■ 6.4 IBM as an autoimmune disease: Simplified.

Site presented by Bill Tillier

↩ Main.


⧈ Webpage Menu:

⧈ 1. Introduction.

⧈ 2. Critical ideas.

⧈ 3. "Commentary on Study".

⧈ 4. "Study"

⧈ 5. "Review" From: Greenberg, (2019).

⧈ 6. Relevant references.

This page highlights IBM as an autoimmune T cell-mediated disease and presents a summary in everyday language aimed at informing the average IBM patient.

Note: there is still significant controversy within the research community concerning the basic causes of inclusion body myositis.

Also see: Highlighted Research



■ 1. Introduction.

▣ 1.1 Over the years, the evidence for the immune/autoimmune basis of IBM has been adding up. In 2019, Greenberg presented two very important publications. The first that I present here is a study conducted that supports the idea that IBM is an autoimmune disorder. This study was published with a commentary by two other IBM researchers (Benveniste & Allenbach). I present a summary of this commentary. The second publication I summarize, referred to here as the review, is a very comprehensive review of IBM.

▣ 1.2 These publications are very complex and it is my intention to summarize them in the most basic and simple terms possible. I have highlighted these publications as a separate page on my website because I think they are of extraordinary merit.

▣ 1.3 I begin by reviewing some of the basic ideas related to the immune system. I then summarize the three articles, the comment, the study, and the review. Finally, I present some of the basic references that support this line of thinking.



■ 2. Some critical ideas.

There are a few technical words and ideas that we have to understand to begin with.

▣ 2.1 Antigens.

⧈ 2.1.1 Two definitions: First—general: an antigen is any harmful substance that enters the body—like pollen, a bacteria or a virus. When you get a sliver in your finger from a piece of wood, the sliver is called an antigen because it has entered the body. Second—specific: Antigens are chemicals—proteins—found on the surface of the invader—on the surface of the bacteria or the virus. An antigen is any substance that can trigger the formation of antibodies (Antigen: antibody generation). We can think of these chemicals on the surface of the invaders as flags. Each specific invader will have it's own specific flag that identifies it—let's think of it as a flag that has an emblem on it. Normal body cells that become infected will display this flag. As well, the bacteria or virus will also display this flag.

⧈ 2.1.2 The immune system keeps careful track of all flags in the body. Pretty well every cell in a person's body displays a flag that tells the immune system that the cell belongs in your body and is healthy. Each person will have the same flag on every cell—think of this as a flag with your initials on it. In this way, the immune system can keep track of what belongs in the body and what doesn't—when the immune system sees a cell that has the emblem of an invader it knows that it doesn't belong in the body and this stimulates the immune system to react—to make antibodies—to fight off the invader.

⧈ 2.1.3 Autoantigen: Sometimes a mistake is made and a normal healthy cell in the body displays an antigen with an invaders flag. This is called an autoantigen. When the immune system sees an autoantigen attached to the normal cell, the immune system attacks the cell as if it was an invader. This is called an autoimmune disease.

⧈ 2.1.4 IBM: This seems to be what happens in IBM. The muscle cells display an antigen flag that makes the muscle cells look like they have been invaded—this antigen has not yet been discovered. The immune system sees this antigen flag on the surface of the muscle cells and produces killer immune cells to get rid of the "invader." These killer immune cells have been discovered (2019 Greenberg study) in IBM muscle cells.

▣ 2.2 Antibodies.

⧈ 2.2.1 When an antigen enters the body, it stimulates the immune system to produce antibodies. Antibodies are Y-shaped chemicals—a type of protein produced in response to the presence of an antigen. The antibody will be produced with a notch on its surface that will recognize and stick to the flag displayed by the antigen. In this way, specific antigens—let's say of a virus—will produce specific antibodies. These specific antibodies will identify the flags on the antigens, attach themselves to the flags, thus attaching themselves to the antigen itself, and then kill the cell the antigen is attached to.

⧈ 2.2.2 Your genetic material—DNA—contains genes. Genes produce chemicals—proteins—to perform different functions in the body. The chemical flags we are speaking about are made out of proteins. It is the job of certain genes in the body to produce these protein flags—these genes occur in a section of our DNA called the MHC class. This section of DNA is known to contain a number of genes that are related to the immune system. MHC proteins are there to help see whether the body's cells have been infected by a virus. No direct genetic mutation is associated with IBM. However, a number of genes in the MHC immune-related area are related to creating a genetic predisposition to IBM. The linkage between IBM and these genes supports the view that IBM is an immune-related disease.

▣ 2.3 The castle.

⧈ 2.3.1 Let's think of the body like a castle. Most of the germs, bacteria, and viruses outside of the castle are invaders and many of them are trying to get inside. The first line of defense against invaders are the walls of the castle, in our case, our skin. Inside the castle it's the job of the immune system to be on constant patrol for any invaders that make it through the walls. There are a number of different types of defenders—different immune cells—each with a little bit different job, but they all work together to identify invaders inside the castle and to attack them.

⧈ 2.3.2 One type of defender is a cell called a macrophage. Macrophages circulate throughout the castle, through blood and the lymph system, looking for invaders. As explained above, invaders can be recognized by the chemical flags they display on their surface. Let's think of it this way: all of the invaders have red uniforms on with an insignia on them.

⧈ 2.3.3 Macrophages identify the cells as foreign invaders and eat them (macrophage: macro means big and phage means eater). Then the macrophages take the insignia flag from the invader and put it on their flagpole. These macrophage cells then circulate throughout the immune system waiving the antigen's flag. This alerts the immune system that there is a problem and it reacts by producing special killer cells that are specifically designed to recognize the flag of the invader. These killer cells are generally a type of cell called a CD8 + T cell. So, in the case of IBM, the immune system produces CD8 + T cells with a KLRG1 flag attached. When these killer cells see the corresponding antigen flag being displayed on the surface of the muscle cell, they link on and destroy the cell.

▣ 2.4 Autoimmune diseases.

⧈ 2.4.1 In some autoimmune diseases autoantibody is the only or main autoimmune feature of the disease and the pathology can be completely explained by the actions of the autoantibody. Therefore it is easy to classify these as antibody-mediated autoimmune diseases. In many autoimmune diseases it is not possible to blame the pathology simply on the action of antibody. In these diseases, which include TIDM, Hashimoto's thyroiditis and rheumatoid arthritis, there is extensive infiltration of immune-associated cells into the affected tissue and the production of autoantibodies. The primary pathology in these diseases is damage to, or destruction of, part of the tissue, but the exact cause of the damage is hard to determine. Often the cellular infiltrate consists of CD4 and CD8 T lymphocytes, B cells, monocytes/macrophages and other inflammatory cells. In the case of IBM, they have already discovered two immune related aspects: autoantibodies—anti-cN1A are found in about 50% of cases and killer CD8 T cells have been found infiltrating into the muscle cells.

⧈ 2.4.2 In some autoimmune diseases, CD8 T cells kill target cells presenting autoantigens on their class I MHC molecules. The difficult task in these autoimmune diseases is sorting out the actual effector mechanism from the potential mechanisms. Unfortunately the presence of a particular cell type in an infiltrate, or the presence of autoantibody, does not necessarily mean it is contributing to the pathology.

⧈ 2.4.3. It is also quite possible that for many autoimmune diseases more than one effector mechanism contributes to the tissue damage. Wood, P. J. (2011). Understanding immunology. (3rd ed.). Harlow, Essex: Prentice Hall.

▣ 2.5 CD8 + T cells: the immune system's elite soldiers.

⧈ 2.5.1 Cytotoxic CD8 + T cells: Cytotoxic means poison to cells. These CD8 + T cells are one of the immune systems special killer cells. Each of these T cells is produced with the specific flag of the antigen that it needs to recognize and kill. These cells are reproduced over and over to produce an army. As long as the immune system keeps seeing the antigen, it will keep producing a response, and more and more of these killer T cells will be produced. Normally, once the infection has been overcome, the antigens will peter out and the production of the specialized killer cells will stop. The cells specific to the antigen that caused the infection will be put into the immune system's memory in case the person gets infected in the future by the same invader.

⧈ 2.5.2 Most killer T cells express T-cell receptors (TCRs) that can recognize a specific antigen. Antigens inside a cell are attached to class I MHC molecules inside the cell, and brought to the surface of the cell by the class I MHC molecule, where they can be recognized by the T cell. If the TCR is specific for that antigen, it latches onto the complex of the class I MHC molecule and the antigen, and the T cell destroys the cell. Based on Wikipedia contributors. (2019, July 26). Cytotoxic T cell. In Wikipedia, The Free Encyclopedia. Retrieved 07:34, September 12, 2019, from https://en.wikipedia.org/w/index.php?title=Cytotoxic_T_cell&oldid=907906446

▣ 2.6 Abnormal proteins in IBM.

⧈ 2.6.1 Amyloids (or amyloid proteins) are made up of different proteins that stick together forming clumps. In the human body, amyloids have been linked to the development of various diseases.

⧈ 2.6.2 Inclusion bodies are clumps of abnormal proteins, in IBM, found inside muscle cells.

⧈ 2.6.3 Vacuoles (or rimmed vacuoles) are small areas of destruction in muscle cells, found in IBM and in some other muscle disorders. Like inclusion bodies, vacuoles also contain abnormal proteins.

⧈ 2.6.4 Inclusion bodies and vacuoles represent the degenerative aspects of IBM.

⧈ 2.6.5 As the Greenberg study points out, the immune features associated with IBM can also explain the degenerative aspects seen in the disease.

▣ 2.7 Summary re: IBM.

⧈ 2.7.1 Summary: In the case of IBM, for some reason, normal muscle cells display an autoantigen flag—that has not yet been discovered. This muscular antigen triggers the never ending immune response—the production of the specialized T killer cells. As muscles produce more and more new muscle cells, these killer T cells keep invading and killing them. This is why Greenberg describes IBM as an autoimmune T cell-mediated disease. As well, other immune-related cells are seen invading the muscle, including, myeloid dendritic cells, macrophages and plasma cells. In addition to this, autoantibodies—anti-cN1A are found in about 50% of cases.



■ 3. Commentary on Study. From: Benveniste & Allenbach, (2019)

▣ 3.1 The Greenberg study shows that IBM is driven by the immune system—by killer T cells—and that this is unique among muscle diseases.

▣ 3.2 The Greenberg study identified very specific killer cells—CD8+ terminally differentiated effector memory (TEMRA) T cells—activated by a presumptive but as yet unidentified muscular antigen. These killer cells display a surface marker—a flag—called a lectin-like receptor G1 (KLRG1). In summary, the study identified an ongoing invasion of muscle cells by very specific killer immune cells—cells that are marked by a very specific chemical flag.

⧈ 3.2.1 As well, circulating blood autoantibodies—anti-cN1A—have been identified. However, Felice reported the anti-cN1A antibody test has a low predictive value for IBM parameters. In a group of IBM patients, only 20 of 40 (50%) of patients tested positive for anti-cN1A.

▣ 3.3 The specific chemical flag on these killer T cells—KLRG1—is known to be strongly induced by chronic viral and other infections.

⧈ 3.3.1 IBM has occasionally been associated with viral infections: with HIV-1 or human T cell leukaemia virus type 1 (HTLV-1).

⧈ 3.3.2 However, no ongoing viral infection is seen in the majority of IBM cases. As Benveniste & Allenbach, (2019) state: in IBM, the ongoing activation of T cells must come from muscle antigens that have not been discovered yet. These antigens presumably are presented on the surface of the muscle cells by flags from a part of the immune system called the major histocompatibility complex (MHC) class I. In summary, the muscular antigen on the surface of the muscle, and it's flag, responsible for stimulating the immune reaction has not yet been discovered.

⧈ 3.3.3 MHC class I over-activation is one of the hallmarks of IBM disease.

▣ 3.4 The immune features associated with IBM can also explain the degenerative aspects seen in the disease—production and accumulation of abnormal proteins within the muscle cells and mitochondria abnormalities.

▣ 3.5 The study suggests the value of trying to develop a medication targeting the killer cells—CD8 + (TEMRA) cells—that display the KLRG1 surface flag. … "We can thus imagine that a medication for IBM that aims to reduce KLRG1+ marked CD8 + T cells may have a good safety profile and may efficiently tackle one of the key actors in the IBM disease mechanism."


Figure 1.


▣ 3.6 Figure modified from Benveniste & Allenbach, (2019).

⧈ 3.6.1 A: Killer cells—CD8+ terminally differentiated effector memory (TEMRA) T cells. These killer cells display a surface marker—KLRG1. They are attached to the flag—antigen—on the muscle surface.

⧈ 3.6.2 B: The antigen flag on the muscle surface—not yet discovered (see below).

⧈ 3.6.3 C: Ongoing production of the antigen flag (arrow 6).

⧈ 3.6.4 D: Degenerative aspects: mitochondria abnormalities.

⧈ 3.6.5 E: Degenerative aspects: mis-folded proteins, inclusions and vacuoles. Reference: Benveniste, O., & Allenbach, Y. (2019). Inclusion body myositis: accumulation of evidence for its autoimmune origin. Brain, 142(9), 2549-2551. https://doi.org/10.1093/brain/awz229




■ 4. Study. From: Greenberg (2019)

▣ 4.1 This is a study of data from muscle biopsies from 411 patients. I would describe it as an extremely complicated article for the average person.

▣ 4.2 Summary. Inclusion body myositis is a late onset treatment-resistant autoimmune disease of skeletal muscle associated with:

⧈ 4.2.1 a blood autoimmune flag—autoantibody (anti-cN1A),

⧈ 4.2.2 a section of DNA linked to immune disorders—an HLA autoimmune haplotype,

⧈ 4.2.3 and muscle disease characterized by killer cells of the immune system attacking muscle cells—cytotoxic CD8+ T cell destruction of muscle cells.

▣ 4.3 The study looked at IBM patient muscle and blood samples compared with large numbers of muscle samples from other muscle diseases.

⧈ 4.3.1 The study identified very specific killer immune cells in IBM muscle, highlighting the role of the immune system in the cause of IBM.

▣ 4.4 A chemical flag—KLRG1—was identified on muscle-invading killer immune cells.

▣ 4.5 The autoimmunity shown in IBM muscle is distinct from other forms of inflammatory muscle diseases. . . . IBM may be the only muscle disease characterized by extensive killer cell muscle attack.

▣ 4.6 The study suggests possible reasons why previous IBM treatments have failed and the potential value of making a medicine targeting the very specific killer cells that attack muscle in IBM.

⧈ 4.6.1 Reference: Greenberg, S. A., Pinkus, J. L., Kong, S. W., Baecher-allan, C., Amato, A. A., & Dorfman, D. M. (2019). Highly differentiated cytotoxic T cells in inclusion body myositis. Brain, 1-15. https://doi.org/10.1093/brain/awz214




■ 5. Review article. From: Greenberg (2019)

▣ 5.1 Several crucial discoveries:

⧈ 5.1.1 In support of an autoimmune interpretation: In the mid-1980s scientists found that a specific type of immune cell—cell-killing T cells (cytotoxic CD8+ T cells) invade the muscle cells of patients with IBM. The observation of CD8+ T cells launched a new, ongoing line of research into IBM, looking at autoimmune abnormalities and on therapies that target T cells. In 2011 Greenberg discovered that a circulating autoantibody is present in IBM. In 2013 the target autoantigen of these [auto]antibodies was discovered in the muscle cells of IBM patients. Recognition of the genetic linkage of IBM to the HLA region (like other autoimmune diseases), has been confirmed by many studies; Muscle cell protein clumps and mitochondrial abnormalities in IBM patients both seem to occur as a result of autoimmunity.

▣ 5.2 Classification

⧈ 5.2.1 IBM lies within the category of muscle diseases called the inflammatory myopathies. This category started with polymyositis in 1887, and has since undergone repeated subdivision. The generally accepted model currently has five major diseases (polymyositis, dermatomyositis, IBM, IMNM and non-specific myositis).

⧈ 5.2.2 Several similar abbreviations of other diseases have created confusion regarding IBM. IBM is an abbreviation for 'inclusion body myositis' not 'inclusion body myopathy.' The abbreviation IBM refers clearly and only to the single disease inclusion body myositis—not to the hereditary inclusion body myopathies (hIBMs). The hIBM diseases lack the two main characteristic features of IBM: its distinctive pattern of muscle weakness and the presence of immune cell muscle invasion. Many publications have used the abbreviation IBM to refer to both IBM and hIBM; this has led to confusion and mistakes in the research. The term sporadic IBM (sIBM) was introduced to try and avoid confusion with hIBM by emphasizing its sporadic, or non-inherited, occurrence. But this can also be confusing because you could think that it is the same disease, in one case occurring sporadically, and in another case, occurring genetically. It should be emphasized that sIBM and hIBM are not the same—they are different diseases. Familial IBM (flBM) refers to the occurrence of typical IBM within families, almost always within a single generation of brothers and sisters. This pattern is similar to the familial occurrence of many other autoimmune diseases, such as myasthenia gravis and multiple sclerosis.

▣ 5.3 Clinical features of IBM

⧈ 5.3.1 The main features seen by the doctor include finger flexor and quadriceps weakness: Finger flexor weakness makes it harder to close the fingers into a fist or to pick up objects. Quadriceps weakness makes it difficult to arise from a squatting position or, for example, to step up onto a chair. Quadriceps muscles are in the upper front part of the leg between the knee and hip. Weakness here destabilizes the knee leading to falling, tripping and poor balance.


Figure 2.


Weakness of finger flexion in patients attempting hand grip (to make a fist) with partial involvement (a) and end-stage (b) inclusion body myositis (IBM).

From: Greenberg, 2019.


Figure 3.


Photograph showing severe shrinkage of the quadriceps femoris (above the knee) in a 77-year-old man with a 13-year history of sporadic inclusion body myositis.
These major muscles are critical in stabilizing the knee and extending the leg forward when walking.

From: Needham, M., & Mastaglia, F. L. (2007). Inclusion body myositis: current pathogenetic concepts and diagnostic and therapeutic approaches. The Lancet Neurology, 6(7), 620-631. https://doi.org/10.1016/S1474-4422(07)70171-0

⧈ 5.3.2 Numbers reflecting the prevalence of IBM are probably underestimates because of the high rate of misdiagnosis. In a good study published in 2017, the overall prevalence of IBM was 46 patients per million people.

⧈ 5.3.3 Typical estimates say, on average, IBM patients notice symptoms coming on between the ages of from 61 to 68 years.

⧈ 5.3.4 IBM is often viewed as affecting people over 50 years old; however, 20 percent of patients develop symptoms in their forties.

⧈ 5.3.5 Men get IBM slightly more often than females, about on average 1.6 times (so for every 16 men there should be 10 women with IBM).

⧈ 5.3.6 IBM is first misdiagnosed as another condition in 40 to 53 percent of patients, and the average from symptom onset to correct diagnosis is 4.6 to 5.8 years.

⧈ 5.3.7 IBM is a progressive disease, on average, IBM patients require the use of a cane after about 7 to 10 years from the time they notice symptoms and need to use a wheelchair from 13 to 15 years after they notice symptoms.

⧈ 5.3.8 IBM typically shows up in middle or late age with slowly progressive, painless difficulty walking or using the hands.

⧈ 5.3.9 Walking difficulties typically result from knee buckling, owing to knee extensor weakness, or tripping owing to ankle weakness.

⧈ 5.3.10 Grip impairment is caused by finger flexor weakness.

⧈ 5.3.11 Symptoms are often initially blamed on age or arthritis; when a neuromuscular disease is suspected, a diagnosis of polymyositis or, less often, motor neuron disease (ALS) is more common than an immediate recognition of IBM.

⧈ 5.3.12 Muscle pain is very uncommon in IBM.

⧈ 5.3.13 Dysphagia (difficult swallowing) is an underestimated part of IBM and is under-reported as a presenting symptom but is commonly present if looked for by asking questions or x-ray studies. Dysphagia becomes more evident as the disease progresses and might result in nutritional deficiency, weight loss and aspiration pneumonia—this is where you choke and food goes into your lungs— a major cause of death in IBM.

⧈ 5.3.14 Breathing problems during the day, and breathing problems during sleep, are common but often go unnoticed because their symptoms are not obvious.

⧈ 5.3.15 IBM has unique physical features seen on examination. The high misdiagnosis rate is partly because many doctors do not recognize these unique features. These features are so clear and unique to IBM, that if the doctor recognizes them, a muscle biopsy may not be necessary to make a diagnosis.

⧈ 5.3.16 A surprising number of patients with IBM (58 percent in one series) meet the diagnostic criteria for LGLL (large granular lymphocytic leukaemia), and a small number have overt leukaemia.

▣ 5.4 Degenerative and autoimmune aspects

⧈ 5.4.1 Today, IBM is often viewed as both a degenerative and an autoimmune disease.

▣ 5.5 Autoimmune biomarkers and mechanisms

▣ 5.5.1 T cells, myeloid dendritic cells, macrophages and plasma cells all invade IBM muscle, but it is the invasion of muscle cells by T cells that is the most obvious microscopic feature of IBM muscle.

⧈ 5.5.2 Although the immune system feature has been known since 1984, past research has focused on abnormal proteins within the muscle cell. However, less than 1 percent of muscle cells in IBM patients show these abnormalities.

⧈ 5.5.3 Past treatments aimed at reducing the attack by the immune system have not been successful making some people think that the disease is not an autoimmune disorder.

⧈ 5.5.4 However, research over the past 10 years has supported the idea that IBM is an autoimmune disorder. For example, a chemical flag from the immune system—an autoantibody (anti-cNIA)—was found circulating within the muscles and blood of IBM patients: this is a chemical signal that the immune system is involved. Large numbers of killer cells (CD8+ T cells), made by the immune system, have been discovered in the muscle and blood of IBM patients. It is these cells that attack the muscle cells, damaging and killing them. This supports the idea that it is an autoimmune disorder. There is no specific genetic mutation associated with IBM. Strong genetic linkage of IBM has been established to a group of genes in a section of our DNA—called the 8.1 MHC haplotype—genes linked to controlling the functions of the immune system. IBM has more autoimmune (T cell) abnormalities than any other muscle disease; the failure of treatments aimed at the immune system made researchers think that IBM was not an autoimmune disorder, but as explained in the review, there are other reasons for the failure of these treatments. Treatment failures probably reflect the inability of current medicines to stop or reduce the army of very specific killer immune cells present in IBM. Understanding IBM as an autoimmune disorder opens doors to finding new and specific treatments.

▣ 5.6 Degenerative abnormalities

⧈ 5.6.1 Enormous attention has been focused for decades on several chemical signals of protein clumps found inside muscle cells, but these abnormalities are present in less than 1 percent of muscle cells in patients with IBM.

⧈ 5.6.2 In technical language, the degenerative features of IBM include rimmed vacuoles and the related myonuclear degeneration, mitochondrial pathology and myofibre (muscle cells) cytoplasmic protein aggregates.

⧈ 5.6.3 In hindsight, a published belief in the degenerative theory now seems to be out of proportion to the data supporting it.

⧈ 5.6.4 Currently, the evidence suggests that causality flows from autoimmunity to degeneration, not the reverse. In other words, the degenerative abnormalities are the result of the effects of the autoimmune process and widespread inflammation and its impacts.

⧈ 5.6.5 Why then has the field of IBM attracted so much more interest in protein aggregates than other autoimmune diseases? Perhaps it is simply easier to see these clumps under the microscope in skeletal muscle than in other tissues.

▣ 5.7 Treatment

⧈ 5.7.1 The best care for most patients with IBM involves strictly nonpharmacological management, including emotional support, physical therapy, education on fall precautions and exercise, respiratory evaluation and dysphagia evaluation.

⧈ 5.7.2 Prednisone and IVIG simply don't work. Patients with IBM receiving long-term treatment (an average of 35 mg daily of prednisone for an average of 5.7 years) had the same number of invaded muscle cells as patients with IBM not receiving treatment. Patients with IBM receiving corticosteroids or IVIG did not experience a major reduction in the total number of muscle killing cells.

⧈ 5.7.3 Alemtuzumab will likely make things worse. ATG (Anti-thymocyte globulin) and alemtuzumab are two types of immune therapies. They rapidly get rid of nearly 100 percent of the immune killer cells, but once the immune system recovers after treatment, killer cells expand in even more numbers than there were before treatment.

        □ Reference: Greenberg, S. A. (2019). Inclusion body myositis: Clinical features and pathogenesis. Nature Reviews Rheumatology 2019, 1. https://doi.org/10.1038/s41584-019-0186-x






■ 6. References

▣ 6.1 Critical References

⧈ Benveniste, O.,& Allenbach, Y. (2019). Inclusion body myositis: accumulation of evidence for its autoimmune origin. Brain, 142(9), 2549-2551.https://doi.org/10.1093/brain/awz229

⧈ Dzangué-Tchoupou, G., Mariampillai, K., Bolko, L., Amelin, D., Mauhin, W., Corneau, A., … Benveniste, O. (2019). CD8+T-bet+ cells as a predominant biomarker for inclusion body myositis. Autoimmunity Reviews, 18(4), 325-333. https://doi.org/10.1016/j.autrev.2019.02.003

⧈ Greenberg, S. A. (2019). Inclusion body myositis: Clinical features and pathogenesis. Nature Reviews Rheumatology 1. https://doi.org/10.1038/s41584-019-0186-x

⧈ Greenberg, S. A. (2020). Pathogenesis of inclusion body myositis. Current Opinion in Rheumatology,32(6) https://doi.org/10.1097/BOR.0000000000000752

⧈ Greenberg, S. A., Pinkus, J. L., Kong, S. W., Baecher-allan, C., Amato, A. A., & Dorfman, D. M. (2019). Highly differentiated cytotoxic T cells in inclusion body myositis. Brain, 1-15. https://doi.org/10.1093/brain/awz207

▣ 6.2 Some relevant references.

⧈ Arahata, K. & Engel, A. G. (1984). Monoclonal antibody analysis of mononuclear cells in myopathies. I: Quantitation of subsets according to diagnosis and sites of accumulation and demonstration and counts of muscle fibers invaded by T cells. Ann. Neurol. 16, 193-208.

⧈ Badrising, U. A., Schreuder, G. M. T., Giphart, M. J., Geleijns, K., Verschuuren, J. J. G. M., & Wintzen, A. R. (2004). Associations with autoimmune disorders and HLA class I and II antigens in inclusion body myositis. Neurology, 63(12), 2396-2398. https://doi.org/10.1212/01.WNL.0000148588.15052.4C

⧈ Benveniste, O., & Allenbach, Y. (2019). Inclusion body myositis: accumulation of evidence for its autoimmune origin. Brain, 142(9), 2549-2551. https://doi.org/10.1093/brain/awz229

⧈ Deng, Q., Luo, Y., Chang, C., Wu, H., Ding, Y., & Xiao, R. (2019). The emerging epigenetic role of CD8+T cells in autoimmune diseases: A systematic review. Frontiers in Immunology, 10(APR). https://doi.org/10.3389/fimmu.2019.00856

⧈ Dzangué-Tchoupou, G., Mariampillai, K., Bolko, L., Amelin, D., Mauhin, W., Corneau, A., … Benveniste, O. (2019). CD8+T-bet+ cells as a predominant biomarker for inclusion body myositis. Autoimmunity Reviews, 18(4), 325-333. https://doi.org/10.1016/j.autrev.2019.02.003

⧈ Engel, A. G. & Arahata, K.(1984). Monoclonal antibody analysis of mononuclear cells in myopathies. II: Phenotypes of autoinvasive cells in polymyositis and inclusion body myositis. Ann. Neurol. 16, 209-215.

⧈ Eura, N., Sugie, K., Kinugawa, K., Nanaura, H., Ohara, H., Iwasa, N., … Kiriyama, T. (2016). Anti-Cytosolic 5'-Nucleotidase 1A (cN1A) Positivity in Muscle is Helpful in the Diagnosis of Sporadic Inclusion Body Myositis: A Study of 35 Japanese Patients. Journal of Neurology and Neuroscience, 07(05), 1-5. https://doi.org/10.21767/2171-6625.1000155

⧈ Felice, K. J., Whitaker, C. H., Wu, Q., Larose, D. T., Shen, G., Metzger, A. L., & Barton, R. W. (2018). Sensitivity and clinical utility of the anti-cytosolic 5'-nucleotidase 1A (cN1A) antibody test in sporadic inclusion body myositis: report of 40 patients from a single neuromuscular center. Neuromuscular Disorders. https://doi.org/10.1016/j.nmd.2018.06.005

⧈ Goyal, N., Cash, T. M., Alam, U., Enam, S., Tierney, P., Araujo, N., … Mozaffar, T. (2016). Seropositivity for NT5c1A antibody in sporadic inclusion body myositis predicts more severe motor, bulbar and respiratory involvement. Journal of Neurology, Neurosurgery & Psychiatry, 87(4), 373-378. https://doi.org/10.1136/jnnp-2014-310008

⧈ Greenberg, S. A. (2019). Inclusion body myositis: Clinical features and pathogenesis. Nature Reviews Rheumatology 2019, 1. https://doi.org/10.1038/s41584-019-0186-x

⧈ Greenberg, S. A. (2020). Pathogenesis of inclusion body myositis. Current Opinion in Rheumatology,32(6) https://doi.org/10.1097/BOR.0000000000000752

⧈ Greenberg, S. A., Pinkus, J. L., Amato, A. A., Kristensen, T. & Dorfman, D. M. (2016). Association of inclusion body myositis with T cell large granular lymphocytic leukaemia. Brain 139, 1348-1360. https://doi.org/10.1093/brain/aww024

⧈ Greenberg, S. A., Pinkus, J. L., Kong, S. W., Baecher-allan, C., Amato, A. A., & Dorfman, D. M. (2019). Highly differentiated cytotoxic T cells in inclusion body myositis. Brain, 1-15. https://doi.org/10.1093/brain/awz214

⧈ Henson, S. M., Lanna, A., Riddel, N. E., Franzese, O., Macaulay, R., Griffiths, S. J., … Akbar, A. N. (2014). P38 signaling inhibits mTORC1-independent autophagy in senescent human CD8+ T cells. Journal of Clinical Investigation, 124(9), 4004-4016. https://doi.org/10.1172/JCI75051

⧈ Herbert, M. K., Stammen-Vogelzangs, J., Verbeek, M. M., Rietveld, A., Lundberg, I. E., Chinoy, H., … Pruijn, G. J. M. (2016). Disease specificity of autoantibodies to cytosolic 5'-nucleotidase 1A in sporadic inclusion body myositis versus known autoimmune diseases. Annals of the Rheumatic Diseases, 75(4), 696-701. https://doi.org/10.1136/annrheumdis-2014-206691

⧈ Hohlfeld, R., & Schulze-Koops, H. (2016). Cytotoxic T cells go awry in inclusion body myositis. Brain, 139(5), 1312-1314. https://doi.org/10.1093/brain/aww053

⧈ Kim, H.-J., & Cantor, H. (2019). Regulatory T cells subdue an autoimmune disease. Nature, 572(7770), 443-445. https://doi.org/10.1038/d41586-019-02271-7

⧈ Knauss, S., Preusse, C., Allenbach, Y., Leonard-Louis, S., Touat, M., Fischer, N., … Stenzel, W. (2019). PD1 pathway in immune-mediated myopathies: Pathogenesis of dysfunctional T cells revisited. Neurology: Neuroimmunology and NeuroInflammation, 6(3), 1-10. https://doi.org/10.1212/NXI.0000000000000558

⧈ Larman, H., Salajegheh, M., Nazareno, R., Lam, T., Sauld, J., Steen, H., … Greenberg, S. A. (2013). Cytosolic 5'?-nucleotidase 1A autoimmunity in sporadic inclusion body myositis. Annals of Neurology, 73(3), 408-418. https://doi.org/10.1002/ana.23840

⧈ Lilleker, J. B., Rietveld, A., Pye, S. R., Mariampillai, K., Benveniste, O., Peeters, M. T. J., … Van Engelen, B. G. M. (2017). Cytosolic 5'-nucleotidase 1A autoantibody profile and clinical characteristics in inclusion body myositis. Annals of the Rheumatic Diseases, 76(5), 862-868. https://doi.org/10.1136/annrheumdis-2016-210282

⧈ Limaye, V. S., Lester, S., Blumbergs, P., & Greenberg, S. A. (2016). Anti- C N1A antibodies in South Australian patients with inclusion body myositis. Muscle & Nerve, 53(4), 654-655. Retrieved from http://doi.wiley.com/10.1002/mus.24989

⧈ Pandya, J. M. et al. (2010) Expanded T cell receptor V-restricted T cells from patients with sporadic inclusion body myositis are proinflammatory and cytotoxic CD28 null T cells. Arthritis Rheum. 62, 3457-3466.

⧈ Pluk, H., van Hoeve, B. J., van Dooren, S. H. J., Stammen-Vogelzangs, J., van der Heijden, A., Schelhaas, H. J., … Pruijn, G. J. M. (2013). Autoantibodies to cytosolic 5'-nucleotidase 1A in inclusion body myositis. Annals of Neurology, 73(3), 397-407. https://doi.org/10.1002/ana.23822

⧈ Rietveld, A., Lim, J., de Visser, M., van Engelen, B., Pruijn, G., Benveniste, O., … Saris, C. (2019). Autoantibody testing in idiopathic inflammatory myopathies. Practical Neurology, 19(4), 284-294. https://doi.org/10.1136/practneurol-2017-001742

⧈ Salajegheh, M., Lam, T., & Greenberg, S. A. (2011). Autoantibodies against a 43 KDa Muscle Protein in Inclusion Body Myositis. PloS One, 6(5), e20266. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/21629782

⧈ Tawara, N., Yamashita, S., Zhang, X., Korogi, M., Zhang, Z., Doki, T., … Ando, Y. (2017). Pathomechanisms of anti-cytosolic 5'-nucleotidase 1A autoantibodies in sporadic inclusion body myositis. Annals of Neurology, 81(4), 512-525. https://doi.org/10.1002/ana.24919

⧈ Tian, Y., Babor, M., Lane, J., Schulten, V., Patil, V. S., Seumois, G., … Peters, B. (2017). Unique phenotypes and clonal expansions of human CD4 effector memory T cells re-expressing CD45RA. Nature Communications, 8(1), 1473. https://doi.org/10.1038/s41467-017-01728-5

⧈ Verma, K., Ogonek, J., Varanasi, P. R., Luther, S., Bünting, I., Thomay, K., … Hambach, L. (2017). Human CD8+ CD57- TEMRA cells: Too young to be called "old." PLOS ONE, 12(5), e0177405. https://doi.org/10.1371/journal.pone.0177405

⧈ Wang, L., Wang, F.-S., & Gershwin, M. E. (2015). Human autoimmune diseases: a comprehensive update. Journal of Internal Medicine, 278(4), 369-395. https://doi.org/10.1111/joim.12395

Yamashita, S., Tawara, N., & Ando, Y. (2017). Anti-NT5C1A autoantibodies for the diagnosis and study of the pathogenesis of sporadic inclusion body myositis. Clinical and Experimental Neuroimmunology, 1-10. https://doi.org/10.1111/cen3.12420


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