Cutting Edge Issues in Polymyositis

Clinic Rev Allerg Immunol (2011) 41:179–189 DOI 10.1007/s12016-010-8238-7

Cutting Edge Issues in Polymyositis Anna Ghirardello & Sandra Zampieri & Elena Tarricone & Luca Iaccarino & Luisa Gorza & Andrea Doria

Published online: 30 December 2010 # Springer Science+Business Media, LLC 2010

Abstract Skeletal muscle is the target tissue of immunoflogistic processes in patients affected with idiopathic inflammatory myopathies (IIM). IIM are classified into three major forms: polymyositis (PM), dermatomyositis (DM), and inclusion body myositis. Recent data suggest that, in the major subsets of myositis, antigens in muscles drive a B-cell antigen-specific immune response. Moreover, some non-immunological mechanisms have been advocated. In this regard, an increased expression of Jo-1 and Mi-2 in muscle biopsies from PM and DM patients compared to normal muscle has been demonstrated; these candidate autoantigens in myositis are expressed at high levels in regenerating muscle cells rather than in mature myotubes. Myositis autoantigen upregulation has also been observed in neoplastic tissues, thus representing a potential link between cancer and autoimmunity in myositis. Myositisspecific autoantibodies (MSA) are disease markers and target intracellular proteins involved in key processes such as translocation and nuclear transcription. Myositis target antigens encompass aminoacyl-tRNA synthetases, the Mi-2 helicase/histone deacetylase protein complex, the signal recognition particle ribonucleoprotein, together with novel target antigens including p155/140, CADM-140, and SAE. Despite their high specificity for autoimmune myositis, MSA target non-muscle restricted proteins ubiquitary to all A. Ghirardello : E. Tarricone : L. Iaccarino : A. Doria (*) Division of Rheumatology, Department of Clinical and Experimental Medicine, University of Padova, Via Giustiniani, 2, 35128 Padova, Italy e-mail: [email protected] S. Zampieri : L. Gorza Department of Biomedical Sciences, University of Padova, Padova, Italy

cell types, making the specific muscle involvement difficult to explain. Non-immunological mechanisms also seem to contribute to the pathogenesis of IIM; activation of endoplasmic reticulum stress response due to muscle regeneration and inflammation but independent to MHC-1 up-regulation has been recently reported in patients with myositis. Keywords Polymyositis . Dermatomyositis . Myositisspecific antibodies . Pathogenesis . Endoplasmic reticulum stress response

Introduction Idiopathic inflammatory myopathies (IIM) are a group of acquired diseases of unknown etiology, characterized by an inflammatory infiltrate of the skeletal muscle. On the basis of clinical, immunopathological, and demographic features, three major forms can be identified: dermatomyositis (DM), polymyositis (PM), and inclusion-body myositis (IBM). These three disorders differ in prognosis and response to treatment [1–5]. When PM or DM occur during childhood, they are classified as juvenile PM–DM [1, 2, 6]. In addition, PM or DM can be associated with cancer or with other connective tissue diseases or overlap syndromes [1, 2]. According to the classical view on the pathogenesis of IIM, DM is considered a microangiopathy, affecting skin and muscle, mainly mediated by humoral immunity due to the presence of CD4-positive T cells and B cells in muscular inflammatory infiltrates [7, 8]. In contrast, PM and IBM are considered as diseases mediated by cellular immunity since in these cases, clonally expanded CD8positive cytotoxic T cells invade muscle fibers that express MHC class I antigens, leading to fiber necrosis.

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This classical view has recently been challenged. In fact, microarray studies on muscle biopsy samples from patients with PM, DM, and IBM resulted in the identification of distinct classes of transcripts the most important of which are Interferon (INF) α/ß inducible transcripts, immunoglobulin, and dendritic cell transcripts [9, 10]. These transcripts pointed towards the presence of particular immune cells such as plasmocitoid dendritic cells, plasma cells, and myeloid dendritic cells in inflammatory infiltrate within muscles. Notably, the presence of these cells, which were subsequently confirmed by immunohistochemical studies [11, 12], indicated the occurrence of specific pathways including INF α/ß mediated tissue injury, antigen-specific antibody response, and local maturation of lymphocytes. Altogether, these data suggest that, in the major subsets of myositis, antigens in muscles drive a B-cell antigenspecific immune response and that B cells mature at least in part within muscles. Interestingly, myositis-specific autoantigens are expressed at high levels in myositis muscle but at low levels in control muscle; moreover, they are highly expressed in regenerating muscle cells rather than mature myotubes [13]. Myositisspecific autoantigens are also expressed in tumor cells suggesting a potential link between autoimmune myositis and cancer [13]. Non-immunological mechanisms also seem to contribute to the pathogenesis of IIM; activation of endoplasmic reticulum (ER) stress response due to muscle regeneration and inflammation, but independent to MHC-1 upregulation, has been recently reported in patients with myositis.

Muscle Regeneration, Oncogenesis, and Autoimmune Myositis Several studies have been carried out in order to explain why, besides the ubiquitary localization of the targeted autoantigens to all cell types, PM and DM are characterized by a specific muscle involvement. The first evidence derived from the study of Casciola and Rosen in which myositis-specific autoantigens were expressed at low levels in normal human muscle and at high levels in biopsies from patients affected with autoimmune myositis in association to muscle regeneration consequent to the flogistic reaction [13]. It is well known that adult skeletal muscle is able to regenerate [14], and a large number of myotubes are usually formed in a few days after acute muscle injury. The regeneration capacity derives from satellite cells which are capable of reiterating replication of DNA, thus recapitulating the developmental program of skeletal myogenesis in response to muscle damage [15]. Whatever the etiology of muscle regeneration, including infection, tumorinduced muscle damage, and trauma, infiltrating inflamma-

Clinic Rev Allerg Immunol (2011) 41:179–189

tory cells, especially monocyte-derived macrophages, have a mandatory role, which consists in the clearing of necrotic tissue, initially by the phagocytosis of necrotic fibers, and then by the release of mitogenic growth factors for myogenic precursor cells [16, 17]. From this point of view, the enhanced expression of the targeted autoantigens in autoimmune myositis can be induced and sustained by both inflammatory and muscle cells. Satellite cells are also responsible for muscle growth during postnatal myogenesis, and it has been demonstrated that the molecular mechanisms involved during regenerative and postnatal myogenesis activate common transcriptional factors, which induce the expression of different isoforms of myosin heavy chain such as the embryonic isoform (MHCemb) [18]. We have recently shown that the overexpression of candidate autoantigens by myoblasts and developing myotubes of newborn rat skeletal muscles is a specific event of myogenesis [19], even in the absence of macrophage-derived growth factors secreted by immunocompetent/inflammatory cells which sustain muscle growth and repair in injured adult muscle [20]. The mechanisms of postnatal myogenesis identified in our newborn muscles, i.e., satellite cell activation and progression along the myogenic lineage is the same process which regulates regenerative myogenesis in adult skeletal muscle occurring after injuries with the only difference that in newborn muscles there is no inflammatory infiltrate. From this point of view, myoblasts and developing myotubes represent themselves a source of autoantigens which may induce and/or amplify immune response in patients affected by autoimmune myositis. The contribution of inflammation to autoimmunity has been highlighted in an attempt to elucidate the widely described association between malignancy and autoimmune myositis [21–25]. Beside this association, there is an increasing recognition that neoplasia is associated not only with muscoloskeletal disorders but also with a wide range of other rheumatic symptoms, most of them of paraneoplastic nature [26–28]. Despite minimal supporting evidence, the standard model for explaining this coincidence is that autoimmunity leads to cancer due to the rapid cell division associated with the regeneration of damaged tissue at the site of inflammation [29]. The alternative model, which has been purposed by Eisenlohr and colleagues [30], is that cellular transformation within a tissue alone can initiate autoimmunity and influence the progression of cancer. The temporal relationship between autoimmune myositis and malignancy can vary: cancer may occur before, at the same time or following the diagnosis of myositis. Beside these observations, the molecular mechanisms underlying this association are still unknown, even though a possible


antigenic similarity between regenerating myoblasts and some cancer cell populations has been demonstrated. In the study published by Casciola-Rosen et al. [13], it has been demonstrated that some tumors (breast, lung adenocarcinoma, and hepatocellular carcinoma), but not the corresponding normal tissues, do express high levels of myositis autoantigens. Notably the expression of these autoantigens by tumor cells as well as by regenerating myoblasts, indicate a possible antigenic similarity between the two cell populations. Therefore, it is possible that an immune response initially directed against cancer cells cross-reacts with regenerating muscle cells [13, 31], subsequently triggering the development of the disease in genetically predisposed individuals. It has also been demonstrated that cells at early stages of neoplastic transformation and below the limits of clinical detection, can provide co-stimulatory danger signals that promote the activation of innate immune cells [32]. We recently observed similar histopathologic features in the skeletal muscle from patients affected with newly diagnosed colorectal cancer at the clinical onset of disease but without myositis and in the skeletal muscle from myositis patients, especially in those with cancer associated myositis. Skeletal muscle biopsies from cancer patients display early signs of a subclinical myopathy, characterized by internally nucleated and regenerating myofibers [33–35], similar to the features that have been observed in the muscle from myositis patients, especially in those with cancer associated myositis. A possible pathogenetic hypothesis may be that factors of tumor origin targeting the skeletal muscle induce muscle damage and regeneration, which results in an initial subclinical myopathy. In the particular subset of individuals genetically predisposed to autoimmunity, regenerating myofibers overexpressing myositis-specific autoantigens, may induce an autoimmune response which is then perpetuated and self sustained by the deposition of immune complexes within the affected skeletal muscle, further progressing towards a clinically relevant cancer associated autoimmune myositis (Fig. 1). These observations, which were reported for the first time in skeletal muscle from patients affected with cancer [33–35], but without myositis, may further support the hypothesis of a pathogenetic link between these two pathologic conditions.

Autoantibodies Circulating antibodies towards ubiquitary cytoplasmic or nuclear constituents are found in about 80% of PM/DM patients. Some of these autoantibodies are shared with other autoimmune diseases while some of them are unique to myositis.

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tumor

Tumor released factors

? skeletal muscle

Subclinical myopathy predisposing genetic background

damage B, T lymphocytes infiltration

Autoantigens expression

regeneration

CANCER ASSOCIATED AUTOIMMUNE MYOSITIS Fig. 1 Pathogenetic hypothesis of the link between cancer and autoimmune myositis

Over the past 18 years, myositis-specific autoantibodies (MSA) have been identified as a phenotypic expression of IIM and as markers of clinical subsets and disease prognosis [36–41]. As in other systemic rheumatic diseases, the identification and characterization of autoantibodies in serum is an important milestone in the diagnosis of IIM. The most important autoantibodies are grouped into two categories based on their accuracy for the diagnosis of myositis: MSA and myositis-associated antibodies (MAA). MAA are not specific to myositis and primarily found in myositis-scleroderma overlap syndrome [42, 43]. Nonetheless, the relative high occurrence of anti-Ro/SSA antibody almost targeting Ro52 isoform in muscle and/or lung immunoinflammatory disease [38, 44, 45] suggests that also (auto)antigenic Ro particles could participate in the priming/substaining of muscle/lung tissue damage and dysfunction, or that some fine epitope-restricted anti-Ro/SSA antibodies represent a phenotypic marker of an immunoinflammatory attack preferentially directed towards skeletal muscle and/or lung. MSA are specific hallmarks for PM or DM. They are highly selective, mutually exclusive, and closely linked to homogeneous clinico-immunogenetic profiles of disease expression, inasmuch as serologic profiling is nowadays used as a

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complementary approach to the Bohan and Peter classification, challenging the established disease definition and therapeutic intervention [36, 42, 46]. Myositis target autoantigens are intracellular proteins involved in key processes such as gene transcription and protein synthesis and translocation: aminoacyl-tRNA synthetase enzymes, the Mi-2 helicase/ histone deacetylase nuclear complex, the signal recognition particle (SRP) [47–50], together with novel antigens including CADM-140, -MJ/p140 (nuclear matrix protein NXP-2), p155/140 (TIF1-γ, transcriptional intermediary factor 1-γ), SAE (Small ubiquitin-like modifier Activating Enzyme) [51– 53], and the most recently described 200/100 kDa unidentified proteins [54]. An updated list of principal autoantibodies and respective autoantigens in autoimmune myositis is reported in Table 1. Of interest, autoantibodies targeting antigens with analogous cellular functions are restricted to similar clinical subsets [55]. The novel autoantibody specificities enrich the spectrum of MSA and seem to be associated with newly conceived clinical subsets [56]. However, up to now, they have been described in restricted ethno-geographic patient cohorts, and biochemical identity of target antigens has not been completely disclosed yet.

protein synthesis. Until now, eight out of 20 aminoacyltRNA synthetases have been described as autoantigens, but the most commonly detected one is Jo-1 (histidyl tRNA synthetase) [47, 56] (Table 1). Anti-Jo-1 serum levels strongly correlate with disease activity representing a good marker for disease monitoring [47]. Autoantibodies directed towards the other synthetases are less common, each achieving no more than 5% prevalence in PM/DM. Individual myositis patients show selective reactivity against a single aminoacyl-tRNA synthetase. Interestingly, two additional anti-ARS autoantibodies have been recently reported: anti-Ha (tyrosil) and anti-Zo (phenylalanyl) [57, 58]. Anti-ARS antibodies define the so-called anti-synthetase syndrome, which is characterized by interstitial lung disease, myositis, polyarthritis/polyarthralgia, Raynaud’s phenomenon, and mechanic’s hands [36]. Each anti-synthetase seems to be associated with a peculiar disease expression: in addition, lung impairment and joint involvement are more common than myositis in early phase of the disease [38, 56, 59, 60]. Whether such antibodies could also have a predictive value for immune-mediated idiopathic lung disease has to be further elucidated.

Anti-Aminoacyl-tRNA Synthetases Autoantibodies

Anti-Mi-2 Autoantibody

Autoantibodies against aminoacyl-transfer RNA (tRNA) synthetases are the most common MSA, collectively found in about 25–35% of patients affected with PM or DM [47]. Aminoacyl-tRNA synthetases catalyze the ATP-dependent binding of any single aminoacid to its cognate tRNA during

Anti-Mi-2 antibody is a specific marker of DM, being present in 10% to 20% of patients [48]. The majority of anti-Mi-2 antibody positive patients, both adults and children, show a classic DM phenotype, with typical florid cutaneous manifestations, including Gottron’s sign or

Table 1 Prevalence of myositis-specific autoantibodies in adult PM/DM, and biological function of target autoantigens

SRP signal recognition particle; NuRD nucleosome remodelinghistone deacetylase; TIF1-γ transcriptional intermediary factor 1- gamma; MAD5 melanoma-differenziation associated gene 5; SUMO-1 smallubiquitin-like modifier 1

Autoantibodies

Target autoantigen and function

Autoantibody frequency in PM/DM % values

Anti-ARS Anti-Jo-1 Anti-PL-7 Anti-PL-12 Anti-EJ Anti-OJ Anti-KS Anti-Ha Anti-Zo Anti-SRP

aminoacyl-tRNA synthetases–protein synthesis Histidyl Threonyl Alanyl Glicyl Isoleucyl Asparaginyl Tyrosyl Phenylalanyl SRP−Protein translocation across the endoplasmic reticulum (6 polypeptides and a single 7SLRNA molecule) Unknown Helicase−Transcription regulation (component of the NuRD complex) TIF1-γ−Nuclear transcription MDA5−Innate immune response against viruses SUMO-1 Activating Enzyme 1−Posttranslational modifications

30–40 20–30 2–5 2–5 2–5