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Information About IBM.

Site presented by Bill Tillier

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This material is a bit out of date but I have kept it up in case it is of use to you. The most up-to-date information is on the main index page and the associated research pages.

Part 1: Primary Information on IBM.

 

Part 2: Some Specific IBM Issues.

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Part 1: Primary Information on IBM.

The following information is fairly challenging, complicated and comprehensive. I suggest that patients read through the PDF overview linked below before going through this page.

My thanks to Robert W. Albrecht for his comments.

An overview of Inclusion Body Myositis in everyday language [Revision: August 2009].

Greek Letters Used: α (alpha) β (beta) γ (gamma) δ (delta) ε (epsilon) λ (lambda)

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Part 2: Some Specific IBM Issues.

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1-1). Basic information on sIBM.

1-1 A). Basic overview and symptoms.

What does it do to me?

The following diagram presents the typical pattern of muscle weakness seen. [From: http://mda.org/disease/inclusion-body-myositis/overview]

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1-1 B). Lifestyle Impacts.

Also see the section on practical coping strategies

sIBM will have a major impact on a patient's lifestyle, primarily, in mobility issues and issues involving daily life functions. For example, many patients have difficulty with functions in the bathroom such as getting up off the toilet and conducting personal hygiene. Bathing and showering become major tasks and are very dangerous given the risk of falling. Eventually, assistance will be required to perform these basic functions along with adaptive devices (for example, overhead track in the bedroom and bathroom).

Activities in the bedroom are also affected. It becomes difficult to roll one self over in bed and being in one position too long can cause bed sores. Getting in and out of bed can be an issue.

For men, although erections are not affected, it becomes impossible to support oneself while making love in the missionary position (man on top).

As the disease progresses, patients may have difficulty feeding themselves.

Activities in the kitchen must also be curtailed as, for example, it becomes impossible to open a can or to lift a full saucepan. As mentioned above, any activity involving the fingers or lifting objects becomes a challenge.

As our activity level decreases it becomes more and more important to eat a balanced diet and to reduce our overall intake of food (because fewer calories are required as we move less). The less weight we carry, the less our muscles will have to lift and also the better to prevent cardiac trouble or diabetes.

Driving becomes challenging as it is often difficult to lift the foot from the accelerator onto the brake pedal (obviously a very dangerous scenario). Steering is also affected as it becomes difficult, even with power steering, to turn the wheel a full rotation. Installation of hand controls can be effective in the short term but eventually these also become impractical. These factors often lead to having to eventually give up driving. Finally, getting in and out of the car becomes difficult and eventually impossible. As the illness progresses, many patients who can no longer walk and who must resort to electric wheelchairs, acquire wheelchair vans for transportation. (Although many patients buy inexpensive scooters this is not recommended as we will be spending essentially all of our waking hours in the chair and this makes it important to have a custom-made seat that is correctly sized for our body. These specialized seats are generally only available on electric wheelchairs. In addition, electric wheelchairs have many other advantages over scooters).

As mentioned above, while sIBM will affect one's lifestyle it should not shorten one's life span. In coping with this illness I have suggested that people need to be flexible and positive in dealing with their symptoms. It is especially important to realize when you need help, to ask for help and to accept help and this may involve eventually having a full-time caregiver. This illness can be very stressful and challenging especially on the spouses and great care is suggested to prevent caregiver burnout occurring in the spouse or other primary caregiver. These changes can be very difficult to accept, especially for older males, but they are directly related to the success in dealing with this frustrating disease. I have found it important that as I have had to give up things, for example, my job, driving, some of my hobbies -- I have been able to replace these activities with other positive ways to still make a contribution to life and to remain engaged in life -- this webpage is an example. Our challenge is to derive as much quality of life as possible while managing these frustrating symptoms. It's my belief that we should always be positive in remembering that this disease does not affect the heart or brain, thus we should be thankful that it is not worse than it is.

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1-1 C). The course, incidence and prevalence of sIBM.

Because IBM is so variable, we don't know two critical things about sIBM:

What is the course of sIBM once it starts?

How is the disorder going to affect people who get it? We need to know this to see if a treatment is effective. For example, if we KNEW that sIBM causes a 10% decline in strength every year, and we treat it and we can see that this decline goes down to 5% a year, then we can infer that the treatment works, at least to some extent. But, we don't know the course of the illness to begin with and this makes it hard to judge how effective treatments are. A treatment may not increase strength but may slow down the progression, again this is hard to judge when we know little about the course of the disorder. Researchers stress that the presentation of IBM (the symptoms that are observed) are quite variable in different people and as well, the rate of progression appears to be quite variable as well. In addition, it is well known that the disorder comes on at different ages, likely ranging from onset in the late 30s and up (20% of cases report symptoms in their 40s and the disease probably has been going on for some time before symptoms are noticed). The hereditary form usually strikes at an earlier age.

Rate of decline: How fast will it progress? There is no "textbook" figure to go by. This is also a bit hard to see as atrophy of the muscle (shrinkage) does not affect perceived strength at first. I have read that an atrophy of about 50% is needed before a person notices that a muscle feels weak. There is no doubt that the disease is affecting muscles for some time (likely years) before a person notices symptoms and goes to a doctor and the diagnosis is made. By the time of the diagnosis, a great deal of muscle has already been damaged. From the time of diagnosis, the rule of thumb seems to be that a patient "will require an assistive device, such as a cane, walker or wheelchair, within several years of onset." (Dalakas, 2006 )

What is the incidence and prevalence of sIBM?: How common is it?

sIBM is a rare disease but the true incidence of sIBM is a bit unclear and not much research exists on the number of cases or of the ages when people are first diagnosed. In the past, studies have suggested that it is diagnosed in only about 5 people per million population, although some doctors have said they feel the actual numbers are much higher.

The most recent research, done in Australia, indicates that the incidence of IBM varies and is different in different populations and different ethnic groups. The authors found that the current prevalence was 14.9 per million in the overall population, with a prevalence of 51.3 per million population in people over 50 years of age. Needham et al, 2008.

Barohn (2006) said there was an annual incidence of 2 to 5 cases per 100,000 (or about 20 to 50 cases per million).* In other words, this implies that about 6000 cases per year would be diagnosed as having sIBM. It is more common in men (2 to 3 males to 1 female).

* Barohn, R J. MD; Herbelin, L BS; Kissel, J T. MD; King, W PT; McVey, A L. MD; Saperstein, D S. MD; Mendell, J R. MD. Pilot trial of etanercept in the treatment of inclusion-body myositis. Neurology Volume 66(2) Supplement 1, pg. S123-S124, January 24, 2006.

Dalakas, 2006 said: sIBM is the most common acquired myopathy in patients above the age of 50 years, and it affects men slightly more often than it does women. Its prevalence is estimated at between 4.3 and 9.3 per 1,000,000, rising to 35.3 per 1,000,000 for people over the age of 50 years.

It is very likely that many people have sIBM who never get diagnosed (and many people are likely diagnosed and treated as PM cases). Also, there may be many people out there with mild cases who get weaker as they age and say "I'm just getting older." So, a lot of people may die having sIBM and never realize it: they never seek medical help. Biopsy is very invasive and expensive, so it is not practical to do in every case. But if we did more, perhaps we would find that sIBM is more common than we think.

sIBM is considered a rare disorder. For comparison, about 1 in 500 people has Multiple Sclerosis (MS). "So, if it is so rare, how can Dalakas call it the most common muscle disease after age 50?" In my opinion, this is a bit misleading because by age 50, all of the other muscle diseases that a person can get have already shown up, so I think sIBM is one of the only muscles diseases left that can show up after 50 (and remember that about 20% of cases show symptoms before the age of 50 as well). Still, people who are severely enough affected to go to the doctor and to get diagnosed with sIBM may only be the tip of a larger iceberg. As it is, our low numbers create a problem: there are not enough people to do good studies on.

The hereditary inclusion body myopathy forms are extremely rare, some forms with as few as 15 cases, others with a few hundred cases confirmed worldwide.

Incidence is a measure of how many people are diagnosed with an illness per 100,000 (or per some other index) over a period of time (usually one year). Thus, incidence is a measure of the risk of developing some new condition within a specified period of time. For example, if a population initially contains 1,000 non-diseased persons and 28 develop a condition over two years of observation, the incidence proportion is 28 cases per 1,000 persons, i.e. 2.8%. The prevalence of a disease is defined as the total number of cases of the disease in the population at a given time, or the total number of cases in the population, divided by the number of individuals in the population. It is used as an estimate of how common a condition is within a population over a certain period of time. From: Incidence (epidemiology). (2008, December 17). Wikipedia, The Free Encyclopedia. Retrieved 03:13, December 29, 2008

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1-1 D). Fact sheets.

An sIBM fact sheet from: The Muscular Dystrophy Campaign (UK).

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1-1 E). Genetics.

Sporadic inclusion bodies myositis is not an inherited disorder and is not passed on to children. The latest view is that sIBM is a disorder influenced by a number of genes (a polygenetic disorder) that is predisposed by the interaction of a number of genes with each other. Based on our understanding of other polygenetic disorders, it is likely that such a predisposition would also interact with environmental variables further increasing or decreasing the probability of an individual developing the disorder. Such variables may be age (young cells decrease the probability, older cells increase the probability) or some exposure to sort of acquired virus. There are very rare forms of IBM (hereditary inclusion body myopathy) that are related to specific genetic mutations and that are passed on to children, however, there has not been a particular gene defect linked to sporadic inclusion body myositis.

When we think about genetic diseases, we generally think of mutations occurring in a particular gene that causes some sort of illness. No such genetic defect has been detected and directly linked to sporadic inclusion body myositis. It's important to realize that different individuals and different groups of people show slightly different combinations of genes. Groups of people from different ethnic backgrounds and from different geographical locations will share distinctive genetic ancestry that differs from groups of people from different areas and different backgrounds. Research on the genetics of sporadic inclusion body myositis has uncovered a group of genes that are present in about 70% of the cases tested. This cluster of genes has also been associated with higher incidences of several other autoimmune disorders such as rheumatoid arthritis. This group of genes is most common in Caucasian people with Northwestern European ancestry. A couple of other signs point to a genetic predisposition in sporadic IBM. One sign is that in a few rare cases, sIBM is seen in brothers and sisters within the same generation. This is called familial IBM and is mentioned below. Finally, the fact that there are several forms that are definitely genetic (although exceedingly rare) that are similar to the sporadic type are an indication that there likely is some sort of genetic interaction somewhere in the sporadic form as well. Research on other diseases has indicated that genetic predispositions often interact with environmental variables. In summary, there may be a pattern of genes involved in creating a susceptibility to getting sIBM but this particular combination of different genes would not likely be passed on to children, therefore, while sIBM may be predisposed by a person's genetic makeup, this form is not considered an inherited disease per se.

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1-1 F). Some basic terminology and relevant abbreviations.
  • Ankle-foot orthosis a brace, usually plastic, worn on the lower leg and foot to support the ankle, hold the foot and ankle in the correct position, and correct foot drop. Also known as a foot-drop brace.
  • aspiration = having food "go down the wrong way" and enter the lungs usually causing pneumonia
  • derm = skin
  • dermatomyositis = a widespread inflammation of the body's muscles with a major skin component (a rash)
  • dysphagia = difficulty in swallowing. In IBM dysphagia is caused by weakness in the muscles in the throat
  • familial: a disease where more than one case occurs in family members in the same generation (more than would normally be statistically expected) but not passed from generation to generation.
  • hereditary [inherited] = genetic cause: passed on from generation to generation
  • idiopathic: a term indicating of unknown cause
  • inclusion = a bundle or clump. An inclusion body is an abnormal structure in a cell nucleus or cytoplasm having characteristic properties when seen under the microscope (using different stains to highlight different things in the tissue sample). Inclusion bodies are a characteristic of sIBM.
  • Knee-Ankle-Foot Orthosis A KAFO is a long-leg orthosis that spans the knee, the ankle, and the foot in an effort to stabilize the joints and assist the muscles of the leg.
  • Myo = muscle
  • myositis = inflammation of the muscle
  • myopathy = pathology (destruction / disease) of muscle
  • "pathy" = disease / death / destruction / severe illness
  • poly = many, multiple
  • "sitis" = inflammation of something
  • sporadic [spontaneous] = unpredictable, it just shows up, cause unknown
  • vacuole = a hole. A vacuole is small cavity in the cytoplasm of a cell, bound by a single membrane and containing water, food, or metabolic waste. Some diseases are characterized by abnormal vacuolization of certain tissues; too many and/or too big (e.g., Alzheimer's has abnormal vacuoles in the brain, as well as various muscle diseases including sIBM). In, addition, the vacuoles often contain abnormal chemicals and other things that shouldn't be there.

Relevant abbreviations:

- AβPP amyloid-β precursor protein
- AD Alzheimer Disease
- AD-IBM Hereditary autosomal dominant inclusion-body myopathy; autosomal dominant inclusion body myopathy
- ADDLs Aβ-Derived Diffusible ligands
- AFO Ankle-foot orthosis
- AH ancestral haplotype
- αB-C αB-crystallin
- α-syn α-Synuclein
- AP alkaline phosphatase
- APC antigen-presenting cell
- APP amyloid precursor protein
- ApoE apolipoprotein E
- AR-hIBM Autosomal recessive Hereditary Inclusion Body Myopathy
- CMA Chaperone-mediated autophagy
- COX cytochrome-c-oxidase
- CTL chymotrypsin-like
- DCs dendritic cells
- DM dermatomyositis
- DMRV distal myopathy with rimmed vacuoles (Nonaka)
- ER endoplasmic reticulum
- ERK extracellular signal regulated kinase
- fIBM familial cases of inclusion-body myositis
- hIBM hereditary inclusion body myopathy
- human leukocyte antigen (HLA)
- IBMPFD IBM associated with Paget's disease and frontotemporal dementia
- IBM3 (previously known as AD myopathy with congenital joint contractures, ophthalmoplegia and rimmed vacuoles).
- IIMs Idiopathic inflammatory myopathies
- IBM2 Inclusion Body Myopathy 2
- KAFO Knee-Ankle-Foot Orthosis
- MHC major histocompatibility complex
- MSTN myostatin
- OMIM Online Mendelian Inheritance in Man
- PGPH Peptidyl-Glutamyl Peptide-Hydrolytic
- PHFs paired helical filaments
- PM polymyositis
- PrPC prion protein [the normal or cellular type]
- p-tau phosphorylated tau protein
- QSM quadriceps-sparing myopathy (Quadriceps-sparing Inclusion Body Myopathy)
- RRF ragged-red fibers
- s-IBM sporadic inclusion body myositis
- SMN survival motor neuron
- TCR T-cell receptor
- TL trypsin-like
- VCP valosin-containing protein
- UPS ubiquitin-proteasome system

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1-2). The current classification of IBM.

1-2A). Classification of the Myositis Forms

Overview:
- Sporadic (or spontaneous) inclusion body myositis (sIBM)
- Familial inclusion body myositis (fIBM)

a). Sporadic (or spontaneous) inclusion body myositis (sIBM):

Inclusion Body Myositis is characterized by three major changes in the muscle cells:

b). Familial inclusion body myositis (fIBM):

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1-2B). Classification of the Myopathy (Inherited) Forms:

a). Overview:

b). Types currently linked to defects on specific chromosomes:

c). Details of the major subtypes of inherited forms as currently described:

[Based upon the classification of the Neuromuscular Disease Center, Washington University, St. Louis, MO., USA]

Note: OMIM is a catalog of human genes and genetic disorders run by the National Center for Biotechnology Information. I have provided the numbers for the OMIM descriptions (where available) for these disorders, click on them for more information.

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1-2C). Idiopathic inflammatory myositis or idiopathic inflammatory myopathies.

Other major diseases under the muscular dystrophy (MD) umbrella include myotonic dystrophy, Duchenne MD, Becker MD, Spinal Muscular Atrophy (SMA) as well as about 120 other diseases so far identified, some with many different subtypes. IBM is unique in its presentation among the muscular dystrophies.

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1-2D). Sporadic inclusion body myositis versus Polymyositis.

Polymyositis (PM) shows some features in common with IBM, and IBM is often first mistakenly diagnosed as polymyositis. It appears that in polymyositis there is the same sort of immune reaction against muscles that occurs in sIBM. In polymyositis, muscle cells display "flags" (MHC class I antigens) on their surfaces alerting the immune system that they are infected or damaged and the immune system attacks (with CD8+ cells) and kills them.

Patterns of inflammation in polymyositis and s-IBM are identical but different from patterns found in other muscular dystrophies that are known to exhibit inflammation (dermatomyositis). Polymyositis tends to come on over weeks or months as opposed to the onset of IBM which is usually over months or years. A major difference is that in PM there is no muscle fiber degeneration noted - there are no inclusions or abnormal proteins seen and PM generally responds well to therapy whereas sIBM does not. Cases of PM that do not respond to treatment are likely actually misdiagnosed IBM. IBM tends to strike a different population (generally of older men) compared to PM. In conclusion, s-IBM and polymyositis appear to share a primary immune process with antigen-driven T cells invading non-vacuolated muscle fibres, but sIBM also appears to involve a secondary degenerative process in which abnormal proteins are involved in vacuolar degeneration of the muscle fibres.

It appears that dermatomyositis is a different disease altogether, although it is still classified along with PM and IBM as an inflammatory myositis.

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1-2E).Terms and types of genetic disease transmission / acquisition that we need to differentiate:

There are several aspects we need to be clear about:
  • spontaneous disorders
  • inherited genetic disorders.
  • spontaneous genetic disorders
  • familial disorders
  • congenital disorders
  • multigenic, multifactorial disorders

a). Spontaneous Disorders. The term spontaneous is used to refer to IBM cases (sIBM) that simply arise in people. In these cases, there is usually no family history, the individual is the only person with the disorder in the family and there is no reason to suspect that it has been inherited. At this point, no specific mutation is linked to sIBM and therefore, it is also assumed that the sIBM will not be directly passed on to offspring.

b). Inherited Genetic Disorders.
When we talk about inherited diseases, we are usually talking about single gene diseases that are are usually linked to a specific genetic mutation. About 4000 such diseases have been identified. These disorders "run in families" and are passed on from a parent to an offspring via sperm or egg cells that carry a mutation. Usually, the individual inherits the same mutation that the parent has (although in some conditions the mutations can change slightly and can become more or less serious over generations). The different types of hIBM fall under the category of inherited genetic disorders. An individual with hIBM can pass it on to his or her offspring. hIBM may show dominant or recessive inheritance, depending upon the type involved.

c). Spontaneous Genetic Disorders.
In spontaneous genetic disease, the egg and sperm cells inherited from mom and dad start out as normal, but after conception, as the cells replicate, a defect in the gene code occurs (a mutation) and causes a disease. This type of new mutation may occur in a sperm or egg cell or it may occur in a body (somatic) cell. If it occurs in a somatic cell, it may well cause disease in the individual (usually cancer) but it will not be passed on to future offspring. If the new mutation occurs in an egg or sperm cell, it may cause a disorder in the individual and may also be passed on to offspring (this is how all genetic diseases originally start out). The individual with the new (spontaneous) egg or sperm cell mutation is the starting point for the inherited disorder in his or her family tree. In these cases, no prior family history will be present as the mutation just occurred in this generation.

d). Familial disease refers to a disease occurring in more members of a family in a single generation than would be expected by chance alone. Not inherited. Familial often is (wrongly) used interchangeably with hereditary or inherited. On this page, familial means that more than one case of sIBM occurs in family members in the same generation, but this does not mean that the disease is inherited or hereditary (it is not passed on from one generation to the next, from parent to child).

e). Congenital diseases: Strictly speaking these are conditions present at birth - symptoms are present at birth. Congenital anomalies may be inherited or sporadic, isolated or multiple, apparent or hidden, gross or microscopic. IBM illnesses are not congenital as they do not manifest symptoms until later in life.

f). Multigenic, Multifactorial Disorders (diseases with complex segregation patterns):
Most common diseases (cancer, heart disease, etc.) are not related to a single gene or to a single mutation and do not conform to the simple, single genetic inheritance picture described above (point 2). They cannot be easily classified as dominant or recessive (they have complex segregation patterns). They are called multifactorial disorders (also called "complex diseases"). There is usually a pattern of genes present which, by themselves, are neither necessary nor sufficient to cause the disease. These genes interact with other genes and with environmental factors to predispose the disease. An example are autoimmune diseases. sIBM likely falls under the category of a multigenic, multifactorial disorder.

Genetic Inheritance Background:
There are two main classes and four types of single-gene genetic diseases:
A). Recessive diseases: These are diseases where two copies of a defective gene must be inherited, one from each parent to get the disease. Inheriting this gene error from only one parent usually causes the person to be a "carrier" of the disease, able to pass it on to offspring, but usually without any sign of symptoms. (hIBM type 2)
B). Dominant diseases: These genetic diseases only require a single copy of the defective gene to be inherited from either mom or dad. The bad gene from one parent dominates the corresponding good gene from the other parent. There is no such thing as a "carrier" of a dominant disease because everyone who has the genetic error gets the disease. (hIBM 1, hIBM 3 and IBMPFD)

With this in mind, there are actually four major types of genetic diseases with different inheritance patterns:
1). Autosomal recessive genetic diseases: Disease occurs when both copies of a mutated gene on chromosome 1 to 22 are inherited from both parents. The two bad copies combine to cause the disorder. (hIBM type 2)
2). Autosomal dominant genetic diseases: Disease occurs when a single mutated copy of a gene on chromosome 1 to 22 is inherited from either parent. The bad copy dominates the other good copy to cause the disorder. (hIBM 1, hIBM 3 and IBMPFD)
3). X-linked recessive genetic diseases: A single gene error on the X chromosome causes disease in men (who have only one copy of X) but usually not in women (who have two copies of X, usually in these cases, one mutated and one healthy, the healthy one is usually enough to compensate). (Hemophilia and Duchenne muscular dystrophy).
4). X-linked dominant genetic diseases: A single gene error on the X chromosome will cause the disease in both men and women. Men have only one copy of X, so get the disorder. In women (who are XX) the bad copy dominates the good copy and they get the disorder. X-linked dominant diseases are much rarer than X-linked recessive diseases.
(Y-linked diseases are essentially unknown.)

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1-3). Diagnosis.

1-3 A). How is sIBM diagnosed?

a). Clinical Signs

Clinical signs are the symptoms the doctor can see when he or she examines you. The first common clinical signs of sIBM are falling down and tripping and weakness in the finger flexors: the muscles involved in grip. Doctors look for the characteristic patterns of weakness and wasting (shrinkage) described above, in particular, in the quadriceps and the finger flexor muscles.

b). Tests Commonly Done

       Important types of changes in the structure of muscle cells are characteristic of sIBM and often appear in a biopsy:

  1. Inflammation is seen in the muscle: inflammatory cells are seen invading the muscle cells.
  2. Degenerative changes in the muscle cell and protein accumulation
  1. There is evidence of mitochondrial involvement as evidenced by segmental deficiency of cytochrome c oxidase (COX-deficient fibers) and ragged-red fibers (RRF) see Needham et al (2007).

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1-3 B). Specific medical diagnostic criteria.

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1-3 C). Ambiguity of a Myositis Diagnosis:

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1-3 D). The importance of a biopsy in sIBM:

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1-4). Causes and abnormalities.

1-4 A). Synopsis of abnormalities seen in sIBM:

Inflammation:

Abnormal proteins:

How the different inflammation and cellular deterioration are related to each other (which come first, what causes what, etc.) is not well understood yet. Also, what abnormalities are responsible for just what symptoms is not well understood.

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1-4 B). Synopsis of possible causes of sIBM:

Overview:

sIBM as an inflammatory / immune system disease (also see 2-5, 2-9):

Update:

The molecular basis of IIMs in humans, as in many other autoimmune rheumatic diseases, is heterogeneous, involving several complex cellular components that probably contribute to differences in disease susceptibility, clinical and histopathological phenotype, and severity. Although this heterogeneity makes the study of the pathogenesis of IIMs extraordinarily complex, it might also provide distinct avenues for novel therapeutic interventions. Controlling the immune response is as complex as its launching. An essential feature of physiological immune response is its self-limitation, by which it is attenuated by several mechanisms. We have only just started to understand the orchestrated life of T lymphocytes, B lymphocytes, and DCs in IIMs, but there are still many unanswered questions about how this usually effective system can go awry and result in false immune-mediated reactions.

On the basis of detailed immunohistochemical studies on muscle biopsies, two major types of inflammatory infiltrate were observed: endomysial and perivascular/perimysial. In endomysial infiltrates there was a striking dominance of CD8+ T lymphocytes, which could even be the predominating infiltrating cell type, followed by macrophages and CD4+ T lymphocytes. These infiltrates often surrounded nonnecrotic fibers and sometimes seemed to invade the fibers. This observation suggests an immune reaction that targets muscle fibers. The perivascular infiltrates, in contrast, were dominated by CD4+ T lymphocytes and macrophages, and sometimes the presence of B lymphocytes suggested an immune reaction that targets microvessels. A role for B lymphocytes as well as one for CD4+ T lymphocytes in the pathogenesis of IIMs is supported by frequently detected autoantibodies in polymyositis and dermatomyositis but less often in inclusion-body myositis. These autoantibodies are both non-specific (frequently also being found in other autoimmune disease) and myositis specific [38,39]. A role for CD4+ T lymphocytes in the disease mechanism is further supported by the genetic association with HLA-DRB1*0301, DQA1*0501, and DQB1*0201, which was particularly seen for subgroups of patients with autoantibodies.

The endomysial infiltrates were reported to be characteristic features of polymyositis and inclusion-body myositis, whereas the perivascular infiltrates were associated with patients with dermatomyositis. However, there are cases with a less distinct localization of infiltrates or with combined endomysial and perivascular cellular infiltrates [3,6]. Moreover, in some cases the inflammatory cell infiltrates are diffusely spread in the tissue, whereas in other cases the infiltrates are very small or are not found at all. In addition, the perivascular changes may be seen in patients without a skin rash, whereas endomysial infiltrates are occasionally seen in cases with a skin rash.

Taken together, these results indicate that there may be two major pathways: one leading to cellular infiltrates with predominating endomysial localization [more often seen in patients with IBM and polymyositis], and another with a predominantly perivascular localization often with microvessel involvement and capillary loss. The latter is more often seen in patients with a skin rash and dermatomyositis, but there seems to be an overlap between clinical phenotypes, histopathology, and immunotypes. These observations suggest that there might be more than just one factor that determines the histopathological and clinical phenotypes, for example genes and environment.
From: Grundtman C, Malmstrom V, Lundberg IE. Immune mechanisms in the pathogenesis of idiopathic inflammatory myopathies. Arthritis Res Ther. 2007 Mar 26;9(2):208.

Overview - The immune response to the muscle cells:

Many doctors, including Dr. Dalakas, are proposing that sIBM is an autoimmune disorder characterized first by a T-cell inflammatory response. In sIBM, the muscle fibers display MHC class I antigens on their surfaces and that this creates an ongoing invasion of the muscle cells by CD8+ cytotoxic T cells that target and kill the muscle cells. These events are also associated with genes in the HLA-DR and DQ regions. Other autoimmune diseases are common in patients with sIBM and/or in their families. Dalakas is also suggesting that the antigens presented are consistent over time implying a persistent stimulation of the immune system by the same antigens. This idea was supported by the finding that the T-cells that invade the muscle cells have the specific rearrangement in the TCR gene for the recognition of these antigens. As of now, they do not know what these antigens are. Dalakas also notes that sIBM is mysterious because it does not respond to immunotherapies and this is confusing as, in theory, these sorts of drugs should help.
Reference: Amemiya K, Granger RP, Dalakas MC. Clonal restriction of T-cell receptor expression by infiltrating lymphocytes in inclusion body myositis persists over time. Studies in repeated muscle biopsies. Brain. 2000 Oct;123 ( Pt 10):2030-9.

IBM has been modeled as having cytotoxic T lymphocyte (CTL)-mediated destruction of MHC class I antigen expressing myofibers. In simple terms, this means that in sIBM, muscle cells (myofibers) display "flags" (called MHC class I antigens) on their surfaces alerting the immune system that they are infected or damaged and the immune system attacks them with CD8+ - CTLs. The CTLs secrete molecules that destroy the muscle cell. A virus might cause this sort of reaction but no virus has yet been discovered related to sIBM. It is also possible that sIBM is an autoimmune disorder and many believe that it is an autoimmune disease, in which the body's own immune system attacks healthy muscles. An antibody is a protein used by the immune system to identify and neutralize foreign objects like bacteria and viruses. Each antibody recognizes a specific antigen unique to its target. Antigens have sites on their surface called epitopes, that are part of class I histocompatibility molecules that interact with specific antibodies. Almost all the cells of the body express these class I molecules. CD8+ T cells bind to these sites. It is known that in the muscles of patients with sporadic inclusion body myositis (sIBM) some of the muscle fibres come to display an immune "flag" (antigen presentation) on their surface. Why? We don't know but the cause likely is either a virus or an autoimmune reaction. This flag starts a chain of events that leads to the long term activation of a response from the immune system. Immune cells see the flag (like a target) and invade the muscle cell with CD8+ cells and kill it.

Today, we see that "muscle is not just a passive target of immune reactions. On the contrary, muscle cells or myoblasts can express various cytokines, chemokines, adhesion molecules, and costimulatory
molecules upon immunological challenge. This enables them to actively participate in immune reactions, for example, as antigen-presenting cells. . . . "Moreover, the innate responses of muscle cells and their
armamentarium of cytokines, chemokines, and MMP do not only affect the mechanisms of immune surveillance but may also be involved in the processes of muscular degeneration and regeneration."
Reference: Bettina Schreiner et al, Expression of toll-like receptors by human muscle cells in vitro and in vivo: TLR3 is highly expressed in inflammatory and HIV myopathies, mediates IL-8 release, and upregulation of NKG2D-ligands. The FASEB Journal express article 10.1096/fj.05-4342fje. Published online November 17, 2005. Recent research (see What's New 2004, the article by Schmidt et al) strengthens the idea that sIBM is caused by some sort of problem in the immune system. This offers the chance that medications can be developed to target breaking a link in the chain of the immune interactions involved between seeing the flag and killing the muscle cell so that the destruction of the muscle cells could be stopped.

In summary, in sIBM, there is a long term activation of the bodies immune response, apparently directed toward specific antigens ("targets") on the muscle cells that leads to inflammatory reactions that in turn lead to progressive muscle destruction and weakness (see Muntzing et al, August 2003, Scandinavian Journal of Immunology 58, 195-200.) We see that the immune system mounts and continues to mount a consistent response for many years after symptoms (weakness) appear. So, what is the antigen responsible: what is the flag or trigger that causes the immune response? Generally, it is either to something foreign (like a bacteria or a virus) or it is an autoimmune disorder. In this model of sIBM, the protein abnormalities seen in the muscle cells are thought to be a secondary effect of the immune attack on the muscle cells, and not a cause of the sIBM.

- i). The Viral Infection Model of sIBM:

- The type of immune response seen in sIBM is similar to our response to certain types of viruses, especially retroviruses, thus, perhaps some undiscovered virus (or combination of viruses) infects the muscles and causes sIBM.

- "The best evidence points towards a connection with retroviruses. At least seven HIV or human T-lymphotropic virus (HTLV)-1-positive patients with sIBM have been reported, and we have seen six more cases in the past 3 years, indicating that the disease might be more common in patients who live longer . . . The disease is triggered by clonally driven subpopulations of activated CD8+ cells that expand in situ and invade muscle fibers expressing MHC class I, as seen in retrovirus-negative polymyositis and sIBM. These cells are retrovirus-specific, because their CDR3 region contains amino acid residues that are specific for viral peptide bound to HLA molecules. The retroviral infection, combined with immune recognition of the retrovirus, is sufficient to trigger the inflammatory process." Dalakas, 2006 [See section 2-9]

- If it's a virus, why is IBM so rare? One reason could be that the virus is rare, or because only a few people get the virus (or combination of viruses). Second, the virus could be a more common type but the virus interacts with an individual's genetics and only a few people have the genetic disposition that interacts with the virus to produce sIBM. (Most people would have a genetic disposition that does not lead to any disease when combined with this unknown virus (or combination)). If there is a link between sIBM and Alzheimer Disease perhaps a virus causes both diseases, a few people may have the genetic disposition that interacts with the virus to lead to sIBM (pretty rare), while more people may have a genetic disposition that interacts with the virus to lead to Alzheimer Disease (Alzheimer is much more common than sIBM). This is all very open to conjecture.

- If it's a virus, why has it not been discovered? If it is HTLV-1, why have only 13 cases been discovered out of the thousands of people who have sIBM?

- Many viruses get into us and live inside us all of our lives. Some viruses seem to be "slow acting" and may take years before we see symptoms. So, this is not quite like catching a cold and getting sick and being better in two weeks. Perhaps the aging of the cells in the body makes us more vulnerable to the virus; it may be there all the time, but when we are young, we are able to fend it off, as we age, its effects are greater.

- ii). sIBM could be an autoimmune disorder:

In an autoimmune disorder, the body recognizes its own tissues as foreign and directs an immune response against them. It is possible that the immune reaction to the muscle in sIBM is an autoimmune reaction. Other important examples of autoimmune disorders include: Multiple sclerosis, Crohn's Disease, Myasthenia gravis, Ulcerative colitis, Guillain-Barré, Rheumatoid arthritis, Systemic lupus erythematosus, polymyositis, and dermatomyositis. See: http://www.niaid.nih.gov/publications/immune/the_immune_system.pdf

- iii). Pros and cons of sIBM as an inflammatory / immune system disease:

- Points for this idea:
= More and more research is establishing the immune reaction in sIBM.
= It is not clear yet what causes it, but the usual suspects are actively being investigated.

Dalakas, 2006 notes 10 factors supporting an immunopathogenic disease mechanism for sporadic inclusion body myositis:

1 Immunogenetic association with DRb1*0301, DQb1*0201 alleles and the B8-DR3-DR52-DQ2 haplotype
2 DQ2 haplotype; the human leukocyte antigen (HLA)-A haplotype is associated with earlier disease onset
3 Occurrence of sporadic inclusion body myositis (sIBM) in family members of the same generation (familial inflammatory IBM), as seen with other autoimmune disorders
4 Association with other autoimmune disorders and autoantibodies
5 Association with paraproteinemia at a significantly higher frequency than in age-matched controls (22.8% vs 2%)
6 Association with common variable immunodeficiency and natural killer cells
7 Association with HIV and human T-lymphotropic virus (HTLV)-1 infection (13 cases reported to date)
8 CD8+ autoinvasive T cells surround major histocompatibility complex (MHC) class I-expressing fibers, express perforin and activation markers of cytotoxicity, and are clonally expanded
9 Ubiquitous upregulation of MHC class I antigen and costimulatory molecules on muscle fibers, even those not invaded by T cells; the counter-receptors of the costimulatory molecules are overexpressed on the autoinvasive T cells
10 Strong upregulation of cytokines, chemokines and their receptors at the protein, messenger RNA and gene level

 

- Points against this idea:
= sIBM is mysterious because it does not respond to immunotherapies that should help.

- Perhaps inflammation is not a primary feature, rather, it is a byproduct of some other chain of events. An initial cause may trigger a series of abnormalities that then cause the immune system reaction. In this case, the critical event that needs intervention (treatment) may occur BEFORE the immune system comes into play.
- There are still a lot of questions to be answered about the role of the immune system in sIBM.

sIBM as a protein disease:

- There is no doubt that there are many protein abnormalities seen in sIBM. The question is, is there an initial protein abnormality that causes the cascade of subsequent protein abnormalities and subsequent immune responses? Or, are the protein abnormalities the result of the immune system activation and attack or some other initial cause (a virus for example).

sIBM and stress inside the cell:

- Many diseases are mediated (made better or made worse by) by day-to-day stress. This is the kind of stress that we commonly understand when the term is used. If a person has high stress levels, the disease often is made worse. It is possible that high stress contributes to causing sIBM and/or to making it worse.

- There is another kind of stress scientists talk about that occurs inside the cell that has been implicated in sIBM. In the cell there is a system of interconnected membranes that transport materials called the endoplasmic reticulum. Proteins in the endoplasmic reticulum (ER) require an efficient system of molecular chaperones whose role is to assure their proper folding and to prevent accumulation of unfolded proteins. When unfolded proteins accumulate, it creates endoplasmic reticulum stress (ER stress or ERS). The response of cells to accumulation of unfolded/misfolded proteins in the ER is termed the "unfolded protein response" (UPR). Cells attempt to protect themselves against ER stress with the UPR.

- [In sIBM] the chronic upregulation of MHC class I exerts a stressor effect in the endoplasmic reticulum (ER), which might lead to a self-sustaining T-cell response. . . The ER maintains quality control by processing, folding and exporting MHC molecules loaded with antigen.. . . In sIBM, the muscle fibers are overloaded with MHC molecules, and the antigenic peptides might not undergo proper conformational change to bind to the MHC class I complex, leading to ER stress and further protein misfolding. Reference: Dalakas, 2006

- Askanas and her team have proposed that the ERS is part of the IBM pathogenic cascade, occurring in response to abnormally unfolded or misfolded proteins; and that the UPR, occurs in a failed attempt to facilitate proper folding of malfolded proteins, and/or their disposal. Reference: Gaetano Vattemi, W. King Engel, Janis McFerrin and Valerie Askanas Endoplasmic Reticulum Stress and Unfolded Protein Response in Inclusion Body Myositis Muscle American Journal of Pathology. 2004;164:1-7.

Science 15 September 2006: Vol. 313. no. 5793, pp. 1564 - 1566, DOI: 10.1126/science.313.5793.1564
Endoplasmic reticulum (ER) and endoplasmic reticulum stress.
by: Jean Marx
Protein synthesis involves a lot more than stringing amino acids together in the right order. To function correctly, each linear strand of amino acids has to fold into just the right three-dimensional shape and may also have to be modified by addition of sugars or other accessory molecules.

Cells making proteins have mechanisms to maintain quality. Recently, cell biologists have learned a great deal about how the cell manages this quality control for the protein assembly line located within a convoluted network of membranous tubes known as the endoplasmic reticulum (ER). Roughly one-third of the cell's proteins, mainly those that end up in cellular membranes or are secreted to the outside, are made in the ER.

Researchers have shown that the ER membrane contains three separate sensor molecules that respond when excessive amounts of unfolded proteins build up inside. This can happen with mutant proteins, such as the ones that cause hereditary Alzheimer's and Parkinson's disease. But it can also occur under more normal conditions if for some reason proteins are synthesized faster than they can fold and be modified. To alleviate this "ER stress," the sensors trigger a series of signaling pathways that shut down the synthesis of most proteins while turning up the production of those needed for protein folding and degradation.

This so-called unfolded protein response (UPR) is intended to protect the cell, but it's not foolproof. Sometimes, for example, the UPR can't eliminate the abnormal protein buildup in the ER. In that event, prolonged activity of the UPR may trigger cell death and may thus contribute to the neuronal loss of Alzheimer's, Parkinson's, and other neurodegenerative diseases. And the UPR may even backfire by protecting the cells of cancerous tumors from the lack of oxygen and nutrients they experience as tumors grow.

In addition to cancer and neurodegeneration, ER stress and the UPR have been linked to several other common human ills, including diabetes and heart disease. In fact, the research has already suggested a new way to guide breast cancer therapy and hinted at a novel drug treatment for diabetes. "The field is expanding so much in terms of mechanism and relevance to disease. It's just popping up everywhere," says cell biologist Randal Kaufman of the University of Michigan Medical Center in Ann Arbor.

Synopsis of specific theories:

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Part 2: Some Specific IBM Issues.

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2-2). sIBM and Peripheral Neuropathy:

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2-3). sIBM and Prion Protein:

Overview: A protein called prion protein (labeled PrP or PrPc), is normally found in human cells. Research has discovered that people with sIBM show increased levels of prion protein in their muscles. Abnormal forms of the prion protein (labeled PrPsc) have been linked to a series of brain diseases, in cattle called Bovine Spongiform Encephalopathy (BSE) ("Mad Cow Disease"), and in humans, a similar disease called Creutzfeldt-Jakob Disease (CJD). In 2001 a group of Italian researchers looked at the prion protein in sIBM patients and found that although its level was increased, it was the normal form. In 2004, the case of a man with both sIBM and CJD was examined. He had increased levels of the abnormal form of the prion protein in his muscle (not just in his brain as would be expected). It was suggested that because his levels of normal prion protein were increased in his muscles (due to his sIBM), that it was somehow easier for his CJD disease to convert the normal muscle prion into the abnormal prion form (this conversion occurring due to him having CJD).

Update:

Cellular prion protein regulaes (beta) -secretase cleavage of the Alzheimer's amyloid precursor protein
Edward T. Parkin*, Nicole T. Watt*, Ishrut Hussain§, Elizabeth A. Eckman, Christopher B. Eckman, Jean C. Manson,
Herbert N. Baybutt, Anthony J. Turner*, and Nigel M. Hooper
[The level of normal prion protein (PrP) in muscle has been reported to be elevated in patients with inclusion-body myositis. (beta) amyloid protein is thought to play a major role in Alzheimer disease and certainly is implicated in IBM. Now, research shows that the production of (beta) amyloid protein is regulated by normal prion protein. The research referenced below, found that high levels of normal prion proteins in human cells prevent (beta) amyloid formation. Conversely, mice genetically modified to lack normal prion protein had significantly higher (beta) amyloid levels. The research notes that this may have implications for both Alzheimer's (the focus of this research) as well as for the prion diseases. Obviously, given prion proteins elevated production in IBM this finding seems relevant here as well.]

Proteolytic processing of the amyloid precursor protein (APP) by (beta) -secretase, (beta) -site APP cleaving enzyme (BACE1), is the initial step in the production of the amyloid (beta) (A (beta) ) peptide, which is involved in the pathogenesis of Alzheimer's disease. The normal cellular function of the prion protein (PrPC), the causative agent of the transmissible spongiform encephalopathies such as Creutzfeldt- Jakob disease in humans, remains enigmatic. Because both APP and PrPC are subject to proteolytic processing by the same zinc metalloproteases, we tested the involvement of PrPC in the proteolytic processing of APP. Cellular overexpression of PrPC inhibited the (beta) -secretase cleavage of APP and reduced A (beta) formation. Conversely, depletion of PrPC in mouse N2a cells by siRNA led to an increase in A (beta) peptides secreted into the medium. In the brains of PrP knockout mice and in the brains from two strains of scrapie infected mice, A (beta) levels were significantly increased. Two mutants of PrP, PG14 and A116V, that are associated with familial human prion diseases failed to inhibit the (beta) -secretase cleavage of APP. Using constructs of PrP, we show that this regulatory effect of PrPC on the (beta) -secretase cleavage of APP required the localization of PrPC to cholesterol-rich lipid rafts and was mediated by the N-terminal polybasic region of PrPC via interaction with glycosaminoglycans. In conclusion, this is a mechanism by which the cellular production of the neurotoxic A (beta) is regulated by PrPC and may have implications for both Alzheimer's and prion diseases.

Update:

PNAS April 17, 2007 vol. 104 no. 16 pps. 6800-6805.
Inducible overexpression of wild-type prion protein in the muscles leads to a primary myopathy in transgenic mice.
Shenghai Huang, Jingjing Liang, Mengjie Zheng, Xinyi Li, Meiling Wang, Ping Wang, Difernando Vanegas, Di Wu, Bikram Chakraborty, Arthur P. Hays, Ken Chen, Shu G. Chen, Stephanie Booth, Mark Cohen, Pierluigi Gambetti, and Qingzhong Kong.
The prion protein (PrP) level in muscle has been reported to be elevated in patients with inclusion-body myositis, polymyositis, dermatomyositis, and neurogenic muscle atrophy, but it is not clear whether the elevated PrP accumulation in the muscles is sufficient to cause muscle diseases. We have generated transgenic mice with muscle-specific expression of PrP under extremely tight regulation by doxycycline, and we have demonstrated that doxycyclineinduced overexpression of PrP strictly limited to muscles leads to a myopathy characterized by increased variation of myofiber size, centrally located nuclei, and endomysial fibrosis, in the absence of intracytoplasmic inclusions, rimmed vacuoles, or any evidence of a neurogenic disorder. The PrP-induced myopathy correlates with accumulation of an N-terminal truncated PrP fragment in the muscle, and the muscular PrP displayed consistent mild resistance to protease digestion. Our findings indicate that overexpression of wild-type PrP in skeletal muscles is sufficient to cause a primary myopathy with no signs of peripheral neuropathy, possibly due to accumulation of a cytotoxic truncated form of PrP and/or PrP aggregation. accumulation of PrP in the muscle fibers (19). The present study reports that strictly muscle-specific overexpression of wild-type human PrPC [the normal or cellular prion protein] under tight regulation by doxycycline in Tg mice leads to a primary myopathy. These data argue that overexpression of wild-type PrP in the skeletal muscle is in itself sufficient to cause a myopathy. Our data demonstrate that overexpression of wild-type PrP [PrPC ] in the skeletal muscles alone is sufficient to cause myopathy. These findings strongly suggest that the elevated levels of PrP found in the skeletal muscles of human primary myopathies, such as inclusion body myositis (3 to 5) and inflammatory myopathies including polymyositis and dermatomyositis (5), may play an important role in the pathogenesis.

Background: Prion protein (PrP or PrPc) is a normal part of cells in mammals. It can become abnormal and is then referred to as PrPsc. Stanley Prusiner has suggested that this abnormal protein alone can cause infections leading to severe diseases. This has been controversial and many scientists initially disagreed with this theory, suggesting that a virus of some sort must also be involved. Recent evidence (Science July 30, 2004) confirms that the abnormal prion protein alone appears to be a sufficient single cause of the problems and that no other virus is needed for infection. Creutzfeldt-Jakob {KROITS- Felt Ya- Cop} disease (CJD): A rare, degenerative, life-threatening brain disorder characterized by severe, progressive dementia; visual disturbances; muscle weakness; and abnormal involuntary movements, such as sudden, brief, "shock-like" muscle spasms (myoclonus), tremor, and relatively slow writhing motions that appear to flow into one another (athetosis). Most frequently, Creutzfeldt-Jakob disease is thought to erupt spontaneously (sporadically), (sCJD) with no detectable cause, although, about 10 percent of cases are familial, suggesting a hereditary predisposition to the disease. Evidence suggests that CJD is somehow caused by abnormalities of the human prion protein gene or contamination with abnormal prion protein (PrPsc) ("prion" was named for "protein infectious agent"). Changes in the prion protein appear to lead to distinctive neurodegenerative abnormalities, i.e., some regions of brain tissue have relatively small, round, "sponge-like" (spongiform) cavities or gaps and looks like a sponge. CJD belongs to a group of related neurodegenerative disorders categorized as "transmissible spongiform encephalopathies." Similar diseases can occur in other animals, for example, bovine spongiform encephalopathy (BSE) (seen in cattle: the so-called "mad cow disease"); Scrapie (in sheep); Chronic wasting disease (in deer); Feline spongiform encephalopathy (FSE in house cats). In rare cases, CJD in humans may has resulted from exposure to contaminated surgical instruments during brain surgery and was also reported in the past due to therapy with pituitary-derived human growth hormone. In addition, a variant form of CJD (V-CJD or nV-CJD) has been reported, primarily in the United Kingdom. V-CJD is a human disease linked to the consumption of material from cows with bovine spongiform encephalopathy (BSE). To date, at most, only a few hundred cases of nV-CJD have been seen in humans. In 2001, an Italian group of researchers lead by Zanusso looked at the prion in patients with sIBM. Increased amounts of prion protein expression and deposition have been described in pathological muscle fibers of two human muscle disorders: sporadic inclusion-body myositis (s-IBM) and hereditary inclusion-body myopathy. They found only the normal form of the prion (PrPc), and not the abnormal (PrPsc) form in s-IBM. The researchers concluded that "the present results exclude that s-IBM is a prion disease". Reference: Zanusso G, et al, "Increased expression of the normal cellular isoform of prion protein in inclusion-body myositis, inflammatory myopathies and denervation atrophy". Brain Pathol. 2001 Apr;11(2):182-9. In a recent (2004) case study of a 68 year old man who had both sCJD and sIBM, the abnormal form of prion protein was found outside of his neural tissues and was found in his muscle (we would expect it in his brain because of his CJD, but finding it in his muscles and outside of his nervous system was a first). Pathological prion protein (PrPsc) is the hallmark of prion diseases affecting primarily the central nervous system. Researchers demonstrated abundant PrPsc (abnormal prion) in the muscle of this patient with sporadic Creutzfeldt-Jakob disease and inclusion body myositis. The researchers conclude that "Extraneural (outside of the nervous system) conversion of PrPc to PrPsc in Creutzfeldt-Jakob disease appears to become prominent when PrPc is abundantly available as a substrate, as in inclusion body myositis muscle." Reference: Kovacs GG et al, Creutzfeldt-Jakob disease and inclusion body myositis: abundant disease-associated prion protein in muscle. Ann Neurol. 2004 Jan;55(1):121-5. The role of prion (PrPc) in normal muscle and the role of increased PrPc in muscles in sIBM is unknown at present. This line of research will be interesting to watch.

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2-5). sIBM as an immunological versus a neurological / neuromuscular disease:

Many patients are referred to neurologists, many also happen to be referred to a rheumatologist and many see both types of doctors. There can be fairly major differences in clinical approaches (how the doctor approaches the disorder and treats you) between these two specialties. These differences also mirror the basic theories of sIBM: if it is an immune disease of some sort, then it traditionally falls more into rheumatology. If it is a muscular problem then it falls more into neurology. Both types of doctors are trying to understand and treat sIBM. Does it matter what kind of doctor you see? -- probably not as both kinds are capable of diagnosing IBM.

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2-6). sIBM and Alzheimer disease (AD):*

Here are two pertinent figures from LaFerla (2007) describing the role of amyloid beta in Alzheimer.

construction

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2-7). sIBM as an age related disorder - oxidative stress and proteostasis.

Aging in general is a very complicated concept and process that occurs on many different levels, from the level of the cell to the level of the whole organism. Generally speaking, aging is related to the number of cellular divisions that occur -- our body's cells divide and reproduce and, as they do, they age. The analogy of a Xerox is perhaps appropriate -- if you copy a page and then copy each successive copy again and again, the first copies are excellent but eventually, the quality of the image deteriorates and after enough copies the image becomes hard to read. Similarly, eventually, as cells reproduce they lose their dividing potential and eventually age just as our Xerox becomes fuzzier and fuzzier. There appear to be complex cellular and genetic mechanisms that control this aging process -- this aging process is natural -- it is built into our cellular mechanisms.

Part of the control of aging is now understood to be genetic -- each chromosome of DNA has a structure on its end called a telomere that acts like a bookend, protecting the end of the chromosome and preventing it from binding with other DNA. Each time a cell divides, the DNA is unwrapped and copied, however the telomeres are not copied in this replication process. In dividing, the DNA is clipped and this clipping occurs at the site of the telomere, therefore when the DNA rewraps the core of the DNA remains identical but the telomere has lost a bit of material and becomes shorter. After about 50 or 60 replications, the telomeres's shortness becomes an issue -- like a pencil eraser that has been used about 50 or 60 times and now is essentially worn off and can no longer perform its normal function. One of the confusing aspects of biology is that cancer produces an enzyme called telomerase that prevents the telomere from shortening -- hence, cancer cells do not age the way normal cells do and essentially are immortal, reproducing over and over without end.

There are several central mechanisms related to aging and implied in age-related disorders. I will currently only highlight two examples, oxidative stress and proteostasis.

Oxidative stress

One aspect of aging is related to normal cellular metabolism which is based upon the consumption of oxygen. In a cell, structures called mitochondria are the main energy factories, producing a chemical called adenosine triphosphate (ATP) that is the main source of chemical energy in the cell. The chemical mechanisms involved in this process use oxygen and a very small percentage of these chemical reactions create what are called partially reduced forms of oxygen. As it turns out, these odd forms of oxygen are extremely toxic and poisonous to the cell. They are sometimes referred to as free radicals. Normally, cells maintain a delicate balance between the formation of these chemical products -- oxidant formation -- versus oxidant elimination. Cells contain a number of natural antioxidant defenses designed to deal with the formation of these oxidant forms and to maintain this delicate balance.Young cells appear to be able to maintain this balance quite effectively. However, as cells age they become less capable of dealing with these chemical products and become more susceptible to damage from free radicals.

Because the mitochondria are the main source of these reactions in the cell, they often are the first to be impacted by free radical damage. This mitochondrial damage has been implicated in aging in general and in a number of age related disorders, including many movement and neurodegenerative disorders.

It has become popular to talk about antioxidants in food (for example, foods high in vitamin C and E and (beta)-carotene) and in supplements (for example, coenzyme Q10 and creatine) as the idea is that adding antioxidants to one's diet will help boost the normal cellular processes, improving the cell's ability to deal with oxidation and thus, in a sense delay aging. Research has demonstrated this approach increases the lifespan of different animals but no human study has yet demonstrated a change in human mortality rates. Research on age related diseases using antioxidant supplements has been encouraging (for example, in Parkinson's disease) but research is in its early stages and no clear trends are confirmed yet.

Superoxide dismutases (SODs).
Manganese Superoxide Dismutase (MnSOD) is an anti-oxidant enzyme, one of the primary defenses used by cells to protect mitochondria against the effects of free radicals. Other antioxidant enzymes include copper superoxide Dismutase and zinc superoxide Dismutase.
A research study done by Tsuruta (2000) found that the expression of copper and zinc superoxide dismutase as well as Manganese Superoxide Dismutase increased in cases of inclusion body myositis. The study concluded that Mn-SOD may have an important role as a protective response against nitric oxide-induced oxidative stress in IBM. The study further concluded that Cu, Zn-SOD and Mn-SOD may have different roles against oxidative damage in vacuolated muscle fibers in IBM.

This description will not delve into the complex science or chemistry involved in these reactions. But several terms are important to understand -- these toxic forms of oxygen are sometimes called reactive species or oxidants and the term free radicals has been used to describe this whole group of chemicals. By definition, a radical is a molecule possessing an unpaired electron -- this is a problem because this unpaired electron is looking for a mate and will react with a number of other chemicals that it runs into - it is called highly reactive. When these reactions happen in a cell it often disrupts the normal chemical processes going on. To be accurate, not all free radicals are strong oxidants and not all oxidants are radicals.

Not all reactive species are pathological -- in fact, the body has developed a critical function for reactive species -- in inflammation, reactive species and strong oxidants are created and used by the body's immune host response to kill invading microorganisms. Conditions that involve chronic inflammation may predispose secondary illness, in part, by producing too many strong oxidants.

As the balance of oxidation versus oxidant elimination tips toward oxidation (that is, as the cell falls behind and is overwhelmed by oxidation) a condition called oxidative stress occurs. Oxidative stress created by reactive species has been implicated in a number of disease conditions including sporadic inclusion body myositis. The protein inclusions of sIBM include a number of markers characteristic of oxidative stress.The idea that oxidative stress may be implied in sIBM is logical as sIBM is clearly an age-related disorder and the problems created by oxidative stress clearly also increase with age. Oxidative stress is one possible mechanism (among others) that may induce unfolded or mis-folded proteins -- the kind that characterize sIBM.

Proteostasis

At the heart of all organic processes are proteins. There are a number of complex steps in the creation, operation and ultimate disposal of proteins within the cell. A careful balance or homeostasis of protein is critical -- this is called proteostasis. As proteins are produced, they are vulnerable to abnormalities in their shape. Within the cell, there are complex mechanisms designed to help correctly form proteins and to watch for and deal with proteins that are abnormally formed. The final shape of a protein is critical to its function and misformed or misshaped / misfolded proteins cannot function and are usually broken down and disposed of by the cell. In addition, proteins are vulnerable to damage after they form and as they wear out, therefore they must be continually recycled, old proteins are broken down and disposed of and replaced by new protein created by the cell. In some cases, these damaged and misshaped proteins won't fit through the cellular "protein garbage disposal" and therefore end up accumulating -- researchers call it aggregating -- into lumps, plaques or inclusion bodies. These abnormal protein structures eventually disrupt the cell's normal biochemical mechanisms and may contribute to the ultimate death of the cell.

Again, we see that the cellular mechanisms that deal with protein shape are age related -- their effectiveness declines with age and the capacity for the cell to effectively manage abnormal protein declines as the cell ages. Therefore, a number of disorders that are age-related are also characterized by protein abnormalities and inclusions of abnormally formed or shaped protein including sporadic inclusion body myositis. Researchers are studying the regulators involved in these protein mechanisms to see if they could boost regulators to help deal with the increase in abnormally shaped proteins that increase as people age and in age-related disorders.

In the case of sporadic inclusion body myositis, several things are clear:

The critical question remains: what triggers sIBM in the average person who gets it and what role is played by the immune system -- is it part of the trigger or is it simply part of the response? Research will have to answer these questions before a better understanding of sIBM can be advanced.

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2-8). The Major Histocompatibility Complex (MHC).

Update.

There has been a great deal of research on this topic in the last several years. Research continues to articulate and focus in on the complex genetic relationships to spontaneous inclusion body myositis. Much of this research is being generated by Dr Francis (Frank) Mastaglia in Perth Australia.

For a recent article on this theme see: PubMed Link

Overview.

The 8.1 ancestral haplotype is strongly associated with sIBM.

Summary:

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2-9). IBM and HIV Related Viruses.

sIBM, HIV-1 and HTLV-1.

"HIV-IBM."

Dalakas et al (2007) have reported the association of sIBM with human immunodeficiency virus (HIV) infection.

Dalakas maintains that some kind of chronic viral infection in genetically susceptible individuals might trigger sIBM. Evidence is accumulating that the virus is some sort of retroviruse(s). This research is suggesting that HIV may be the first virus discovered to do this (? along with HTLV-1 ?), causing "HIV-IBM." But Dalakas is also leaving the door wide open in terms of other viruses, presumably there is another retrovirus candidate that is much more common than HIV (or HTLV-1) that will be discovered in the future. The four HIV patients in this study ALSO presented with symptoms of IBM and were ALSO diagnosed with IBM so, they were the natural people to study. I think what Dalakas is saying is that in these four people, HIV *caused their IBM,* but that there are likely other, yet undiscovered, retroviruses that will be discovered that will be linked to other sIBM cases. Again, if you studied other IBM patients "enough," eventually another [retro] virus (or multiple other viruses) might be discovered. Let's say for illustration retrovirus Able Baker is discovered to be linked to IBM, so, it may be that we have a number of IBM variants;

HIV-IBM,
HTLV-1-IBM,
Able Baker-IBM,
Able Charlie-IBM,
etc??.
etc??.

Here are a number of excerpts extracted from his March 2007 report (Dalakas et al, 2007).

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Webpage References.

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Mail Bill: btillier@shaw.ca