The ancestral haplotype and sIBM.

This page provides some further background information and references to the possible link between a genetic predisposition to autoimmune disorders and sIBM.

1). Overview.

Self versus Non-self.
The HLA gene region.
Molecular biology of MHC proteins.
MHC Class I antigen processing.
What is an 8.1 ancestral haplotype (AH)?
This haplotype is linked to Autoimmune Diseases.
TNF-a Levels.

2). What's this got to do with sIBM?

The general role of HLA in IBM.
8.1 ancestral haplotype HLA DRB1*0301 (HLA-DR3) and IBM.
The DRB1*0301 area.
Detailed investigation of the MHC region in patients with s-IBM.
Pathways to Disease.

3). References

General References on the 8.1 ancestral haplotype.
References that specifically refer to IBM.


The MHC and its subset, the HLA, consists of a section of genes on chromosome 6. Most of the genes in this region code for proteins involved in the immune system. HLA molecules play an important role in regulating the types and degree of immune responses to certain environmental agents. The MHC appears to be the strongest risk factor for predisposing most common autoimmune diseases and people with certain combinations of HLA alleles (gene versions) have a much higher risk of developing specific autoimmune diseases than those without these alleles. Research has linked sIBM with a number of these gene areas.

Self versus Non-self.

The immune system defends the body by recognizing agents that represent self and those that represent non-self, and launching attacks against harmful members of the latter group. Distinguishing between self and non-self and between harmful non-self and harmless non-self is a difficult problem, and a variety of mammal disorders (immunodeficiency and autoimmunity) arise from failures of discriminatory systems.

Some self/non-self discrimination is effected by hard-wired mechanisms that recognize features displayed only by pathogens. The mannan-binding lectin pathway of the complement system, for instance, recognizes mannose sugars that appear only in the polysaccharide coats of various species of bacteria.

The most versatile mechanisms of discrimination, however, are not hard-wired; rather, they involve the immune system learning to recognize non-self. For instance, the plasma membrane of every nucleated cell contains molecules of a large glycoprotein called the major histocompatibility complex (MHC). These proteins have configurations and amino acid sequences that are unique to every individual. Cytotoxic T cells (T cells that directly destroy cells) contain surface-mounted receptors that they use to determine if a given cell is virally infected by reading the peptides displayed on its MHC molecules. During their development, T cells are selected for self-reactivity. If a given cell contains receptors that bind strongly to an existing molecule in the body, it is destroyed by forced apoptosis, leaving behind T cells that can be safely released into the body.


The HLA gene region.

The human leukocyte antigen (HLA) system lays within a larger section of genes called the major histocompatibility complex (MHC). The MHC spans a region of about four million base pairs, which is equivalent to 0.1 % of the human genome, and it contains over 200 genes. The HLA is a large group of genes on the short arm of chromosome 6. Most of the genes in this region code for proteins involved in the immune system. The function of the immune system is to defend the body against foreign pathogens (such as bacteria, viruses and malignant cells). This requires a system which can distinguish between self and non-self, and some of the proteins in the HLA system are a part of this system. Specifically, the genes of the major histocompatibility complex (MHC) encode cell-surface proteins that play a central role in presenting peptide antigens to T lymphocytes as an early step in immune activation. Foreign invaders (antigens) are cut into small peptide pieces, which are then bound to HLA molecules on the surface of cells, displayed for T cells to "see." The HLA molecules with the bound peptides are recognized by T-lymphocytes and immune reactions against the intruders are generated.

The proteins encoded by HLAs are the proteins on the outer part of somatic cells that are (effectively) unique to that person. The immune system uses the HLAs to differentiate self cells and non-self cells. Any cell displaying that person's HLA type belongs to that person (i.e., it is not an invader). Any cell displaying some other HLA type is "not-self" and is an invader (like a virus). HLA molecules therefore play an important role in regulating the types and degree of immune responses to certain environmental agents.

HLA types are inherited. Allelic variants of genes encoding the human MHC Class I (HLA-A, -B, -Cw) and Class II (HLA-DR, -DQ, -DP) molecules are among the most polymorphic in the human genome and those most consistently found associated with the development of human autoimmune diseases, including SLE (Lupus erythematosus), Myasthenia Gravis, and Sjögren's Syndrome and the inflammatory myopathies (sIBM included). Certain combinations of HLA genes may also protect against certain disorders.

MHC class 1 are found on the surface of most cells in the body:
Proteins (both native and foreign, such as the proteins of viruses) produced inside most cells are displayed on HLA antigens (specifically class I MHC) on the cell surface. When a cell gets infected with a virus, it sheds the infectious bug's antigens and directs T-cells to them using MHC type 1. The MHC holds out the antigen like a hand waving a red flag, waiting for a T-cell to respond.

MHC class 2 are found only on the surface of antigen-presenting cells:
When a foreign pathogen enters the body, specific cells called antigen-presenting cells (APCs) engulf (ingest) the pathogen (the foreign antigens) through a process called phagocytosis. Proteins from the pathogen are digested into small pieces (peptides) and loaded onto HLA antigens (specifically MHC class II ). The MHC class II with the foreign protein bits are then displayed on the cells surface by the APCs for certain cells of the immune system called T cells, which then produce a variety of effects to eliminate the pathogen (often killing the cell).

Summary: The primary immunological function of Major Histocompatibility Complex (MHC) molecules is to bind to and "present" antigenic peptides on the surfaces of cells for recognition (binding) by the antigen-specific T cell receptors (TCRs) of lymphocytes. Scientists speculate that "the dysregulation of MHC mediated immunologic recognition events contributes to a breakdown of self-tolerance and the resultant development of autoimmune pathology" - people with certain types of HLA antigens are more likely to develop certain autoimmune diseases, including sIBM (O'Hanlon, 2005).

Following from: http://en.wikipedia.org/wiki/Major_histocompatibility_complex


Molecular biology of MHC proteins.

The classical MHC molecules (also referred to as HLA molecules in humans) have a vital role in the complex immunological dialog that must occur between T cells and other cells of the body. At maturity, MHC molecules are anchored in the cell membrane, where they display short polypeptides to T cells, via the T cell receptors (TCRs). The polypeptides may be "self," that is, originating from a protein created by the organism itself, or they may be foreign, originating from bacteria, viruses, pollen, etc. The overarching design of the MHC-TCR interaction is that T cells should ignore self peptides while reacting appropriately to the foreign peptides. Foreign peptides that provoke an immune response are termed immunogens.

The immune system has another, equally important method to identify antigens: B cells with their membrane-bound antibodies, also known as B cell receptors (BCRs). However, while the BCRs of B cells can bind to antigens without much outside help, the TCRs of T cells require "presentation" of the antigen: this is the job of MHC. It is important to realize that the vast majority of the time, MHC are kept busy presenting self-peptides, which the T cells should appropriately ignore. A full-force immune response usually requires the activation of B cells via BCRs and T cells via the MHC-TCR interaction. This duplicity creates a system of "checks and balances" and underscores the immune system's potential for running amok and causing harm to the body.

All MHC molecules receive polypeptides from inside the cells they are part of and display them on the cell's exterior surface for recognition by T cells. However, there are major differences between MHC class I and II in the method and outcome of peptide presentation.


MHC Class I antigen processing.

MHC class I molecules are found on almost every nucleated cell of the body. MHC Class I molecules are heterodimers, consisting of a single transmembrane polypeptide chain (the a-chain) and a b2 microglobulin (which is encoded elsewhere, not in the MHC). The a chain has two polymorphic domains, a1, a2, which binds peptides derived from cytosolic proteins. The peptides are mainly generated in the cytosol by the proteasome. The proteasome is a macromolecule that consist of 24 subunits of which half of them contain proteolytic activity. The proteasome degrades intracellular proteins into small peptides that are then released into the cytosol. The peptides have to be translocated from the cytosol into the endoplasmic reticulum (ER) to meet the MHC class I molecule which has its peptide binding site in the lumen of the ER. The peptide translocation from the cytosol into the lumen of the ER is accomplished by the Transporter associated with Antigen Processing TAP. TAP is a member of the ABC transporter family and is a heterodimeric multimembrane spanning polypeptide consisting of TAP1 and TAP2. The two subunit form a peptide binding site and two ATP binding sites that face the lumen of the cytosol. TAP binds peptides on the cytoplasmic site and translocates them under ATP consumption into to the lumen of the ER. The MHC class I molecule is then in turn loaded with peptides in the lumen of the ER. The peptide loading process involves several other molecules which form a large multimeric complex consisting of TAP, tapasin, calreticulin, calnexin and ER60. Once the peptide is loaded onto the MHC class I molecule it leaves the ER through the secretory pathway to reach the cell surface. The transport of the MHC class I molecules through the secretory pathway involves several posttranslational modifications of the MHC molecule. Some of the posttranslational modifications occur as early as in the ER and involve change to the N-glycan of the protein. Followed by extensive changes to the N-glycan in the golgi organelle. The N-glycans mature fully before they reach the cell surface. Peptides that fail to bind MHC class I molecules in the lumen of the endoplasmic reticulum are removed from the ER via the sec61 channel into the cytosol were they might undergo further trimming in size and might translocated by TAP back into ER for binding to an MHC class I molecule. MHC class I molecules are loaded with proteins generated in the cytosol, it is the primary way for a virus-infected cell to signal to T cells. It interacts exclusively with CD8+ T cells (also known as cytotoxic T cell lymphocytes or CTLs). The fate of a virus-infected cell is almost always apoptosis, or programmed cell death, initiated by the CD8+ T cell. This response seems like "killing the messenger," but the messenger in this case is virally infected and probably represents a risk of contagion for neighboring cells.

Web resources:


What is an 8.1 ancestral haplotype (AH)?

A haplotype is a set of closely linked genes that tends to be inherited together as a unit. The 8.1 ancestral haplotype is part of the MHC complex. Thus, one of the most conspicuous properties of MHC haplotype is that that some alleles occur more frequently together than expected by chance. The non-random pairing of alleles in the MHC is called gametic or linkage disequilibrium (LD) and it is influenced by the low recombination rate in the MHC region.

Another aspect of the haplotype is the age of the genes. This haplotype is called ancestral because the MHC is estimated to be over 500 million years old and classical MHC molecules can be found throughout the vertebrates. Classical MHC-like genes have nearly identical intron/exon structures in all vertebrates.


This haplotype is linked to Autoimmune Diseases.

The MHC appears to be the strongest risk factor for most autoimmune diseases and people with certain HLA alleles (genes) have a much higher risk of specific autoimmune diseases than those without these alleles. The 8.1 ancestral haplotype (AH) is a common Caucasoid haplotype. It is unique in its association with a wide range of immunopathological diseases.
In some cases the effect can be dramatic. In the rather common autoimmune diseases, insulin-dependent diabetes mellitus (IDDM) and rheumatoid arthritis, approximately 2/3 of the patients have a specific predisposing HLA allele. A person with the predisposing alleles DQB1*0301 (DQ8) and DQB1*02 (DQ2) and a family history of IDDM has 25 percent risk of getting IDDM. If the person has these HLA alleles, but no family history of IDDM, the risk of getting the disease falls to1/25. In most autoimmune diseases, the HLA associated risk is rather weak (typically the risk is increased two or threefold).

Recent articles describing the HLA associations for allergies (Cardaba, 1996), autoimmune liver diseases (Donaldson, 1994) (Czaja, 1995) (Leung, 1996), autoimmune thyroid diseases (Weetman, 1994), autoimmune vasculitis (Weyand, 1995b), coeliac disease (Sollid, 1989), dermatitis herpetifomis (Hall, 1996), IDDM (Nepom, 1995) (Sanjeevi, 1995b) (She, 1996), inflammatory bowel diseases (Satsangi, 1996), multiple sclerosis (Haegert, 1994), myasthenia gravis (Tournier-Lasserve, 1993), psoriasis vulgaris (Ikaheimo, 1996), rheumatoid arthritis (Winchester, 1994) (Weyand, 1995a), Sjögren's syndrome SLE (Hess, 1994) and different tumors (Lee, 1996) are important not only from a screening perspective, but also because they give insights into the etiology and pathogenesis of the diseases. There are many more diseases where HLA class II alleles seem to confer an increased risk and many new associations to genes at the short arm of chromosome 6 are being continuously discovered. The exact mechanisms behind the MHC associated risk for autoimmune diseases remains unknown.

The molecular basis of many genetic diseases in man have been identified through gene cloning. For the most part, these diseases conform to the principles of Mendelian segregation: their segregation can be classified as either dominant or recessive and phenotypic effects can be followed within pedigrees. The genetic lesions underlying the disease pathology of these single gene disorders (e.g.. Cystic fibrosis, muscular dystrophy, haemochromatosis) have been shown to be specific mutations which affect the amino acid sequence and function of the cognate proteins, or which directly affect gene expression.

Diseases of the autoimmune type do not conform to this genetic picture. They do not segregate in a simple Mendelian pattern, they cannot be easily classified as dominant or recessive (they have complex segregation patterns) and are not single genes disorders. The underlying molecular pathology is different in that common functional variants of particular genes (polymorphisms or "aetiological mutations") which are neither necessary nor sufficient in themselves to account for disease, are present at increased frequency in patients. These interact epistatically [The suppression of a gene by the effect of an unrelated gene] with other genes and gene variants to predispose to disease. The word 'predispose' here allows for the likely involvement of ubiquitous environmental factors. It has been suggested that the absence of general infections may be the ubiquitous environmental factor.

The MHC is associated with most if not all diseases of the autoimmune type which affect 4% of the population. Insulin dependent diabetes mellitus (IDDM), muscular sclerosis (MS), systemic lupus erythematosus (SLE), rheumatoid arthritis and Coeliac disease all show a major genetic contribution from within the MHC. Genetic studies show other non-MHC loci are also involved. For instance, in IDDM, 12 chromosomal locations are implicated in the aetiology of the disease. Other autoimmune diseases are similarly complex. Which of the many genes mapping within the MHC is primarily involved is not resolved. The antigen presenting HLA class II molecules (particularly HLA-DQ) were originally identified as a contributing factor in both susceptibility and resistance to IDDM and class II alleles have been implicated in other autoimmune diseases, but these associations are not simple. The strong genetic contribution of the IDDM1 locus within the MHC is not fully accounted for by HLA class II variants. More recent haplotype studies have looked at the contribution of particular combinations of class II alleles or haplotypes to autoimmune disease e.g. in MS. Further haplotype studies along these lines provide more powerful genetic tests for disease associations in candidate a region, particularly when employed in genetically isolated patient populations. These approaches when used in combination with animal models of disease and functional evaluation of candidate genes, offer hope for future successes in the unraveling of this major group of debilitating diseases. From: http://www-immuno.path.cam.ac.uk/~immuno/mhc/mhc.html (defunct)



The tumor necrosis factor (TNF) gene lies within the human leukocyte antigen (HLA) class III region on chromosome 6p21.3. TNF is one of the chemical messengers (proteins) that helps to regulate the inflammatory process. During a normal immune response, TNF attaches to special cells throughout the body. This, in turn, "switches on" immune cells, causing them to release chemicals that can contribute to inflammation. When people produce too much TNF, it overwhelms the immune system's ability to control inflammation leading to "autoimmune" diseases like rheumatoid arthritis and sIBM.


TNF-a Levels.

Several studies have showed that individual differences in TNF production could be linked with the 8.1 major histocompatibility complex (MHC) ancestral haplotype, HLA A1-B8-DR3-DQ2-TNF308A-lymphotoxin alpha (LT)+252A, overrepresented in several inflammatory and autoimmune diseases. Overproduction of TNF-a could be a factor in sIBM and a new study of a drug that reduces TNF-a appears to help the symptoms of sIBM. See: Enbrel page.


What's this got to do with sIBM?



Research has documented the association of the northwestern European 8.1 ancestral haplotype (AH) (HLAA* 0101; B*0801; Cw*0701; DRb1*0301; DQA1*0501) with the development of inflammatory myopathies in small groups of North American Caucasian patients. s-IBM frequently is associated with human leucocyte antigen (HLA)- DRb1*0301 (HLA-DR3).

Newer: Genetic factors are presumed to play a role in sIBM, on the basis of an association between sIBM and certain human leukocyte antigen (HLA) genes, especially the DRb1*0301 and DQb1*0201 alleles. Alleles of the 8.1 ancestral haplotype in the center of the MHC class II region seem to confer susceptibility to IBM. The B8-DR3-DR52-DQ2 haplotype is found in 67% of sIBM patients, similar to the frequency of this haplotype in myasthenia gravis. The B8-DR3-DR52-DQ2 haplotype is also associated with earlier disease onset, indicating that immuno regulatory genes are inherently connected with the manifestation of symptoms. Dalakas, MC (August, 2006) Sporadic inclusion body myositis-diagnosis, pathogenesis and therapeutic strategies.Nature Clinical Practice Neurology 2: 437-447.

[In addition to the sporadic type with its probable genetic predisposition pattern, there are also several types that are specifically linked to genetic causes and that are inherited from generation to generation. These are described as the] hereditary inclusion body myopathies (hIBM), a heterogeneous group of non-inflammatory, inherited syndromes. A subset of hIBM that spares the quadriceps muscles results from mutations in the GNE gene. Dalakas, MC (August, 2006) Sporadic inclusion body myositis diagnosis, pathogenesis and therapeutic strategies.Nature Clinical Practice Neurology 2: 437-447.

Older: There is little doubt that sIBM has a major immunological aspect to it. Dalakas (2005) supports the view that sIBM is an autoimmune disorder characterized first by a T-cell inflammatory response. In sIBM, the muscle fibers consistently express (display) MHC class I antigens on their surfaces* suggesting an antigen driven, T cell mediated and ongoing invasion of the muscle cells by CD8+ cytotoxic T cells that target the muscle cells, eventually destroying them. These events are also associated with genes in the HLA-DR and DQ regions. Other autoimmune diseases are common in patients with sIBM and/or in their families. Dalakas is also suggesting that the antigens presented are the same ones over time implying a persistent stimulation of the immune system by the same antigens. This was supported by the finding that the T-cells that invade the muscle cells have the specific rearrangement in the TCR gene for the recognition of these antigens, appearing in a restricted number of expanded clones that are identical in different muscles of an individual and that these clones persist over many years. As of now, they do not know what these antigens are. Dalakas also notes that sIBM is mysterious because it does not respond to immunotherapies. [Also see: Brain. 2000 Oct;123 ( Pt 10):2030-9. Clonal restriction of T-cell receptor expression by infiltrating lymphocytes in inclusion body myositis persists over time. Studies in repeated muscle biopsies. By: Amemiya K, Granger RP, Dalakas MC.]

*In fact, the upregulation of major histocompatibility complex (MHC) class I can be used as a further clue to the correct diagnosis of sIBM and this method has been demonstrated to be a valid test for s-IBM and other inflammatory myopathies. See: Van der Pas J, Hengstman GJ, ter Laak HJ, et al. Diagnostic value of MHC class I staining in idiopathic inflammatory myopathies. J Neurol Neurosurg Psychiatry 2004; 75:136-139.


The general role of HLA in IBM (based on O'Hanlon, 2005).

The DQA1*03 alleles and their commonly linked DRB1*04 alleles were observed as protective factors for IBM. In addition, the DRB1*0701; DQA1*0201 haplotype block was identified as a possible protective factor for IBM and PM.

The HLA-B*5101 and Cw*14 alleles, often found in linkage disequilibrium in Caucasians, were risk factors for IBM. PM, DM, and IBM patients each shared immunogenetic risk factors common among North American Caucasians of European descent (that is, linked DRB1*0301; DQA1*0501 alleles of the 8.1 AH). Despite these similarities, IIM patients also have distinct HLA associations characteristic of 1 or more clinical groups. The HLA DQA1*0201 allele was defined as a shared protective factor for PM and IBM but not DM patients (p < 0.05). Conversely, the HLA-B*0801 allele is an apparent risk factor for both PM and DM but not IBM patients. DQA1*03 alleles were observed as protective factors unique to IBM (pc < 0.05) while Cw*14 alleles conferred risk for IBM. Significant differences in HLAB* 3501, DQA1*0101, *03 and DRB1*01 allele frequencies were detected between the IBM and PM clinical groups (PC = 0.03, 0.01, 0.02, and 0.01, respectively). Similarly, significant differences in DQA1*0101, *0201, *03 and DRB1*01,*04 allele frequencies were detected between IBM and DM patients (PC = 0.006, 0.05, 0.006, 0.01, and 0.008, respectively).

The HLA-A*0301 and B*35 alleles ranked highest among those alleles discriminating IBM cases.

RF analyses of HLA Class II alleles revealed that DRB1*0301 was clearly the most significant predictor of total IIM cases including the PM, DM, and IBM groups.

O'Hanlon (2005) concludes that "despite the prevalence of alleles associated with the 8.1 AH in the Caucasian population, only a small fraction of these individuals will ultimately develop an immunemediated
disease. The identification of the otherwise common 8.1 AH as a genetic risk factor in Caucasians highlights the complex polygenic and multifactorial nature of autoimmune disease predisposition. It is estimated that 25 or more genes, various epigenetic and stochastic events, in combination with the necessary and sufficient environmental exposures may be required for the development of a specific autoimmune disease." . . . Among the PM, DM, and IBM clinical groups, IBM patients had the most distinctive immunogenetic features. Notable examples are alleles consistent with the DRB1*0101; DQA1*0101 haplotype which were previously identified as potential risk factors for sporadic IBM and were confirmed in our study. We have possibly extended the DRB1*0101; DQA1*0101 association in IBM to include HLA Class I alleles (HLA-A*03; B*35; Cw*04) consistent with an extended haplotype in linkage disequilibrium. In addition, Class I alleles consistent with the HLA-B*5101-Cw*14 haplotype were also identified as possible risk factors unique among IBM patients. Curiously, IBM patients maintained an association with linked Class II alleles DRB1*0301 and DQA1*0501 despite the absence of Class I alleles associated with the 8.1 AH. These data suggest that different combinations of HLA Class I and II alleles may further distinguish IBM patients from PM and DM patients. In fact, Kok has identified an independent risk factor for IBM mapping between the DRB1*0301 and C4 complement genes perhaps consistent with a fragment or block of the Caucasian 8.1 AH.

O'Hanlon (2005) further concludes: Our findings of shared HLA risk and protective factors among the IIM support the critical and necessary role genetic features play in the immune dysregulation that ultimately leads to myositis. In addition, our identification of distinct genetic features associated with specific clinical groups of IIM might affect interactions with environmental factors resulting in different immune responses that are ultimately reflected in the clinical syndromes of PM, DM and IBM. Our challenge is to begin to identify those environmental factors in an effort to prevent or mitigate disease pathology.

8.1 .

8.1 ancestral haplotype HLA DRB1*0301 (HLA-DR3) and IBM.

Research studies on people with sIBM have strongly linked having sIBM to genes in this region.

Note: sIBM is not directly inherited, rather, an increased risk of developing disorders (sIBM) is passed along when these particular patterns of alleles (gene versions) are inherited, that is to say, there appear to be genetic susceptibility factors in sporadic IBM. This is NOT the same as the situation with the inherited myopathies - they are caused by specific mutations on a single gene. Here, the risk of having sIBM is apparently increased by having a certain combination of genes present in your makeup that act together and in interaction with the environment to predispose certain types of autoimmune disorders.


The DRB1*0301 area.

The full name is 8.1 ancestral haplotype HLA DRB1*0301. This name refers to a gene location on a chromosome, in this case, in the HLA antigen region of chromosome #6 (part of the Major Histocompatibility Complex (MHC)). HLA stands for "Human Leukocyte Antigen" HLA genes appear to be the genetic system responsible for the presentation of "foreign" peptides to the immune system. The second part of the name -DR - refers to the specific gene location. The HLA-DR, loci produce antigens that normally present peptides which have been broken down from bacterial or other proteins that have been engulfed by the cell in a process of immune surveillance. They are only expressed on cells actively involved in the immune response, e.g. B lymphocytes, monocytes and activated T lymphocytes. The third part of the name is the number, e.g. 0301, and it refers to the actual antigen at the locus.


Detailed investigation of the MHC region in patients with s-IBM.

A study by Price (2004) identified several HLA Class III markers of the 8.1 AH associated with sporadic IBM independent of the DRB1*0301 allele. The study also showed that susceptibility to sIBM is linked not only to the 8·1 ancestral haplotype but also, in some individuals, to the 35·2 haplotype, suggesting the complexity of genetic factors in sIBM. Price concluded that the 8.1AH and 35.2AH may confer susceptibility to sIBM independently or they may share a critical allele.

Oldfors (2005) also says that the susceptibility gene for sIBM is likely to lie between HLA-DRB1 and HOX12. A candidate gene would be the butyrophilin-like MHC class II associated gene (BTL-II).


Pathways to Disease.

A drawing from the March 2005 issue of Scientific American from an article on lupus is helpful to show how different factors relate to each other in causing a disease.




General References on the 8.1 ancestral haplotype.

Trends in Genetics, In Press, Corrected Proof, Available online 8 September 2005,
An evolutionary framework for common diseases: the ancestral-susceptibility model
Anna Di Rienzo and Richard R. Hudson
Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA
Unlike rare mendelian diseases, which are due to new mutations (i.e.derived alleles), several alleles that increase the risk to common diseases are ancestral. Moreover, population genetics studies suggest that some derived alleles that protect against common diseases became advantageous recently. These observations can be explained within an evolutionary framework in which ancestral alleles reflect ancient adaptations to the lifestyle of ancient human populations, whereas the derived alleles were deleterious. However, with the shift in environment and lifestyle, the ancestral alleles now increase the risk of common diseases in modern populations. In this article, we develop an explicit evolutionary model and use population genetics simulations to investigate the expected haplotype structure and type
of disease-association signals of ancestral risk alleles.

Biomedicine & Pharmacotherapy 57 (2003) 274-277
Pathogenesis of autoimmune diseases associated with 8.1 ancestral haplotype: a genetically determined defect of C4 influences immunological parameters of healthy carriers of the haplotype
Giuseppina Candore, Maria Assunta Modica, Domenico Lio, Giuseppina Colonna-Romano, Florinda Listì, Maria Paola Grimaldi a, Mariangela Russo, Giovanni Triolo, Antonia Accardo-Palumbo, Maria Clara Cuccia, Calogero Caruso
Subjects with certain HLA alleles have a higher risk of specific autoimmune diseases than those without these alleles. The 8.1 ancestral haplotype (AH) is a common Caucasoid haplotype carried by most people who type for HLA-B8, DR3. It is unique in its association with a wide range of immunopathological diseases. To gain insight into the identification of the mechanism(s) of disease susceptibility of 8.1 AH carriers, we have investigated the prevalence of circulating immune complexes and non-organ-specific autoantibodies in healthy carriers of the haplotype. The results show that carriers of 8.1 AH display both a significant increased prevalence of immune complexes and higher titers of anti-nuclear autoantibodies. This AH carries a single segment characterized by no C4A gene. This null allele does not code for a functional C4A protein that likely plays an anti-inflammatory role being specialized in the opsonization and immunoclearance processes. So, this genetic defect has been claimed to allow that an increased production of autoantibodies directed vs. cells that have undergone apoptosis and are not efficiently disposed because a reduced antigenic clearance. The results obtained in the present study fit very well with this hypothesis. In the AH carriers the simultaneous high setting of tumor necrosis factor (TNF)-a may supply the autoantigens (providing an excess of apoptotic cells) that drive the autoimmune response. In conclusion, the C4 defect associated to the increased spontaneous release of TNF-a, modifying a certain number of immunological parameter may be the most characterizing feature of the 8.1 AH. In the majority of individuals, an autoimmune response clinically relevant will develop only in the presence of other immunological abnormalities.
The HLA region encompasses over 4 Mb of DNA on the short arm of chromosome 6 and is traditionally divided into the class I, class II and class III regions. It is known to contribute to a large number of immune-related disorders and genetic studies have shown that individuals with certain HLA alleles have a higher risk of specific autoimmune diseases than subjects without these alleles [4,16]. Particularly, the association in all Caucasian populations of an impressive number of autoimmune diseases with genes from the HLAB8, DR3 haplotype that is part of the AH 8.1 HLA-A1, Cw7, B8, TNFAB*a2b3, NFN*S, C2*C, Bf*s, C4A*Q0, C4B*1, DRB1*0301, DRB3*0101, DQA1*0501, DQB1*0201 has been reported by different research groups [2,4,15]. The clusters of genes that, because of their close linkage on the same chromosome, are inherited together, i.e. the haplotypes, are called ancestral when they define highly conserved haplotypes that appear to be derived from a common remote ancestor. These conserved stretches of genomic DNA account for at least 30% of HLA haplotypes in Caucasians [2,4,6]. The 8.1 ancestral haplotype (AH), that is the most common haplotype in Caucasians with its highest frequency in northern and western Europe, is also associated in healthy subjects with a number of immune system dysfunctions. It has been proposed that a small number of genes within the 8.1 AH modify immune responsiveness and hence affect multiple immunopathological diseases [2,4,6,8,15].
The HLA class III region is now known to contain at least 62 genes. As putative functions are ascribed to the products of these genes, it is becoming increasingly apparent that many of these are involved in the immune and inflammatory responses [12,20]. Research is investigating which genes carry polymorphisms that might affect immunological pathways common to the pathogenesis of several diseases associated with the 8.1 AH [2,8,13,15]. Complement genes have often been considered in this context. Three components of the complement system, which is the principal effector mechanism of humoral immunity and is important in the clearance of immune complexes, opsonization and cell lysis, are encoded in the class III region. In particular, C4 participates in the classical pathway, which may be activated by the binding of C1 to antigen- antibody complexes [19]. Most human chromosomes carry two C4 genes, C4A and C4B, which form part of a duplicated segment of DNA spanning ~75 kb. However, the number of expressed C4 genes can range from none to four. The C4A and C4B genes encode proteins that differ by only four amino acids, but nevertheless have profoundly different covalent binding activities [12]. Both isotypes of C4 are highly polymorphic and the 8.1 AH carries a single segment characterized by no C4A gene [2,15]. The null allele, carried by this AH, do not code for a functional C4 protein. This genetic defect of complement function might allow the prolonged persistence of immunizing antigens that can lead to an increased production of autoantibodies directed vs. cells that have undergone apoptosis and are not efficiently disposed because a reduced antigenic clearance [2,18,19].
To gain insight into the identification of the mechanism(s) of disease susceptibility of 8.1 AH carriers, we have investigated the prevalence of circulating immune complexes and nonorgan- specific autoantibodies in healthy carriers of the haplotype, using as controls young subjects negative for this AH.
4. Discussion
Complement has both inflammatory and anti-inflammatory functions, the latter reflected by its role in clearing immune complexes from the circulation and removing them from tissues. When immune complexes cannot be eliminated, the complement activation triggers inflammation. There is an apparent paradox since patients with hereditary deficiencies of complement proteins of the classical pathway are at increased risk for the prototypic autoantibody-mediated disease, systemic lupus erythematosus. However this paradox is only apparent. In fact, complement also binds to cells that have undergone apoptosis, helping to eliminate them from tissues. In complement deficiency, these partially degraded cellular components might accumulate and evoke an autoimmune response [2,18,19]. According to this hypothesis, the stage at which complement may have a pathogenic role in autoimmunity is the failure to clear autoantigens. The complement component C4 is involved in the early stages of the complement cascade. The two isoforms C4A and C4B show considerable polymorphism and the number of C4 genes present on a haplotype can vary [12,18]. The 8.1 AH carries a single segment characterized by a short C4B gene and no C4A gene [2,15, see also Table 1]. The C4A*Q0 allele, carried by HLA 8.1 haplotype, does not code for a functional C4 protein. This duplication of C4 gene allows the qualitative diversities for their proteins [12,18]. The C4B protein likely plays a proinflammatory role by propagating the complement activation pathways that leads to the generation of the membrane attack complex and the generation of anaphylatoxins. On the other hand, the C4A protein likely plays an anti-inflammatory role being specialized in the opsonization and immunoclearance processes. In any case, the serum C4 levels as assayed by routine nephelometry mostly depend on C4B gene [12,18]. Thus, functional consequences of C4Q0 do not include a reduced level of the C4 protein (Table 2) but a prolonged persistence of immunizing antigens, as documented by a reduced clearance of circulating immune-complexes (Table 3), that can lead to an altered immune response against self antigens as documented by increased levels of ANA (Table 4) [2,8,15,18,19].
The pleiotropic proinflammatory cytokine TNF-a maps to chromosome 6 within HLA. Several polymorphic areas are documented within the TNF gene cluster. In particular, the TNF-a -308 polymorphism, substituting G/A, influences TNF-a production in vitro. The -308 A allele is preferentially carried by 8.1 AH, that is in fact characterized by an high setting of TNF-a [8,10]. This constitutive high production determines increased cortisol production and in turn both increase of apoptotic processes and increased production of type 2 cytokine interleukin-10 that facilitates the production of certain immunoglobulin isotypes [2,8]. So, in the AH carriers the simultaneous high setting of TNF-a may supply the autoantigens (providing an excess of apoptotic cells) that drive the autoimmune response. The uptake of autoantigen by immature dendritic cells in the presence of inflammatory cytokines as TNF-a causes these cells to mature into antigen-presenting cells, allowing the presentation of autoantigens to T cells. Finally, T cells will provide help to autoreactive B cells, which have taken up autoantigen by means of their immunoglobulin receptors. Such B cells mature into plasma cells that secrete autoantibodies [2,8,13].
In conclusion, the C4 defect associated to the increased spontaneous release of TNF-a, modifying a certain number of immunological parameter may be the most characterizing feature of the 8.1 AH. The consequent modification of the immunological scenario might be involved in the predisposition to the impressive number of diseases and the changes in immune response observed in these subjects. In the majority of subjects, an autoimmune response clinically relevant will develop only in the presence of other abnormalities. For instance in Lupus have been described severe apoptotis defects that can supply a large amount autoantigens that drive the autoimmune response [2,19].


HLA related references that specifically refer to IBM.

Nov 2006
=Neuromuscul Disord. 2006 Nov;16(11):754-8. Epub 2006 Aug 28.
Familial inclusion body myositis in a mother and son with different ancestral MHC haplotypes.
Mastaglia F, Price P, Walters S, Fabian V, Miller J, Zilko P.
Centre for Neuromuscular and Neurological Disorders, University of Western Australia, 4th Floor, A Block, Queen Elizabeth II Medical Centre, Nedlands WA 6009, Australia.
Abstract: An Ashkenazi Jewish family in which the mother and a son both have inclusion body myositis (IBM) is reported. The condition developed at an earlier age and was more rapidly progressive and less responsive to treatment in the son than in the mother or other IBM patients in our clinic. Genetic analysis showed that the mother carried alleles of the 8.1 MHC ancestral haplotype (AH; HLA-B8, DRB1(*)0301), which is found in 85% of IBM patients in Western Australia. The son did not inherit this haplotype, but carried alleles characteristic of the 52.1AH (HLA-B5, DRB1(*)1502) of paternal origin. The findings indicate that in this family either the 8.1AH or 52.1AH may carry susceptibility for IBM and that the 52.1AH is associated with a more severe and treatment-resistant form of the disease.

Excerpts. Although inclusion body myositis is generally sporadic, it is rarely familial and has been reported in twins [1] and in a small number of families with an autosomal recessive pattern of inheritance [2]. A dominant pattern of transmission has also been reported in a three-generation family from Colorado [3], and also occurs in some forms of non-inflammatory hereditary inclusion body myopathy [4].

There is increasing evidence for the involvement of genetic susceptibility factors in sporadic IBM [5,6]. We demonstrated a strong association with the Class II HLA antigen DR3 [7] which was confirmed by other workers [2,8,9]. We subsequently showed that in Caucasians, alleles characteristic of either the 8.1 MHC ancestral haplotype (AH) (HLA-A1, B8, DRB1*0301) or the 35.2AH (HLA-A11, B35, DRB1*0101) may confer susceptibility independently [10]. When HLA-DR3-positive controls and sIBM patients were compared, carriage of HLA-DR3 without other components of the 8.1AH was less common in patients, suggesting HLA-DR3 per se is not the direct cause of disease. This is supported by the lack of any association between sIBM and the 18.2AH that also includes DRB1*0301 (HLA-A30, B18, DRB1*0301). We showed that the critical segment of the 35.2AH was marked by HLA-DR1 and the central MHC allele BTLII*2. The pattern was markedly different amongst Japanese sIBM patients, where there was a strong association with DRB1*1502 and the 52.1AH [11].

We report here the occurrence of familial inclusion body myositis in a mother and son of Ashkenazi Jewish origin with two different HLA ancestral haplotypes, the mother having the 8.1AH and the son the 52.1AH.

Discussion. The diagnosis of IBM was based on the pattern of muscle involvement clinically and on MRI [13], and was confirmed by the muscle biopsy findings in both cases. However there were differences in the clinical phenotype and severity of the pathological changes in the two patients. The rate of progression was more rapid in the son, and he showed less response to immunotherapy than his mother and has become more severely disabled. He has more severe involvement of the anterior tibial muscle groups resulting in bilateral footdrop, whereas the mother has more severe involvement of the neck flexors as well as mild facial weakness which is unusual in sIBM. These features of the son's disease are unusual amongst patients with sIBM in Western Australia in our experience, as is the high serum CK level. The biopsies from both cases showed widespread upregulation of MHC Class I and II antigens, invasion of muscle fibres by auto-aggressive T-cells and increased numbers of COX-negative fibres. Rimmed vacuoles and cytoplasmic eosinophilic inclusions were also present in both cases but were more numerous in the biopsy from the son.

We considered the possibility that the son may incidentally have another form of inclusion body myopathy, such as that associated with mutations in the GNE gene, as inflammatory changes have been reported in some cases of that condition [14]. However, we feel that this is unlikely as the clinical phenotype is not typical of that condition in which the quadriceps muscles are usually spared. Moreover, the overall combination of pathological changes in this case is more in keeping with inclusion body myositis, as is the response to IVIg administration which has been reported previously in some cases of sporadic IBM [15].

The occurrence of an inflammatory inclusion body myopathy phenotypically similar to sporadic IBM in two generations of the present family is open to a number of possible interpretations. The first is that the disease is due to a dominant mutation in an as yet unidentified gene. However, the possibility of a dominant mechanism of transmission cannot be proven given that there are only two affected individuals in two successive generations. An alternative explanation is that this is a pseudo-dominant pattern related to a shared genetic predisposition to develop sporadic IBM [6]. This conclusion is supported by our immunogenetic studies if one assumes that MHC haplotypes represent a necessary but not sufficient factor in the development of IBM (since the majority of carriers of the 8.1AH and 52.1AH do not develop IBM). It would then follow that the mother and son also share a second susceptibility factor on a different chromosome, not linked with the MHC. The possibility of an underlying genetic susceptibility to autoimmune disease also needs to be considered in view of the family history of myasthenia gravis and primary biliary cirrhosis.

The 8.1AH has been associated with various autoimmune diseases including sporadic IBM. Here the son lacked the maternal 8.1AH and inherited the 52.1AH from his father. The 52.1AH was not associated with sporadic IBM in a largely Anglo-Celtic cohort of West Australian cases [10], but has now been associated with sporadic IBM in a Japanese cohort [11]. Because inflammatory sporadic IBM is rare in Jewish populations (Argov, personal communication), it is not known which HLA haplotypes predispose to the condition in this ethnic group. Both HLA-DRB1*03 and HLA-DRB1*15 are known to be present in Ashkenazi populations but have a low frequency [16]. Indeed A1-B52-DRB1*15/16 has been described as a characteristic Jewish haplotype [17].

The immunogenetic findings in the present cases extend our previous observations [10] and confirm that susceptibility to IBM can be carried by three different MHC haplotypes: the 8.1AH, 35.2AH or 52.1AH. The findings also suggest that the phenotypic differences between the mother and son may reflect the effects of different underlying HLA susceptibility haplotypes, the 8.1AH being associated with a more benign and more treatment-responsive form of IBM than the 52.1AH. However we cannot exclude the possibility that these differences could also be due to the differential effects in the mother and son of some other disease-modifying gene. Further observations in larger cohorts of patients with sporadic IBM are required to confirm these conclusions and to determine whether the HLA haplotype influences the response to treatment in IBM.

November 2005
=Medicine (Baltimore). 2005 Nov;84(6):338-349.
Immunogenetic Risk and Protective Factors for the Idiopathic Inflammatory Myopathies: Distinct HLA-A, -B, -Cw, -DRB1 and -DQA1 Allelic Profiles and Motifs Define Clinicopathologic Groups in Caucasians.
O'Hanlon TP, Carrick DM, Arnett FC, Reveille JD, Carrington M, Gao X, Oddis CV, Morel PA, Malley JD, Malley K, Dreyfuss J, Shamim EA, Rider LG, Chanock SJ, Foster CB, Bunch T, Plotz PH, Love LA, Miller FW.
From National Institute of Environmental Health Sciences (TPO, DMC, EAS, LGR, FWM), Center for Information Technology (JDM, JD), National Cancer Institute (SJC, CBF), and National Institute of Arthritis and Musculoskeletal Disease (PHP), National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland; University of Texas-Houston Health Science Center (FCA, JDR), Houston, Texas; Basic Research Program (MC, XG), SAIC Frederick National Cancer Institute, Frederick, Maryland; University of Pittsburgh School of Medicine (CVO, PAM), Pittsburgh, Pennsylvania; Malley Research Programming Inc (KM), Rockville, Maryland; Mayo Clinic (TB), Rochester, Minnesota; and United States Food and Drug Administration (LAL), Rockville, Maryland.
ABSTRACT:: The idiopathic inflammatory myopathies (IIM) are systemic connective tissue diseases in which autoimmune pathology is suspected to promote chronic muscle inflammation and weakness. We have performed low to high resolution genotyping to characterize the allelic profiles of HLA-A, -B, -Cw, -DRB1, and -DQA1 loci in a large population of North American Caucasian patients with IIM representing the major clinicopathologic groups (n = 571). We confirmed that alleles of the 8.1 ancestral haplotype were important risk markers for the development of IIM, and a random forests classification analysis suggested that within this haplotype, HLA-B*0801, DRB1*0301 and/ or closely linked genes are the principal HLA risk factors. In addition, we identified several novel HLA factors associated distinctly with 1 or more clinicopathologic groups of IIM. The DQA1*0201 allele and associated peptide-binding motif (KLPLFHRL) were exclusive protective factors for the CD8+ T cell-mediated IIM forms of polymyositis (PM) and inclusion body myositis (IBM) (PC< 0.005). In contrast, HLA-A*68 alleles were significant risk factors for dermatomyositis (DM) (PC = 0.0021), a distinct clinical group thought to involve a humorally mediated immunopathology. While the DQA1*0301 allele was detected as a possible risk factor for IIM, PM, and DM patients (p < 0.05), DQA1*03 alleles were protective factors for IBM (PC = 0.0002). Myositis associated with malignancies was the most distinctive group of IIM wherein HLA Class I alleles were the only identifiable susceptibility factors and a shared HLA-Cw peptide-binding motif (AGSHTLQWM) conferred significant risk (PC = 0.019). Together, these data suggest that HLA susceptibility markers distinguish different myositis phenotypes with divergent pathogenetic mechanisms. These variations in associated HLA polymorphisms may reflect responses to unique environmental triggers resulting in the tissue pathospecificity and distinct clinicopathologic syndromes of the IIM.

October 2005
=Curr Opin Neurol. 2005 Oct;18(5):497-503.
Diagnosis, pathogenesis and treatment of inclusion body myositis.
Oldfors A, Lindberg C.
PURPOSE OF REVIEW: We provide an update of progress gained from research into sporadic inclusion body myositis (s-IBM). RECENT FINDINGS: Most research on s-IBM has focused on the inflammatory reaction or the accumulation of pathological proteins in vacuolated muscle fibres. The inflammatory reaction is characterized by clonal expansions of lymphocytes, predominantly CD8 cytotoxic T cells, which invade and destroy muscle fibres. That costimulatory molecules have been identified demonstrates that muscle fibres can act as antigen presenting cells, and the expression of various chemokines in muscle indicates their importance in the immunopathogenesis of s-IBM. The region of interest for a susceptibility gene in the major histocompatibility complex has been narrowed, and for the first time it has been demonstrated that a chronic viral infection can trigger the inflammatory process leading to s-IBM. The nature of the accumulated material associated with the vacuoles has been extensively investigated over the past few years. Amyloid-b and phosphorylated tau protein in intracellular inclusions are a characteristic finding in s-IBM, which may lead to calcium dyshomeostasis and endoplasmic reticulum stress. The proteasomal system is upregulated, including immunoproteasomes. 'Molecular misreading' leading to ubiquitin mRNA mutations and accumulation of pathological ubiquitin in muscle fibres may be associated with proteasomal dysfunction. There is still no efficient treatment for s-IBM, but the effects of new, more specific immunotherapies have begun to be explored. SUMMARY: Recent findings indicate that both inflammatory reaction and abnormal protein accumulation are important for the pathogenesis in s-IBM. The link between them continues to await elucidation.

May 2005
=Neurol Sci. 2005 May; 26 Suppl 1:s7-8.
Autoimmune muscular pathologies.
Dalakas MC.

Neuromuscular Diseases Section, NINDS, Bethesda, MD, USA, dalakasm@ninds.nih.gov.

The T cell-mediated mechanism responsible for Polymyositis and inclusion Body Myositis and the complement-mediated microangiopathy associated with Dermatomyositis are reviewed. The management of autoimmune myopathies with the presently available immunotherapeutic agents as well as new therapies and ongoing trials are discussed. b-chemokine receptor expression in idiopathic inflammatory myopathies.

=Lancet Neurol. 2005 Jan;4(1):6-7. Review.
Neuromuscular disorders: molecular and therapeutic insights.
Mastaglia FL.
Sporadic inclusion-body myositis (sIBM) is the most common myopathy that presents in patients over age 50 years and is characterised pathologically by abnormal protein aggregates in muscle fibres and by a cytotoxic CD8 lymphocytic response. There has long been debate about the relation between these two features, and the identity of the antigens involved in the immune response is not known. The strong association of sIBM with HLA-DR3 (DRB1*0301) has until now been regarded as evidence of a primary autoimmune pathogenesis in this disorder. The mapping study of the class II and central MHC region of chromosome 6 by Price and colleagues 1 casts doubt on this interpretation and strongly suggests that the association is not with DRB1*0301 itself but with another gene on the 8·1 ancestral haplotype in linkage disequilibrium with DRB1*0301, and which might not be part of the immune process. The study also showed that susceptibility to sIBM is linked not only to the 8·1 ancestral haplotype but also, in some individuals, to the 35·2 haplotype, confirming the complexity of genetic factors in sIBM. However, the studies of Fratta and coworkers 2 - showing the presence in muscle fibres of potentially toxic aberrant protein transcripts (e.g., ubiquitin UBB+1) that can interfere with proteasomal degradative mechanisms - provide another possible explanation for the abnormal protein accumulation and for the generation of antigenic peptides that could be driving the T-cell response.
Relevant references:
1 Price P, Santoso L, Mastaglia F, et al. Two major histocompatibility complex haplotypes influence susceptibility to sporadic inclusion body myositis: critical evaluation of an association with HLA-DR3. Tissue Antigens 2004; 64: 575-80.
2 Fratta P, Engel WK, Van Leeuwen FW, Hol EM, Vattemi G, Askanas V. Mutant ubiquitin UBB+1 is accumulated in sporadic inclusion body myositis muscle fibers. Neurology 2004; 63: 1114-17.

=Neurology. 2004 Dec 28;63(12):2396-8.
Associations with autoimmune disorders and HLA class I and II antigens in inclusion body myositis.
Badrising UA, Schreuder GM, Giphart MJ, Geleijns K, Verschuuren JJ, Wintzen AR, Maat-Schieman ML, van Doorn P, van Engelen BG, Faber CG, Hoogendijk JE, de Jager AE, Koehler PJ, de Visser M, van Duinen SG; Dutch IBM Study Group.
Department of Neurology, K5Q, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands. ubadrising@lumc.nl
Whether autoimmune mechanisms play a role in the pathogenesis of inclusion body myositis (IBM) is unknown. Human leukocyte antigen (HLA) analysis in 52 patients, including 17 with autoimmune disorders (AIDs), showed that patients were more likely to have antigens from the autoimmune-prone HLA-B8-DR3 ancestral haplotype than healthy control subjects, irrespective of the presence of AIDs.
Patients lacked the apparently protective HLA-DR53 antigen. The results provide further support for an autoimmune basis in IBM.

=Curr Opin Rheumatol. 2004 Nov;16(6):707-13.
Have recent immunogenetic investigations increased our understanding of disease mechanisms in the idiopathic inflammatory myopathies?
Chinoy H, Ollier WE, Cooper RG.
Rheumatic Diseases Centre, Hope Hospital, Salford M6 8HD, UK.
PURPOSE OF REVIEW: The idiopathic inflammatory myopathies (IIM) continue to provide a challenge given the variable effectiveness of the available treatments, and immunogenetic studies are ongoing to further elucidate IIM disease mechanisms. This review examines how recent research has improved our understanding of the mechanisms that lead to IIM. RECENT FINDINGS: HLA-DRB1 studies in a large homogenous cohort of UK Caucasian patients have confirmed that polymyositis (PM) and dermatomyositis (DM) are not genetically identical diseases while other studies have shown that tumor necrosis factor alpha is genetically implicated in disease susceptibility. Some remarkable results from an international collaboration, correlating gene-environment interactions, clearly suggest that ultraviolet light is capable of modulating both clinical and immunologic features of IIMs. Studies on microchimerism are unraveling interesting associations in juvenile DM patients, and bolstering the hypothesis that myositis may be an 'allo-immune' disease. mRNA gene expression profiling is helping to increase our understanding of myositis pathogenesis, whilst animal models have provided new information on the roles of Th1 responses and nitric oxide synthase in muscle disease. New candidate genes have been examined in inclusion body myositis (IBM), and a novel gene transfer experiment has been conducted, which led to significant changes in expression of the IBM phenotype. SUMMARY: Improving the understanding of the immunogenetics and immunopathogenesis of the IIMs may in the future provide novel therapeutic targets, and thus improve outcomes in these difficult diseases

=Tissue Antigens. 2004 Nov;64(5):575-80.
Two major histocompatibility complex haplotypes influence susceptibility to sporadic inclusion body myositis: critical evaluation of an association with HLA-DR3.
Price P, Santoso L, Mastaglia F, Garlepp M, Kok CC, Allcock R, Laing N.
School of Surgery and Pathology, University of Western Australia, Nedlands, Australia. pprice@cyllene.uwa.edu.au
Previous studies of sporadic inclusion body myositis (sIBM) have shown a strong association with HLA-DR3 and other components of the 8.1 ancestral haplotype (AH) (HLA-A1, B8, DR3), where the susceptibility locus has been mapped to the central major histocompatibility complex (MHC) region between HLA-DR and C4. Here, the association with HLA-DR3 and other genes in the central MHC and class II region was further investigated in a group of 42 sIBM patients and in an ethnically similar control group (n = 214), using single-nucleotide polymorphisms and microsatellite screening. HLA-DR3 (marking DRB1*0301 in Caucasians) was associated with sIBM (Fisher's test). However, among HLA-DR3-positive patients and controls, carriage of HLA-DR3 without microsatellite and single-nucleotide polymorphism alleles of the 8.1AH (HLA-A1, B8, DRB3*0101, DRB1*0301, DQB1*0201) was marginally less common in patients. Patients showed no increase in carriage of the 18.2AH (HLA-A30, B18, DRB3*0202, DRB1*0301, DQB1*0201) or HLA-DR3 without the central MHC of the 8.1AH, further arguing against HLA-DRB1 as the direct cause of susceptibility. Genes between HLA-DRB1 and HOX12 require further investigation. BTL-II lies in this region and is expressed in muscle. Carriage of allele 2 (exon 6) was more common in patients. BTL-II(E6)*2 is characteristic of the 35.2AH (HLA-A3, B35, DRB1*01) in Caucasians and HLA-DR1, BTL-II(E6)*2, HOX12*2, RAGE*2 was carried by several patients. The 8.1AH and 35.2AH may confer susceptibility to sIBM independently
or share a critical allele.

=Eur Neurol. 2004;51(4):215-20. Epub 2004 May 17. Related Articles, Links
Apolipoprotein E and alpha-1-antichymotrypsin polymorphisms in sporadic inclusion body myositis.
Gossrau G, Gestrich B, Koch R, Wunderlich C, Schroder JM, Schroeder S, Reichmann H, Lampe JB.
Department of Neurology, Medical Clinic II, Technical University Dresden, Dresden, Germany. ggossrau@uni-bonn.de
Sporadic inclusion body myositis (s-IBM) is a progressive muscle disease of unknown aetiology. Characteristically, intracellular amyloid deposits are detectable, including beta-amyloid precursor protein, phosphorylated tau, alpha1-antichymotrypsin (alpha1-ACT) and apolipoprotein E (ApoE). Polymorphisms and mutations of the encoding genes have been identified in a variety of neurodegenerative diseases including Alzheimer's disease (AD). Beside other factors, polymorphisms may lead to protein accumulation in both diseases. In particular, polymorphisms within the ApoE and alpha1-ACT gene have been implicated in the aetiology of AD and s-IBM. We analysed ApoE and alpha1-ACT gene polymorphisms in 35 s-IBM patients. We could not identify any statistical significant correlation between distinct ApoE and alpha1-ACT genotypes and the risk of developing s-IBM. Additionally, ApoE and alpha1-ACT genotypes seem not to influence the onset age of s-IBM. A combination of different alpha1-ACT and ApoE genotypes appears not to enhance the risk of developing s-IBM. Therefore, allelic variations of alpha1-ACT and ApoE are unlikely to be genetic key factors in the aetiology of s-IBM.

=J Neurol. 2003 Nov;250(11):1313-7.
Analysis of HLA class I and II alleles in sporadic inclusion-body myositis.
Lampe JB, Gossrau G, Kempe A, Fussel M, Schwurack K, Schroder R, Krause S, Kohnen R, Walter MC, Reichmann H, Lochmuller H. Klinik fur Neurologie, Technische Universitat Dresden, Fetscherstrasse 74, 01307, Dresden, Germany. johannes.lampe@schering.de
Sporadic inclusion body myositis (s-IBM) is characterised by progressive weakness of proximal and distal limb muscles. Most patients are aged over 50 years at disease onset. Muscle biopsy reveals an inflammatory myopathy and cytoplasmic amyloid deposits. The mononuclear infiltrate is dominated by CD8+ T-cells. Several investigators have described associations between s-IBM and certain HLA antigens and alleles. However, to date neither HLA class I nor II alleles have been analysed in a large series of patients. We typed various HLA class I and II alleles in 47 patients suffering from s-IBM using sequence specific-primer pairs (SSPPCR). The results were compared with published German controls. Additional Bonferroni adjustment was performed over all allele groups corresponding to serologically defined antigens within one HLA class I or II locus. After Bonferroni adjustment, we found a significant increase in frequency of the following HLA alleles for s-IBM patients when compared with normal controls: A*03 (p = 0.0002), B*08 (p = 0.002), DRB1*03 (p = 0.0000002), and DQB1*05 (p = 0.02). HLA typing may be helpful to distinguish between subgroups of s-IBM patients. Moreover, HLA analysis may aid in identifying patients who might profit from future therapeutic strategies.

=Inclusion body myositis: genetic factors, aberrant protein expression, and autoimmunity.
Current Opinion in Rheumatology. 13(6):469-475, November 2001.
Oldfors, Anders MD, PhD; Fyhr, Ing-Marie MD, PhD
Sporadic inclusion body myositis (s-IBM) is an inflammatory myopathy mainly affecting elderly individuals. It has a chronic progressive course leading to severe disability. Immunosuppressive treatment is in most instances ineffective. S-IBM is morphologically characterized by mononuclear cell infiltrates and vacuolated muscle fibers with pathologic accumulation of a large number of different proteins. Recent research has focused on the expression of various factors that may contribute to the inflammatory reaction and the typical inclusions. This review summarizes the new information on genetic factors, abnormal protein expression and inflammation, which provides a basis for linking the different typical morphologic features of s-IBM to a cascade of pathogenic events.

=Immunogenetics. 1999 Jun;49(6):508-16.
Mapping of a candidate region for susceptibility to inclusion body myositis in the human major histocompatibility complex.
Kok CC, Croager EJ, Witt CS, Kiers L, Mastaglia FL, Abraham LJ, Garlepp MJ.
Australian Neuromuscular Research Institute, Queen Elizabeth II Medical Centre, Nedlands, Western Australia.
Inclusion body myositis (IBM) is a form of idiopathic inflammatory myopathy of unknown aetiology. A strong association with HLA class II (HLA-DR3) suggested a role for genes in the human major histocompatibility complex (MHC) in the predisposition to this disease. In this study, we have taken advantage of the ancestral haplotype (AH) concept and historical recombinations to map for a possible susceptibility gene(s) in the MHC. We performed detailed typing of three MHC-related HSP70 genes and defined allelic combinations in the context of MHC AH. We also modified existing methods to give a simple and accurate method for typing two TNF microsatellites. Using the HSP70 and TNF markers and HLA-DR, -B, and C4 typing of our patients with IBM, we defined a potential site for the
MHC-associated susceptibility gene(s) in the region between HLA-DR and C4.

=Curr Opin Rheumatol. 1998 Nov;10(6):543-7.
Genetics of inclusion body myopathies.
Argov Z, Eisenberg I, Mitrani-Rosenbaum S.
Department of Neurology, Hadassah University Hospital, Jerusalem.
We review the current knowledge about the genetic susceptibility to develop inflammatory inclusion body myositis, especially in relation to the increased presence of the HLA DR3 allele in patients with familial and sporadic forms, indicating an autoimmune predisposition. The main focus of the review is the clinical and genetic presentations of the various hereditary inclusion body myopathies. Criteria for diagnosis and classification of these myopathies are presented. The spectrum of the recessive forms of hereditary inclusion body myopathies currently linked to chromosome 9p1-q1 is described, with emphasis on the up-to-date status of the gene search for these forms.

=J Neuroimmunol. 1998 Apr 15;84(2):139-42.
HLA allele distribution distinguishes sporadic inclusion body myositis from hereditary inclusion body myopathies.
Koffman BM, Sivakumar K, Simonis T, Stroncek D, Dalakas MC.
We studied the HLA class II associations in patients with sporadic inclusion body myositis (s-IBM) and hereditary inclusion body myopathies (h-IBM) and attempted to distinguish these myopathies on the basis of HLA allele assignments. Forty-five patients, 30 with s-IBM and 15 with h-IBM, underwent HLA class II allele-specific typing using polymerase chain reaction sequence-specific primers for 71 alleles contained in the DRbeta1, DRbeta3-5, and DQbeta1 loci. In s-IBM, we found a high (up to 77%) frequency of DRbeta1*0301, DRbeta3*0101 (or DRbeta3*0202) and DQbeta1*0201 alleles. No significant association with alleles in the DR and DQ haplotypes was found among the 15 h-IBM patients. The strong association of prominent alleles with s-IBM, but not h-IBM, suggests that s-IBM is a distinct disorder with an immunogenetic background that differs from h-IBM.

=Clin Exp Immunol. 1994 Oct;98(1):40-5.
HLA associations with inclusion body myositis.
Garlepp MJ, Laing B, Zilko PJ, Ollier W, Mastaglia FL. Australian Neuromuscular Research Institute, Queen Elizabeth II Medical Centre, Nedlands.
Inclusion body myositis (IBM) is defined clinically by a characteristic pattern of progressive proximal and distal limb muscle weakness and resistance to steroid therapy, and histologically by the presence of distinctive rimmed vacuoles and filamentous inclusions as well as a mononuclear infiltrate in which CD8+ T cells are predominant. Muscle damage is believed to be mediated by autoimmune mechanisms, but very little information is available on the immunogenic features of IBM. MHC class I and DR antigens were typed on 13 caucasoid patients with IBM using standard serological techniques or by allele-specific oligonucleotide typing. Complement components C4 and properdin factor B (Bf) were typed by immunofixation after electrophoresis. Restriction fragment length polymorphisms (RFLP) in the class III region were analysed using cDNA probes for C4 and 21-hydroxylase (CYP21) after Taq 1 digestion. IBM was associated with DR3 (92%), DR52 (100%) and HLA B8 (75%). The phenotype data were examined for likely haplotypes by considering together the alleles at the class I, DR and complement loci along with the C4 and CYP21 RFLP. Ten of the DR3+ subjects had a 6.4-kb C4-hybridizing fragment characteristic of a deletion of C4A and CYP21-A. These patients probably carried all, or at least the class II and III regions, of the extended haplotype marked by B8/C4A*Q0/C4B1/BfS/DR3/DR52, which has been associated with several autoimmune diseases and is present in 11% of the healthy caucasoid population. Of the remaining subjects, two had evidence of the extended haplotype marked by B18/C4A3/C4BW*0/BfF1/DR3, which is present in less than 5% of the healthy population and has been associated with insulin-dependent diabetes mellitus. These data provide support for an autoimmune etiology for, and genetic predisposition to, IBM.

=Baillieres Clin Neurol. 1993 Nov;2(3):579-97.

Immunogenetics of inflammatory myopathies.
Garlepp MJ.
Australian Neuromuscular Research Institute, Queen Elizabeth II Medical Center, Nedlands.
The genes most commonly considered when investigating immunogenetic associations with autoimmune diseases, including inflammatory muscle disease (IMD), are those encoded in the major histocompatibility complex (MHC), the T-cell receptor (TCR) genes and the immunoglobulin genes. In caucasoids HLA DR3 is associated with adult polymyositis (PM) and juvenile dermatomyositis (JDM) and is probably increased in frequency in adult DM. In inclusion body myositis (IBM) DR3 and DR1 have been separately reported to be increased but few patients have been analysed. The DR3 in IMD is almost always present on the ancestral haplotype marked by HLA-B8, C4A*Q0 and DR3 and presumably accounts for the association with C4A*Q0 which has been reported in some subgroups of IMD. In other races the associations are less clear although DR6 may be increased in blacks with PM. In PM, DR3 is strongly associated with the presence of antibodies to histidyl tRNA
synthetase (Jo-1). DR52 is even more strongly associated with the presence of this autoantibody and this association can be demonstrated in black and white patients. It is unlikely that DR3 is associated with autoantibodies to other aminoacyl-tRNA synthetases or signal recognition proteins although fewer cases have been reported and racial differences may exist. Antibodies to the Pm-Scl antigen are also associated with DR3 while autoantibodies to Mi-2 may be associated with DR53. In caucasoids DR4 was increased in D-penicillamine induced IMD but again there may be inter-racial differences. Amongst caucasoids with mixed connective tissue disease (MCTD) there is an increased frequency of DR4 and this allele is associated with the development of antibodies to ribonucleoprotein (RNP). In other races the data are minimal. Very few investigations of associations between TCR polymorphisms or immunoglobulin allotypes and IMD have been reported. The phenotype Gm 3;5 has been associated with PM in caucasoids and may interact with DR3 in predisposing to disease. The Gm phenotype 1,3;5,21 has been associated with MCTD and with the development of anti-RNP, with or without MCTD, in caucasoids. Multiple genetic factors are likely to determine the development of IMD and the particular combination of alleles at predisposing loci may differ between races and according to the inducing agent. Furthermore, the predisposing genetic factors may vary between subgroups of IMD.