune response against a vascular-endothelial component. In PM and IBM, initially non-necrotic muscle fibers are invaded and eventually destroyed by CD8+ T cells and macrophages. The autoaggressive T cells have the phenotype of activated (HLA-DR+) memory (CD45RO+) cells. T cell receptor (TCR) analyses revealed that the autoaggressive T cells are oligoclonal. In inflammatory lesions, muscle fibers express a number of cytoplasmic and surface molecules that are not detectable in normal muscle fibers. These molecules, which include HLA-class I antigens, heat-shock proteins, adhesion molecules and Fas, are probably induced by locally secreted cytokines. Although many of the muscle fibers invaded by CD8+ T cells express the Fas 'death receptor', signs of apoptosis are absent. However, the autoaggressive CD8+ T cells possess perforincontaining granules, which they orient towards the contact zone with the target muscle fiber. This is consistent with a perforin- and secretion-dependent mechanism of muscle fiber injury.
Excepts:
"In contrast, in PM and IBM there is a conspicuous endomysial inflammatory exudate containing large numbers of CD8+ T cells and only sparse B cells, along with collections of cytotoxic macrophages that surround nonnecrotic muscle fibers."
"it is safe to conclude that in the inflammatory myopathies, many inflammatory cells, muscle fibers and endothelial cells express a complex array of different cytokines. The local production of cytokines is likely to induce several cell interaction and adhesion molecules on these tissue elements."
"Taken together, these results establish that the autoaggressive (autoinvasive) T cells in the inflammatory lesions of PM and IBM muscle represent activated CD8+ memory T cells."
"Conclusions: The results of the studies reviewed here are consistent with the following sequence of pathogenetic events. First, some muscle fibers, which do not constitutively express detectable levels of MHC class I, are induced to express MHC class I and class I-associated (auto)antigen(s). Next, the MHC class I-positive muscle fibers are surrounded by CD8+ T cells, some of which traverse the basal lamina of the muscle fiber and contact the muscle fiber surface. After recognition of "their" antigen, the CD8+ become activated and secrete perforin and perhaps other cytotoxic effector molecules. In the early stages of muscle fiber invasion, the surface membrane of muscle fibers appears to remain intact at the light microscopic [21] and electronmicroscopic [1]
level. Pore-like structures could not be detected in the sarcolemma of muscle fibers attacked by T cells in PM [1]. One possible explanation is that perforin pores/channels on nucleated cells in vivo are smaller in size than the pores generated in vitro on erythrocytes and other target cells by the addition of purified perforin. Perforin pores containing less than 10-20 monomers would escape detection by electron microscopy [49]. Another explanation for the lack of morphologically visible muscle cell damage is that the surface membrane of the muscle fiber is rapidly repaired at least during the early stages of muscle fiber invasion. Repair could occur, for example, by shedding or endocytosis of poredamaged membrane (reviewed in ref.[32])."

.