⧈ 4.1.2 Theories of what may cause IBM:

Autoimmunity, protein degeneration, mitochondrial abnormalities.

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⚀ Basic theories.

⚀ IBM as an autoimmune disease: Overview.

□ This section is based on research studies on IBM.

□ Critical ideas. 

□ "Study"

□ "Commentary on Study."

□ "Review" From: Greenberg (2019).

□ Other articles.

□ IBM summary.

□ References.

⚀ Protein degeneration

⚀ Mitochondrial abnormalities.

⚀ More ideas on causes.

⚀ Basic theories.

□ Because the presentation of IBM is so variable, over the years, scientists have faced challenges in defining the symptoms of IBM and comprehending its underlying causes or triggers. Medical conditions with apparent and consistent symptoms are relatively simpler to classify, diagnose, and investigate the root cause of.

□ In 1984 evidence of an immune reaction was described in IBM. Later, abnormal proteins were discovered in the impacted muscles of people with IBM, which led to the proteinExcited degeneration theory. Subsequently, problems were seen in the mitochondria of IBM patients. Each of these discoveries generally points to a different cause or, scientists need to discover a single cause that would account for all of these different abnormalities.

□ The most prominent impacts of IBM appear to be related to the autoimmune theory, however, at this stage there is no consensus among scientists.

Footnote 1: it could be the case that the immune response causes proteins to become abnormal, and it also could be the case that abnormal proteins could trigger an immune response.

⚀ IBM as an autoimmune disease: Overview.

□  Today, a leading theory is that IBM appears to be an autoimmune disease that damages the muscle cells and also causes protein abnormalities.

□ In autoimmune diseases, in response to some unknown cause, the immune system begins to produce antibodies that attack the body's tissues. Normally, the immune system is triggered by some foreign invader (like a virus), which causes the production of antibodies designed to attack and kill the invader. In autoimmune diseases, immune defenses attack normal body tissues. Common examples are rheumatoid arthritis, lupus, Type 1 diabetes, and Sjögren's syndrome. Treatment for autoimmune diseases generally focuses on reducing immune system activity.

□ For some reason, the medications that normally reduce the activity of the immune system have not improved the symptoms of IBM.

□ IBM is often seen occurring along with other autoimmune disorders; commonly Sjögren's syndrome and rheumatoid arthritis.

□ The family members of patients with IBM often have various other autoimmune disorders (for example, Crohn's disease, rheumatoid arthritis, autoimmune hepatitis, lupus, etc.).

□ Greenberg from the NORD Webpage: “Numerous factors support that sIBM is an autoimmune disorder, especially the presence of certain inflammatory white blood cells in the muscle tissue of affected individuals. Autoimmune disorders occur when the body's immune system mistakenly attacks healthy tissue. The inflammatory findings associated with sIBM led to it to be classified as an autoimmune inflammatory muscle disease along with other prominent inflammatory muscle diseases such as dermatomyositis and polymyositis. The identification of an autoantigen (NT5C1A) has confirmed IBM's status as an autoimmune disease. However, sIBM, like a number of other autorimmune diseases, has not responded to some of the conventional therapies normally used to treat autoimmune disorders suggesting that distinct factors account for its refractory nature. In particular, cytotoxic T cells in sIBM muscle are highly differentiated and their phenotype overlaps with those of T cells in T-cell large granular lymphocytic leukemia, a similarly refractory disease.
In addition to the inflammatory process, researchers have emphasized that some muscle tissue of individuals with sIBM shows degenerative changes. Specifically, the muscle tissue of affected individuals sometimes contains sub-cellular compartments called vacuoles. These compartments have been reported to contain abnormal clumps of many different proteins. These clumps, often called 'inclusion bodies', give the disorder its name. This significant degenerative component has led some researchers to argue that sIBM is primarily a degenerative muscle disorder and not an inflammatory one. However, these changes are seen in other refractory autoimmune diseases (e.g., Sjogren syndrome and primary biliary cholangigits) and appear to be reflective of chronic exposure of tissues to highly T cell rich inflammatory environments. It is unknown what triggers or underlies the inflammatory or degenerative changes that characterize sIBM, a feature shared by all other autoimmune diseases.
Some individuals with sIBM may have a genetic predisposition that makes them more susceptible to developing sIBM. A genetic predisposition means that a person may carry a gene for a disease but it may not be expressed unless something in the environment triggers the disease.” LINK

◘ Point form summary:

▪ “An antibody is a protein produced by the immune system in response to the presence of foreign substances called antigens. Antigens are usually proteins on the surface of bacteria, viruses, fungi, or other potentially harmful substances. The immune system recognizes these antigens as foreign and responds by producing antibodies that can specifically bind to them” (ChatGPT 3.5). Once the antibody attaches to the antigen it is used to identify and kill these foreign objects. Think of the antibody as the bullet and the antigen as the target.

▪ In some cases, the immune system mistakenly sees part of the person's own body as an antigen target — this is then called an autoantigen.

▪ An autoantibody is an antibody that mistakenly targets a self-antigen (an autoantigen).

▪ In IBM, the autoantigen (target) has not been discovered yet.

▪  In IBM, the autoantibody (bullet) has been discovered — it is anti-cN1A, and it is found in the blood.

▪ Unfortunately, the presence of the anti-cN1A autoantibody in the blood cannot be used as a test for IBM because it only appears in about 50% of all IBM cases and occasionally appears in other diseases.

▪ Research has shown that in IBM, the muscles are attacked by specific immune system bullets called — killer cells — CD8+ (TEMRA) T cells. These killer cells display a flag on their surface called KLRG1+ (Killer cell lectin-like receptor G1).

▪ The Abcuro company has developed a drug — ABC008 — designed to target and kill T cells that show the KLRG1+ flag. ABC008 is a monoclonal antibody. A monoclonal antibody (mAb) is a Chemical made in the laboratory that is designed to target a very specific protein, in this case the KLRG1+ flag.

▪ There are two hopes involved here.
1). The first hope is that because the target of ABC008 is so specific, it will not disrupt the overall function of the immune system — it will just knock out this one specific type of T cell.
2). The second hope is that by killing and reducing the number of these T cells that are attacking the IBM muscle, it will help reduce the damage.

▪ Clinical studies are now underway to test this drug.

□ This section is based on research studies on IBM.
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 (see Section 3) 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 in Section 4. The second publication I summarize, referred to here as “the review,” is a very comprehensive review of IBM (Section 5).

◘ These publications are very complex and it is my goal 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 high merit.

◘ 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.

□ Critical ideas.

A healthy immune system defends the body against disease and infection. But if the immune system malfunctions, it may mistakenly attack healthy cells, tissues, and organs. Called autoimmune disease, these attacks can affect any part of the body, weakening bodily function and even turning life-threatening.

Scientists know about more than 100 autoimmune diseases. Some are well known, such as Type 1 diabetes, multiple sclerosis, lupus, and rheumatoid arthritis, while others are rare and difficult to diagnose. Patients may suffer years before getting a proper diagnosis with unusual autoimmune diseases. Most of these diseases have no cure. Some require lifelong treatment to ease symptoms.
Research increasingly suggests that autoimmune diseases likely arise from the interactions of environmental and genetic risk factors.
From: https://www.niehs.nih.gov/health/topics/conditions/autoimmune/index.cfm



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

◘ Some definitions:

▪ Antigens — stimulate.

First — general: any harmful substance that enters the body — like pollen, a bacteria or a virus have specific molecules on their surfaces, known as antigens.

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 markers or 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.

▪ Antibody — responce. A protein created by B cells in direct response to specific antigens. An antibody attaches itself to its respective antigen, marking it for other immune cells to “see” and destroy.

▪ Antigen-presenting cells (APCs). Special immune system cells that digest invading cells or soluble protein antigens and present them to the T cells and B cells so they know what to attack.

▪ B cells. Immune cells that produce antibodies for specific antigens that will bind to the antigens and mark them for destruction by other immune cells.

▪ Cytokines. Proteins released by immune cells to communicate with other immune cells; certain cytokines, such as interferon and interleukin, help regulate specific immune system functions.

▪ Major histocompatibility complex (MHC). A set of proteins on the surface of certain immune cells that influence the interaction of normal cells with immune cells. Antigen-presenting cells show digested antigens to T cells through the MHC on their surface, which allows the T cell to “see” the antigen and recognize it as foreign. The connection between the MHC and the receptor on the T cell is the first signal necessary to activate the T cell to respond to a tumor and destroy it. MHC proteins are controlled by genes.

▪ Monoclonal antibodies (mAbs). Antibodies made in a laboratory that are designed to target specific parts of cells, which may include certain proteins or molecules on the surface of the cells; they are meant to stimulate an immune response in the same way as naturally produced antibodies would.

▪ T cells. Immune cells that recognize specific antigens during antigen presentation— when the flag is waived; T cells are the major players in the immune system's fight against foreign invaders and cancer. Their activation and activity are two of the main focuses in immunotherapy research.

▪ Upregulate. Increase either the overall immune system response or the specific responses of certain immune cells.

▪ Downregulate. Decrease either the overall immune system response or the specific responses of certain immune cells.

◘ Overview.

▪ The immune system keeps careful track of all of the normal flags in the body — the ones that are supposed to be there. Every cell in a person's body displays a flag that tells the immune system that the cell belongs in your body. 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 flag 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.
Using the same mechanism, cells that are old or sick are also marked for elimination (and replacement).

▪ 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 trigger the production of 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 the immune system can kill the cell the antigen is attached to.

▪ Your 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. This section of DNA contains many genes related to the immune system. MHC proteins help see whether a virus has infected the body's cells.

◘ The castle.

▪ Let's think of the body like a castle. Germs, bacteria, and viruses are always trying to get inside the castle. The first line of defense against invaders is the castle's walls, in our case, our skin, mucous membranes, saliva, etc.
Inside the castle, the immune system's job is to constantly patrol for any invaders that make it through the walls. There are several different types of defenders — different immune cells — each with a slightly different job, but they all work together to identify invaders inside the castle and attack them.

▪ The second line of defense against invaders involves effector mechanisms that are nonspecific and do not require prior exposure to the specific pathogen. A major part of this response is a type of defender cell called a macrophage. Macrophages circulate throughout the castle, through blood and the lymph system, always looking for invaders. Also, part of the second line of defense is the inflammation response, including fever and swelling.
-As explained above, invaders can be recognized by the chemical flags on their surfaces. Let's think of it this way: all the invaders have red uniforms and they all carry a yellow flag. Macrophages identify the cells as foreign invaders and eat them (macrophage: macro means big and phage means eater). This second line of defense is called innate immunity and is nonspecific: it targets any invader with a red uniform it sees.
-Then the macrophages take the flag from the invader and put it on their surface. These macrophage cells circulate throughout the immune system displaying the invader's flag. This alerts the immune system that there is a problem, and it reacts by producing special killer cells specifically designed to recognize the specific yellow flag of the invader. These killer cells are generally a type of cell called a CD8 + T cell.

▪ In the third line of defense, soldiers are created to respond to attack the specific invaders – in this case those with a yellow flag. These soldiers include antigens, T cells, B cells, antibodies, memory B cells and T cells, and killer T cells. This response is called acquired immunity.

◘ Autoimmune diseases.

▪ In some autoimmune diseases the 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 just 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 often hard to determine. Often the cellular infiltrate consists of CD4 and CD8 T lymphocytes, B cells, monocytes/macrophages and other inflammatory cells.

▪ 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.

▪ 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.

-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

◘ Multiple sclerosis as an example.

▪ Recently, the results of a significant study were reported showing that some 99.5% of multiple sclerosis (MS) patients have Epstein-Barr virus infection. This is complicated because 94% of healthy individuals also have Epstein-Barr virus. This study was done on over 10 million people who had served in the United States military (Bjornevik et al., 2022). Research has shown that the immune system attacks the Epstein-Barr virus but that the Epstein-Barr target (EBNA1) is similar to a myelin sheath protein (GlialCAM). Sometimes, a cross-reaction occurs, and the immune system mistakenly targets the myelin sheath protein, causing MS symptoms (Lanz et al., 2022). Two questions arise. What factors play a role in triggering this cross-reaction leading to the development of MS? Second, could the same sort of mechanism be going on in IBM, and if so, what are the factors involved?

□ Study. From: Greenberg et al. (2019)

◘ This is a study of data from muscle biopsies from 411 patients (40 with IBM).

◘ Summary. Inclusion body myositis is a late onset treatment-resistant autoimmune disease of skeletal muscle associated with: with a blood autoantibody, anti-cN1A, genome-wide studies showing marked association with an HLA autoimmune haplotype, and muscle pathology, characterized by widespread myofibre expression of MHC class 1 and 2 molecules, high cytokine expression, and the destruction of myofibres by cytotoxic CD8+ T cells … The study identified a unique cytotoxic lymphocyte signature and a highly differentiated T-cell signature in IBM muscle, highlighting the relevance of highly differentiated cytotoxic T cells to the pathogenesis of IBM. In particular, killer cell lectin-like receptor G1 (KLRG1), an inhibitory T- and NK-cell receptor that is known to mark highly differentiated cytotoxic T cells, is identified on IBM blood and muscle-invading T cells (p. 2591).

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

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

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

◘ 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.

◘ 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.

◘ The destruction of myofibres by cytotoxic CD8+ T cells has been recognized as a prominent pathology of IBM since seminal studies in 1984. The clonal nature of the IBM blood and muscle T-cell expansion has been emphasized for decades providing evidence of antigen-driven T-cell stimulation. More recently and consistent with this view, the highly differentiated phenotype of the CD8+ T-cell expansion in IBM blood and muscle has been recognized (p. 2599).

◘ 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/awz207 OPEN ACCESS

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

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

◘ 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 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.

▪ 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.

◘ The specific protein, a surface flag, on these killer T cells — KLRG1 — is known to be strongly induced by chronic viral and other infections.

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

▪ 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.

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

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

◘ 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.


◘ Figure modified from Benveniste & Allenbach, (2019).

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

▪ B: The antigen flag on the muscle surface — not yet discovered.

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

▪ D: Degenerative aspects: mitochondria abnormalities.

▪ 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 OPEN ACCESS

□ Review article. From: Greenberg (2019)

◘ Several crucial discoveries 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 Salajegheh/Greenberg discovered that a circulating autoantibody against a 43 kDa muscle protein [antigen] is present in the blood of IBM patients. Salajegheh et al. (2011)

▪ In 2013 the target autoantigen from 2011 was identified by Larman/Greenberg as cytosolic 5 0-nucleotidase 1A (cN1A; NT5C1A) (Larman et al., 2013).

▪ 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.

◘ Diagrams




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

□ Other articles.

◘ Keller et al. (2017).

▪ The mononuclear infiltrates in IBM predominantly consist of CD8 + cytotoxic T cells (CTLs) surrounding nonnecrotic muscle fibers. More than 30% of all invading cells and around 50% of invading CD8 + T cells depict activation flag positivity. Unlike in healthy individuals, scattered clusters of nonnecrotic muscle fibers ectopically express MHC class I molecules on their surface in a moderate to a substantial degree, and infiltrating CD8 + T cells form close contacts with these MHC class I expressing fibers (Fig. 1). While many muscle fibers with cytoplasmic abnormalities (such as lined vacuoles) do not express MHC class I, regenerating muscle fibers in IBM muscle do show sarcolemmal expression of this molecule. Although macrophages constitute only a minor fraction of the mononuclear infiltrates invading nonnecrotic muscle fibers, they account for up to 80% of the infiltrates surrounding necrotic fibers. Distinct from DM but consistent with lymphocytic infiltrates observed in PM, muscle invading CD8 + T cells stain positive for pore-forming and cytolytic molecules such as perforin, granzyme A, and granulysin. It has been demonstrated that perforin polarization within endomysial CD8 + T cells occurs toward target myofibers, indicative of immune synapse formation and arguing strongly for a possible recognition of specific antigens presented via MHC class I expressing myofibers. In line with this, muscle fibers in IBM patients express co-stimulatory molecules such as ICOS-L, CD276, and BB1 on their surface.


▪ Collectively, mounting evidence from in vitro studies, animal models, and human muscle samples suggests that inflammation in IBM can trigger and sustain cell stress in skeletal muscle with subsequent accumulation of unwanted proteins and irreversible muscle fiber damage.

◘ Lundberg et al. (2021).

▪ Evidence that IBM is an autoimmune disease includes the presence of predisposing immunogenetic risk factors, a large number of antibody-secreting plasma cells within IBM muscle tissue, and the frequent occurrence of autoantibodies recognizing the NT5C1A protein in the blood of patients with IBM. Furthermore, the observation that cytotoxic CD8 + T cells surround and invade muscle fibers in IBM muscle specimens provided early evidence that T cells could mediate muscle damage. Indeed, subsequent studies revealed that CD8 + T cells are clonally expanded in muscle tissue and that the same clones are found in both blood and multiple muscles from the same patient, where they persist. Although the T cell targets remain unknown, these findings suggest that T cell stimulation by the relevant auto-antigen persists for years in these patients. Interestingly, some T cell clone identities are shared between different patients with IBM, suggesting a common as yet undefined target auto-antigen among those with IBM. Importantly, studies showed that both CD4+ and CD8 + T cells in patients with IBM have unusual properties, including aberrant loss of CD28 or CD5 expression with the gain of CD16, CD94, and CD57 expression is associated with terminally differentiated T cells92,93. Phenotypically similar to the abnormal lymphocytes seen in patients with T cell large granulocytic leukemia, the infiltrating T cells in IBM would also be expected to have increased cytotoxic potential and resistance to apoptosis. These features may help explain why IBM is refractory to glucocorticoids and other immunomodulatory therapies, but this population of T cells could also be a promising target for therapeutic intervention.
In addition to the invasion of myofibres by CD8+ CD57+ T cells, IBM muscle specimens are notable for rimmed vacuoles and protein inclusions within muscle fibers. For example, in one study, aggregates of p62 and TDP43 proteins were found in 12 percent of IBM myofibres but only rarely in those of other IIM subtypes. Although other reports suggest that p62 accumulation may be a non-specific feature of IIM, TDP43 positivity is recognized as highly specific for IBM. Hence, IBM might have a considerable degenerative component, but it has not been shown whether the accumulation of these proteins would lead to muscle cell degeneration. Furthermore, it remains unclear whether these changes occur in response to intensive immune-mediated damage or reflect some other underlying non-immune pathological process.

◘ Goyal et al. (2022).

▪ Here, we have further performed deep immunophenotyping of the IBM blood T cell compartment to resolve at higher resolution the nature of the T cell expansions and found that CD4 + and CD8 + T cells were skewed towards the highly differentiated Tem2, Tem4, and TemRA phases. This skewing suggests that IBM T cells are chronically exposed to undefined antigens. CD8 + T cells in the Tem and TemRA phases, unlike naïve T cells, are resistant to corticosteroids and apoptosis.

▪ The expansion of the KLRG1+ CD4 population was particularly striking. Especially high proportions of KLRG1+ CD8 + T cells (>73%) were present in 41% of IBM patients, in contrast to 0% of normal having levels above this threshold.

▪ The expansion of a differentiated CD4 + population in IBM has not been previously noted. This expansion included the CD28 - Tem4 population, suggesting that these CD4 + T cells may function as cytotoxic T cells, not helper T cells, as the CD4+ CD28 - population has cytotoxic capacity and has been identified in other autoimmune diseases.

▪ These findings continue to suggest a central role for highly-differentiated KLRG1+ T cells in the pathogenesis of IBM and minimal involvement of NK cells, in agreement with quantitative studies in the muscle that have suggested far fewer muscle invading NK cells than T cells. 9 We also found that CD8 + T cells that co-expressed the NK cell flag CD56 expressed the highest levels of KLRG1. Prior in vitro studies have shown that activation induces CD56 expression in a subset of T cells that proliferate less, express more inflammatory cytokines, and are capable of HLA-unrestricted cytotoxicity. The presence of CD56+ CD8 + T cells that express KLRG1 is noteworthy as it speaks to the “NK cell-like” behavior and increased cytotoxicity of the CD8 + T cells in IBM..

▪ Collectively, our findings reveal that the selective expansion of blood KLRG1+ T cells in IBM patients is confined to the TemRA and Tem cellular compartments.

◘ Johari et al. (2022).

▪ Results We observe dysregulation of genes involved in calcium homeostasis, particularly affecting the T-cell activity and regulation, causing disturbed Ca2+ -induced apoptotic pathways of T cells in IBM muscles. Additionally, LCK/p56, which is an essential gene in regulating the fate of T-cell apoptosis, shows increased expression and altered splicing usage in IBM muscles.

▪ Interpretation Our analysis provides a novel understanding of the molecular mechanisms in IBM by showing a detailed dysregulation of genes involved in calcium homeostasis and its effect on T-cell functioning in IBM muscles. Loss of T-cell regulation is hypothesized to be involved in the consistent observation of no response to immune therapies in IBM patients. Our results show that loss of apoptotic control of cytotoxic T cells could be one component of their abnormal cytolytic activity in IBM muscles.

▪ We observed a significant association with genes involved in various calcium-related pathways and identified disturbed calcium regulation specific to T cells in IBM muscles, highlighting the relevance of calcium homeostasis for T-cell activity in IBM muscles. In particular, we identified calcium-induced T lymphocyte apoptosis to be disturbed in IBM muscles.

▪ antigen-driven T-cell cytotoxicity is the most reproducible and plausible part of the complex molecular pathomechanism in IBM. However, it remains unknown what antigen drives this IBM-specific immune cascade.

▪ LCK is a T lymphocyte-specific protein tyrosine kinase involved in downstream events of antigen-TCR interaction. LCK/p56 is essential in transducing signals leading to apoptotic cell death in mature T cells. Its activity is tightly regulated to protect against hyperactivation of T cells and autoimmunity, thus maintaining T-cell homeostasis. … In our analysis, LCK is both differentially expressed and differentially spliced in IBM muscles. Additionally, further evidence is provided by immunoanalysis of IBM muscles showing strong expression of the LCK protein in the T-cell infiltrates. Disturbed T-cell apoptosis and the dysregulation of LCK in IBM muscles provide novel insights into the molecular mechanisms of IBM. Considering the crucial regulatory activity of LCK, it might be a potential therapeutic target for IBM patients.

▪ Our analyses show novel molecular events in IBM muscles which increase our understanding of IBM and provide valuable additions to improve the therapeutic interventions considering the disturbed calcium homeostasis, dysregulation of LCK, and associated deregulation of apoptotic control of T cells in IBM muscles.

□ IBM summary.

◘ 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 muscle surface 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 et al. study); CD8+ T cells expressing KLRG1, a flag on the T cells indicating highly differentiated immune cells. These cells infiltrate muscle and circulate in the blood of IBM patients.

What could start this reaction off? As Dr. Lubinus suggests, "We don't know how the inflammation gets started in IBM; in one theory, a protein from a virus is recognized by the immune system as foreign; however, as part of an autoimmune reaction, the immune system response (e.g., T cells) cross-reacts with a normal protein in the muscle which has been misidentified as foreign, and this generates an on-going immune response of the T-cells as described."

◘ IBM Key points:
-In IBM, they have already discovered two major immune related aspects: 1) autoantibodies — anti-cN1A are found in about 50% of cases and 2) killer CD8 T cells have been found infiltrating into the muscle cells.
-In IBM, the chronic antigenic stimulation of T cells must come from some as yet unidentified muscle antigens, presumably presented on the surface of the muscle cells by major histocompatibility complex (MHC) class I molecules. MHC class I overexpression is one of the hallmarks of IBM pathology (see 2.2.3).
-In the case of IBM, the immune system produces CD8 + T cells with an overexpressed KLRG1 flag (killer cell lectin-like receptor G1) attached. KLRG1 is an inhibitory receptor of the C-type lectin-like family. It is used as a flag of terminally differentiated NK and T cells and is strongly induced by chronic viral and other infections. When these killer cells see the corresponding antigen flag displayed on the muscle cell's surface, they link and destroy the cell (see 2.3.3).
-Antibodies that target cytosolic 5'-nucleotidase 1A (the antibody is now commonly referred to as anti-cN1A or as anti-cN1A antibody) have been discovered in the blood of IBM patients. This autoantibody appears highly specific to IBM, however, it does not appear in all IBM patients and may also appear in patients with other diseases or even in healthy people.
-It remains unknown what muscle surface [auto]-antigen drives this IBM-specific immune cascade: CD8+ T-cell clonality (Greenberg, 2020; Johari, 2022).
-Although abnormal proteins are seen in a limited number of IBM muscle cells, "Collectively, mounting evidence from in vitro studies, animal models, and human muscle samples suggests that inflammation in IBM can trigger and sustain cell stress in skeletal muscle with subsequent accumulation of unwanted proteins and irreversible muscle fiber damage" (Keller et al., 2017).
-The presence of the abnormal aggregations of amyloid beta can be demonstrated by microscopic examination of tissue after staining with Congo red in up to 70% of IBM muscle fibers and mostly found in nonvacuolated areas (Keller et al., 2017).
-Approximately 95% of patients with IBM carry HLA-DR3, while 70% have HLA-B8 supporting a general genetic predisposition to acquiring autoimmune disorders (Price et al., 1999).
-Goyal showed that KLRG1+ CD8+ T cells are highly differentiated cells that are over-represented in the blood of patients with IBM. A monoclonal antibody should kill 'G1 without compromising the ability of regulatory T cells to suppress autoimmunity (Goyal et al. 2022).
-The CD8 + T-cell infiltration and overexpression of class I MHC antigens in all muscle fibers indicate an autoimmune cascade and are the most consistent finding together with the degeneration of myofibers (Johari et al., 2022).
-Johari et al. 2022 identified calcium-induced T lymphocyte apoptosis to be disturbed in IBM muscles.
-Antigen-driven T-cell cytotoxicity is the most reproducible and plausible part of the complex molecular pathomechanism in IBM. However, it remains unknown what antigen drives this IBM-specific immune cascade (Johari et al., 2022).
-Johari et al. (2022) observed genes associated with the mobilization of Ca 2+, the release of Ca 2+, the quantity of Ca 2+, and the flux of Ca 2+ as significantly dysregulated in IBM muscles, indicating a possible widespread disturbance with the handling of calcium entry and release in cells. In T cells, especially, this disturbance could dramatically impact their activation and differentiation, and most likely, the regulation of T-cell apoptosis will be disturbed.
-LCK is a T lymphocyte-specific protein tyrosine kinase involved in downstream events of antigen-TCR interaction. LCK/p56 is essential in transducing signals leading to apoptotic cell death in mature T cells … LCK is both differentially expressed and differentially spliced in IBM muscles. … Disturbed T-cell apoptosis and the dysregulation of LCK in IBM muscles provide novel insights into the molecular mechanisms of IBM. Considering the crucial regulatory activity of LCK, it might be a potential therapeutic target for IBM patients (Johari et al., 2022).
- Conclusion. 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.

□ References.

◘ 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 OPEN ACCESS

▪ Dykes, L. (2021, November 4). Niti Goel, MD: Depletion of KLRG1+ T cells in clinical trial of ABC008 in inclusion body myositis. Rheumatology Network. link

▪ 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 OPEN ACCESS

▪ Goyal, N. A., Coulis, G., Duarte, J., Farahat, P. K., Mannaa, A. H., Cauchii, J., Irani, T., Araujo, N., Wang, L., Wencel, M., Li, V., Zhang, L., Greenberg, S. A., Mozaffar, T., & Villalta, S. A. (2022). Immunophenotyping of inclusion body myositis blood T and NK cells. Neurology, 10.1212/WNL.0000000000200013. https://pubmed.ncbi.nlm.nih.gov/35131904/

▪ Johari, M., Vihola, A., Palmio, J., Jokela, M., Jonson, P. H., Sarparanta, J., Huovinen, S., Savarese, M., Hackman, P., & Udd, B. (2022). Comprehensive transcriptomic analysis shows disturbed calcium homeostasis and deregulation of T lymphocyte apoptosis in inclusion body myositis. Journal of Neurology. https://doi.org/10.1007/s00415-022-11029-7 OPEN ACCESS.

▪ Keller, C. W., Schmidt, J., & Lünemann, J. D. (2017). Immune and myodegenerative pathomechanisms in inclusion body myositis. Annals of Clinical and Translational Neurology, 4(6), 422-445. https://doi.org/10.1002/acn3.419 OPEN ACCESS.

▪ Larman, B. H., Salajegheh, M., Nazareno, R., Lam, T., Sauld, J., Steen, H., Won Kong, S., Pinkus, J. L., Amato, A. A., Elledge, S. J., & 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.

▪ Lundberg, I. E., Fujimoto, M., Vencovsky, J., Aggarwal, R., Holmqvist, M., Christopher-Stine, L., Mammen, A. L., & Miller, F. W. (2021). Idiopathic inflammatory myopathies. Nature Reviews Disease Primers, 7(1), 86. https://www.nature.com/articles/s41572-021-00321-x

▪ Salajegheh, M., Lam, T. & Greenberg, S. A. Autoantibodies against a 43kDa muscle protein in inclusion body myositis. PLOS ONE 6, e20266 (2011).

▪ Salam, S., Dimachkie, M. M., Hanna, M. G., & Machado, P. M. (2022). Diagnostic and prognostic value of anti-cN1A antibodies in inclusion body myositis. Clinical and Experimental Rheumatology, 10.PMID: 35225226. OPEN ACCESS.

◘ 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

▪ Bjornevik, K., Cortese, M., Healy, B. C., Kuhle, J., Mina, M. J., Leng, Y., Elledge, S. J., Niebuhr, D. W., Scher, A. I., Munger, K. L., & Ascherio, A. (2022). Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science, 375(6578), 296-301. https://doi.org/10.1126/science.abj8222.

▪ Bolko, L., Jiang, W., Tawara, N., Landon-Cardinal, O., Anquetil, C., Benveniste, O., & Allenbach, Y. (2021). The role of interferons type I, II and III in myositis: A review. Brain Pathology, 31(3), 1-13. https://doi.org/10.1111/bpa.12955 OPEN ACCESS

▪ 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. Eura2016.pdf

▪ 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://www.nature.com/articles/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

▪ Lanz, T. V., Brewer, R. C., Ho, P. P., Moon, J.-S., Jude, K. M., Fernandez, D., Fernandes, R. A., Gomez, A. M., Nadj, G.-S., Bartley, C. M., Schubert, R. D., Hawes, I. A., Vazquez, S. E., Iyer, M., Zuchero, J. B., Teegen, B., Dunn, J. E., Lock, C. B., Kipp, L. B., … Robinson, W. H. (2022). Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM. Nature, 603(7900), 321-327. https://www.nature.com/articles/s41586-022-04432-7

▪ 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

▪ Price, P., Witt, C., Allock, R., Sayer, D., Garlepp, M., Kok, C. C., French, M., Mallal, S., & Christiansen, F. (1999). The genetic basis for the association of the 8.1 ancestral haplotype (A1, B8, DR3) with multiple immunopathological diseases. Immunological Reviews, 167(1), 257-274. https://doi.org/10.1111/j.1600-065X.1999.tb01398.x.

▪ 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://www.nature.com/articles/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

⚀ Protein degeneration:

□ Another theory is that something causes degeneration in the cells of the muscle. There are often holes seen in the muscle (vacuoles) and “inclusion bodies” of abnormal proteins (predominantly containing amyloid and TDP-43) although, it has not been shown that these bodies are responsible for the degeneration.

□ 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.

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

□ 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.

□ Inclusion bodies and vacuoles represent the degenerative aspects of IBM.

□ As the Greenberg study shows, the immune features associated with IBM can also explain the degenerative aspects seen in the disease.

⚀ Defective mitochondria:

□ Over the years, abnormalities associated with part of the cell called the mitochondrion (plural mitochondria) have been implicated and recent research has emphasized this aspect.

 Di Leo, V., Bernardino Gomes, T. M., & Vincent, A. E. (2023). Interactions of mitochondrial and skeletal muscle biology in mitochondrial myopathy. Biochemical Journal, 480(21), 1767-1789. https://doi.org/10.1042/BCJ20220233 pdf.

◘ Mitochondrial dysfunction in skeletal muscle fibres occurs with both healthy aging and a range of neuromuscular diseases. The impact of mitochondrial dysfunction in skeletal muscle and the way muscle fibres adapt to this dysfunction is important to understand disease mechanisms and to develop therapeutic interventions. Furthermore, interactions between mitochondrial dysfunction and skeletal muscle biology, in mitochondrial myopathy, likely have important implications for normal muscle function and physiology. In this review, we will try to give an overview of what is known to date about these interactions including metabolic remodelling, mitochondrial morphology, mitochondrial turnover, cellular processes and muscle cell structure and function. Each of these topics is at a different stage of understanding, with some being well researched and understood, and others in their infancy. Furthermore, some of what we know comes from disease models. Whilst some findings are confirmed in humans, where this is not yet the case, we must be cautious in interpreting findings in the context of human muscle and disease. Here, our goal is to discuss what is known, highlight what is unknown and give a perspective on the future direction of research in this area.

 McLeish, E., Slater, N., Sooda, A., Wilson, A., Coudert, J. D., Lloyd, T. E., & Needham, M. (2022). Inclusion body myositis: The interplay between ageing, muscle degeneration and autoimmunity. Best Practice & Research Clinical Rheumatology, 101761. https://doi.org/10.1016/j.berh.2022.101761. OPEN ACCESS.

 Nelke, C., Kleefeld, F., Preusse, C., Ruck, T., & Stenzel, W. (2022). Inclusion body myositis and associated diseases: An argument for shared immune pathologies. Acta Neuropathologica Communications, 10(1), 84. https://doi.org/10.1186/s40478-022-01389-6. OPEN ACCESS.

◘ The prototypical pathomorphology of IBM comprises four major categories:
1- Highly specific inflammatory features consisting of endomysial T cell infiltrates showing a predominance of CD8 +lymphocytes.
2- Rimmed vacuoles and a range of misfolded proteins either associated with the vacuoles or lying beneath the myofibrils.…Of note, amyloidogenic deposits (misfolded proteins with a β-pleated structure) must not be mistaken for amyloid-β, which is processed by secretases and shed to the extracellular (not intracellular) space.
3- Mitochondrial damage with ragged-red, -blue or -brown fibers as well as cytochrome c oxidase (COX)-negative (and SDH-positive) fibers.…The absence of mitochondrial damage renders the diagnosis of IBM highly unlikely.
4- The extent of tissue damage increases over time as characterized by increased fibrous and fatty tissue in the endomysium.

 Cantó-Santos, J., Grau-Junyent, J. M., & Garrabou, G. (2020). The Impact of Mitochondrial Deficiencies in Neuromuscular Diseases. Antioxidants, 9(10), 964. https://doi.org/10.3390/antiox9100964 OPEN ACCESS

◘ The aim of the review is to discuss the mechanisms underlying energy production, oxidative stress generation, cell signaling, autophagy, and inflammation triggered or conditioned by the mitochondria. Briefly, increased levels of inflammation have been linked to reactive oxygen species (ROS) accumulation, which is key in mitochondrial genomic instability and mitochondrial respiratory chain (MRC) dysfunction.

◘ Other NMDs with mtDNA deletions are sporadic inclusion body myositis (sIBM) (reported in 67% of sIBM patients) [108,109]

 Hedberg-Oldfors, C., Lindgren, U., Basu, S., Visuttijai, K., Lindberg, C., Falkenberg, M., Larsson Lekholm, E., & Oldfors, A. (2021). Mitochondrial DNA variants in inclusion body myositis characterized by deep sequencing. Brain Pathology, 31(3). https://doi.org/10.1111/bpa.12931 OPEN ACCESS

◘ In conclusion, deep sequencing and quantification of mtDNA variants revealed that IBM muscles had markedly increased levels of large deletions and duplications, and there were also indications of increased somatic single nucleotide variants and reduced mtDNA copy numbers compared to age-matched controls. The distribution and type of variants were similar in IBM muscle and controls indicating an accelerated aging process in IBM muscle, possibly associated with chronic inflammation.

 Oikawa, Y., Izumi, R., Koide, M., Hagiwara, Y., Kanzaki, M., Suzuki, N., Kikuchi, K., Matsuhashi, T., Akiyama, Y., Ichijo, M., Watanabe, S., Toyohara, T., Suzuki, T., Mishima, E., Akiyama, Y., Ogata, Y., Suzuki, C., Hayashi, H., Kodama, E. N., … Abe, T. (2020). Mitochondrial dysfunction underlying sporadic inclusion body myositis is ameliorated by the mitochondrial homing drug MA-5. PLOS ONE, 15(12), e0231064. https://doi.org/10.1371/journal.pone.0231064. OPEN ACCESS

 Catalán-García, M., García-García, F. J., Moreno-Lozano, P. J., Alcarraz-Vizán, G., Tort-Merino, A., Milisenda, J. C., Cantó-Santos, J., Barcos-Rodríguez, T., Cardellach, F., Lladó, A., Novials, A., Garrabou, G., & Grau-Junyent, J. M. (2020). Mitochondrial Dysfunction: A Common Hallmark Underlying Comorbidity between sIBM and Other Degenerative and Age-Related Diseases. Journal of Clinical Medicine, 9(5), 1446. https://doi.org/10.3390/jcm9051446 OPEN ACCESS

⚀ More ideas on causes.

□ An older theory was that a virus was the cause, however, no virus has yet been clearly linked to causing IBM.

□ It is possible that a yet undiscovered factor is the cause or trigger.

□ Until the basic causes are discovered, a specific treatment will remain elusive.