- Email: [email protected]
The pathogenesis of inflammatory muscle diseases:
Autoimmunity Reviews 1 (2002) 226–232
The pathogenesis of inflammatory muscle diseases: On the cutting edge among the environment, the genetic background, the immune response and the dysregulation of apoptosis Alberto Pignone*, Ginevra Fiori, Angela Del Rosso, Sergio Generini, Marco MatucciCerinic Department of Medicine, Section of Rheumatology, University of Florence, Viale Pieraccini 18, Villa Monna Tessa, 50139 Florence, Italy Received 7 May 2002; accepted 25 May 2002
Abstract Inflammatory muscle diseases (IMD), including dermatomyositis (DM) and polymyositis (PM), affect skeletal muscle, leading to profound tissue modification. The etiology of IMD is unknown, but multiple steps of the disease pathogenesis have been identified. The main alterations involve the immune response. Cellular infiltrates found in the muscle provide strong evidence for the involvement of a preferential immune mechanism of muscle damage. The pathologic differences found between PM and DM indicate a different role played by cell-mediated and humoral immune alterations. It is well accepted that in the pathogenetic pathway both host genes and environmental factors are involved. Apoptosis, or programmed cell death, is a complex process that plays a key role in many physiological events. It regulates the turnover of immune cells and is one of the mechanisms involved in ensuring a competent, non-autoreactive repertoire of lymphocytes. Apoptosis as a mechanism of muscle fibre death has been described in several neuromuscular disorders and muscular dystrophies, and evidence of a lack of apoptosis in IMD suggests a failure of apoptotic clearance of inflammatory cells playing a role in the maintenance of chronic cytotoxic muscle fibre damage. Most likely, the failure of apoptosis seems to be the main hallmark of the pathogenesis of IMD. 䊚 2002 Elsevier Science B.V. All rights reserved. Keywords: Inflammatory muscle diseases; Polymyositis; Dermatomyositis; Apoptosis
*Corresponding author. Tel.yfax: q39-055-4279271. E-mail address: [email protected] (A. Pignone), [email protected] (G. Fiori), [email protected] (M. MatucciCerinic). 1568-9972/02/$ - see front matter 䊚 2002 Elsevier Science B.V. All rights reserved. PII: S 1 5 6 8 - 9 9 7 2 Ž 0 2 . 0 0 0 5 5 - 1
A. Pignone et al. / Autoimmunity Reviews 1 (2002) 226–232
1. Introduction Inflammatory muscle diseases (IMDs), including dermatomyositis (DM) and polymyositis (PM), affect skeletal muscle, leading to profound tissue modification. Inflammatory cells surround, invade and destroy muscle fibres, usually resulting in symmetrical muscle weakness, slowly progressing over weeks to months or even years. The etiology of IMDs is unknown, but multiple steps of the disease pathogenesis have been identified. The main alterations involve the immune response, either for the cellular or the humoral system, but it is well accepted that in the pathogenetic pathway both host genes and environmental factors are involved. All these factors may contribute to increase the susceptibility to autoimmunity by affecting the overall reactivity and quality of the cells of the immune system that are restricted in the pathogenic process w1x. The current hypothesis is that IMDs result from immune-mediated damage occurring in genetically susceptible individuals in response to environmental stimuli. The aim of this review is to focus the current knowledge about the main potential factors contributing to the pathogenesis of IMDs and to address the hypothesis that dysregulation of apoptosis may play a pivotal role in the disease pathogenesis. 2. Genetics In IMDs, and in particular in PM, family members may be affected with other systemic rheumatic diseases or even organ-specific autoimmune diseases w2x. The presence of PMyDM in omozygotic twins and the major risk in developing the disease in the patient’s relatives support the hypothesis for a genetic background for PMyDM w3,4x. It has been reported that IMDs occur in individuals with a restricted background of major histocompatibility complex (MHC) genes. Indeed, the clinical features of IMDs are linked to the presence of other MHC genes that are involved in the production of myositis-specific antibodies. The significance of the genetic background is stressed by the evidence that: (a) an association exists between PM, DM and the MHC class I and II antigens; (b) ancestral haplotype human leucocyte antigen (HLA)-B8,
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DR3 is associated with other autoimmune diseases w5x; and (c) sufficient data suggest that the supertype specificity DR52 is linked to the production of various antibodies anti-histidyl-tRNA synthetase w6 x . 3. Environmental factors Reports of geographic clustering of myositis cases and the observation that subsets of patients, defined by different myositis-specific antibodies, who develop the disease in different periods of the year suggest that PMyDM might be triggered by environmental factorsyinfectious agents w7x. Among these, Coxsackie viruses, for their muscle tropism, are considered as potential inducers of PMyDM. Increased levels of serum antiviral antibodies and the isolation of the virus from patients’ stools supports this link w8,9x. The infection of neonatal mice by Coxsackie virus B1 leads to the development of acute viral myositis, which changes from an acute to a chronic inflammatory process in 60% of cases. In this experimental model, chronic inflammation, as well as fibre necrosis and regeneration, and focal accumulation of mononuclear cell infiltrates are similar to human PM w10x. Virus persistence may perpetuate an inflammatory response against muscle, but others factors are also required for full induction of the disease w11x. Animal models provide clear evidence that viral infection can cause chronic muscle inflammation and that a variety of autoimmune phenomena might be involved in the pathogenesis. An infectious or environmental agent may represent a target against which an immune reaction is directed in the muscle or cross-react with muscle, evolving to a chronic, self-perpetuating process that eventually leads to an autoimmune process. It is also possible that the different subsets of disease (PM or DM) could be the result of different environmental agent stimuli. 4. Immune-mediated alterations The cellular infiltrates found in muscle in IMDs provide strong evidence for the involvement of a preferential immune mechanism of muscle damage. However, the pathologic differences found
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between PM and DM indicate a different role played by cell-mediated and humoral alterations. In PM, the inflammatory infiltrate, characterised by the presence of T-cells focused on the muscle fibres w12–14x, is most prominent in the endomysial area. Cytotoxic CD8q T-lymphocytes largely outnumber macrophages and B-lymphocytes. Tcells and macrophages surround and invade nonnecrotic muscle fibres, suggesting the involvement of cell-mediated cytotoxicity in muscle damage. Thus, CD8q T-lymphocytes, the primary cells capable of carrying out antigen-directed cytotoxicity, are the dominant cells at the site of muscle fibre damage in PM. This pathologic observation demonstrates that the muscle damage is immunemediated w15x. The T-cell cytotoxic activity is mainly due to the release of intracellular granules containing tumour necrosis factor (TNF)-b, granzymes and perforin. In particular, perforin creates pores in the target cell membrane, leading to osmotic lysis and death by necrosis. The evidence that Th1 CD4q T-cells may also have a direct cytotoxic effect w16x has led some authors to investigate other possible killing modes responsible for muscle cell death. Recently, Sugiura and co-workers have demonstrated in PM that Th1 clones of CD4q T-cells may exert strong cytotoxicity on muscle cells through the FasyFasL pathway w17x. In contrast to PM, in DM the cellular infiltrate is primarily characterised by B-lymphocytes and CD4q T-cells, suggesting that fibre damage could be mediated through humoral immune mechanisms. The cellular infiltrate is most prominent in the perivascular areas. In DM, when compared to PM, B-lymphocytes are much more prominent in different areas, macrophages are approximately equally distributed, and the ratio of CD4qyCD8q T-lymphocytes is highest in the perivascular and lowest in the endomysial areas. B-lymphocyte activation is characterised by the increased expansion of RPI05 negative cells, which represents a hallmark differentiating DM from PM w18x. In DM, CD8q T-lymphocytes are present at the surface of the muscle fibres, but they are much less prominent than in PM; an invasion of muscle fibres by these cells is rarely observed in DM. This pattern is compatible with a process in which antigen-driven CD4q helper T-lymphocytes pro-
vide help to B-lymphocytes to generate antibodies that, together with complement, participate in damage of the muscular vessels. The hypothesis that vascular damage is the key process leading to muscle damage in DM is supported by the reduction of capillaries per muscle fibre compared with controls and PM. This change occurs very early in the disease process and is related to the perifascicular atrophy commonly observed in biopsies of DM muscle w19x. Thus, capillary damage may be the initial lesion in DM. Indeed, the deposition of immunoglobulin and complement in muscle arterioles and capillaries suggests that these vascular changes are mediated by an immune mechanism. Muscle cells normally express only low levels of MHC class I. In PM and DM, MHC class I molecules are up-regulated, probably as a result of the release of cytokines from the infiltrating lymphocytes and macrophages. CD8q T-cells require recognition of class I molecules on the target cell to exert their cytotoxic function. Although the expression of MHC class I molecules is not sufficient to initiate a cytotoxic attack, the up-regulation of these molecules on myocytes in these patients favours T-cell-mediated muscle damage. The intracellular adhesion molecule (ICAM)-1 and the complementary adhesion molecules lymphocyte function-associated antigen-1 (LFA-1) are also expressed on cytotoxic CD8q T-cells and on adjacent muscle fibres w20,21x, enabling cytotoxic lymphocytes to target muscle fibres. The up-regulation of these molecules seems to be directly involved in cytotoxic activity. In PM, the activation marker HLA-DR is present on approximately onethird of all lymphocytes found in the muscle and on approximately half of the other cells invading muscle cells. Almost all lymphocytes in the muscle express the CD45RO surface marker, indicating antigen-primed memory T-cells. The ratio of ¨ uncommitCD45R yCD45RA, a marker of naıve ted T-cells, is increased in muscle compared to the circulating ratio, providing further evidence that most lymphocytes are actively committed directly to the muscle in an inflammatory process. Immunopathology studies have also identified a small subpopulation of the infiltrating lymphocytes bearing the Ki-67 nuclear antigen associated with cellular proliferation; this suggests that a portion
A. Pignone et al. / Autoimmunity Reviews 1 (2002) 226–232
of the T-cells found in the muscle have proliferated in situ, likely as an antigen-driven response taking place directly in the muscle w22x. Cytokines are highly potent low-molecular-weight proteins that regulate the intensity and duration of the immune response. Unfortunately, their low concentration, and often-transient secretion, makes them difficult to identify in tissue. In the literature there is agreement that TGF-b is present in almost all biopsies of IMD w23–25x, even if it does not appear to be specific. Lundberg et al. hypothesised a central role for IL-1a in the pathogenetic mechanism of IMD w26x. This is supported by other data demonstrating that IL-a up-regulates the expression of MHC class I molecules and effects muscle cells metabolism, both by blocking the action of insulin-like growth factor, and by inhibiting glucose transport and lactate production, with consequent nutritional disturbances. In DM, both a reduction in the number of capillaries and microvascular injury heavily impair muscle perfusion and cause hypoxia, thus potentially up-regulating IL-1a. The same contradictory results exist for the role exerted by IL-1, IL-2, IL-4 and TNF-a. Few investigators found the presence of chemokines, a group of small polypeptides that act as chemoattractants and regulate the expression of integrins in leukocyte membrane wmacrophage inhibiting protein-a and -b (MIP-1ay1b) and RANTESx. Their role is, at the moment, not known in the pathogenesis of IMDs. 5. Apoptosis Apoptosis or programmed cell death is a complex process that plays a key role in many physiological events, such as embryogenesis and immunologic tolerance. It regulates the turnover of immune cells and is one of the mechanisms involved in ensuring a competent, non-autoreactive repertoire of lymphocytes. Indeed, apoptosis seems to have a crucial role in regulating the immunologic process w27x. Morphologically, apoptosis is characterised by nuclear condensation and fragmentation, and biochemically, by cleavage of DNA into oligonucleosomal fragments. Programmed cell death is the result of a very complex, genetically determined program, which is associated with a
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large number of specific gene expressions and protein syntheses. The Bcl-2 proto-oncogene encodes a specific protein that is one of the main protective cellular systems against apoptosis, whereas the expression of the Fas ‘death receptors’ (CD95yAPO-1) is one of the main pathways responsible for the induction of apoptosis. The final process is the result of a balance between apoptosis-inhibiting and -promoting factors. In IMDs, the necrotic process of muscle cells is considered to be immune-mediated w28x. Thus, the process of cell death has always had a central role in the pathogenesis of IMDs. However, a profound difference exists among the necrotic and apoptotic mechanisms leading to cell death. While the necrosis of muscle cell is a well-known event, there is now a great debate on the role played by apoptosis in the pathogenesis of IMDs. Dysregulated apoptosis seems to be linked to the development of many autoimmune disorders w29x, including those developed in animal models, such as experimental allergic encephalomyelitis w30x. Apoptosis as a mechanism of muscle fibre death has been described in several neuromuscular disorders and muscular dystrophies, as well as under experimental conditions in denervated and reinnerveted rat muscle w31x. In this perspective, many authors investigated whether in IMDs, in addition to necrosis, apoptosis might be considered as an alternative form of cell death, both for muscle and inflammatory cells. Fas antigen was not detected in healthy human muscle, while in IMDs it has been found expressed on the surface of invaded muscle fibres w32x. Despite these observations, it is surprising that no evidence has been put forward to support an enhancement of the apoptotic pathway as a possible mechanisms of muscle cell death. In particular, no features of muscle fibre apoptosis, such as DNA fragmentation as expression of apoptosis-related proteins, have been detected w33x. A possible explanation for this apparently contradictory result is provided by the same report, demonstrating that both Fas and the protective molecule Bcl-2 are co-expressed in inflamed muscle cells. In the juvenile form of DM, an overexpression of the Bcl-2 protective system has been shown w34x. More recently, other researchers demonstrated the expression of other molecules with
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its failure. This evidence is contrary to the other hypothesis that apoptotic cells may break immune tolerance to autoantigens, triggering an autoimmune reaction w38x in IMDs w39x. Thus, the potential pathogenetic impact of an alteration of such a complex physiologic regulatory system such as apoptosis in the inductionymaintenance of autoimmune diseases still requires further studies on a large number of patients with all the clinical and histopathological subsets of IMDs. Take-home messages
Fig. 1. Apoptosis and inflammatory muscle disease. IMDs, inflammatory muscle diseases; PM, polymyositis; DM, dermatomyositis.
antiapoptotic effect in IMD, such as Fas-associated death domain-like IL-1-converting enzyme (FLICE)-inhibitory protein (FLIP) w35x and human IAP-like protein, an inhibitor of caspase activity w36x. All these data suggest a prevalent inhibition of the apoptotic pathway, with consequent muscle resistance to Fas-mediated apoptosis. In addition, for the T-cell apoptotic pathway, an up-regulation of the FasyFas ligand system without the corresponding presence of DNA fragmentation has recently been shown w37x. The immunoreactivity for promoting cell survival proteins, such as bcl-x and cyclin-dependent kinase inhibitors (p16 and p57), has been proposed as a possible explanation for the absence of the apoptotic process in IMDs. The evidence for a lack of apoptosis in IMDs (Fig. 1) suggests that failure of apoptotic clearance of inflammatory cells plays a role in the maintenance of chronic cytotoxic muscle-fibre damage. 6. Summary The pathogenesis of IMDs is the result of a complex interaction between the environment, the genetic background and the immune response. In this scenario, apoptosis is dysregulated, and the body of the literature indicates that apoptosis most likely contributes to the pathogenesis of IMDs by
● Inflammatory muscle diseases include dermatomyositis and polymyositis. ● DM and PM result from immune-mediated damage. ● Apoptosis is a mechanism of muscle fibre death. ● A failure of apoptotic clearance of inflammatory cells may contribute to the perpetuation of chronic cytotoxic damage of muscle fibre.
References w1x Marrack P, Kappler J, Kotzin BL. Autoimmune disease: why and where it occurs. Nat Med 2001;7:899 –905. w2x Shamim EA, Miller FW. Familial autoimmunity and the idiopathic inflammatory myopathies. Curr Rheumatol Rep 2000;2:201 –11. w3x Griffiths MM, Encinas GA, Remmers EF, Kuchroo VK, Wilder RL. Mapping autoimmunity genes. Curr Opin Immunol 1999;11:689 –700. w4x Encinas JA, Kuchroo VK. Mapping and identification of autoimmunity genes. Curr Opin Immunol 2000;12:691 –7. w5x Garlepp MJ. Genetics of the idiopathic inflammatory myopathies. Curr Opin Rheumatol 1996;8:514 –20. w6x Arnett FC, Targoff IN, Mimori T, Goldstein R, Warner NB, Reveille JD. Interrelationship of major histocompatibility complex class II alleles and autoantibodies in four ethnic groups with various forms of myositis. Arthritis Rheum 1996;39:1507 –18. w7x Leff RL, Burgess SH, Miller FW, et al. Distinct seasonal patterns in the onset of adult idiopathic inflammatory myopathy in patients with anti-Jo and anti-signal recognition particle autoantibodies. Artrithis Rheum 1991;34:1391 –6. w8x Travers RL, Hughes GR, Sewall JR. Coxsackie B neutralization titers in polymyositisydermatomyositis. Lancet 1977;1:1268.
A. Pignone et al. / Autoimmunity Reviews 1 (2002) 226–232 w9x Schiraldi O, Iandolo E. Polymyositis accompanying Coxsackie virus B infection. Infection 1978;6:32 –4. w10x Tam PE, Schmidt AM, Ytterberg SR, Messner RP. Viral persistence during the developmental phase of Coxsackie virus B1-induced murine polymyositis. J Virol 1991;65:6654 –60. w11x Tam PE, Schmidt AM, Ytterberg SR, Messner RP. Duration of virus persistence and its relationship to inflammation during the chronic phase of Coxsackie virus B1-induced murine polymyositis. J Lab Clin Med 1994;123:346 –56. w12x Arahata K, Engel AG. 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 1984;16:193 –208. w13x Engel AG, Arahata K. Monoclonal antibody analysis of mononuclear cells in myopathies. II. Phenotypes of autoinvasive cells in polymyositis and inclusion body myositis. Ann Neurol 1984;16:209 –15. w14x Mantegazza R, Bernasconi P, Confalonieri P, Cornelio F. Inflammatory myopathies and systemic disorders: a review of immunopathogenetic mechanisms and clinical features. J Neurol 1997;244:277 –87. w15x Hohlfeld R, Engel AG, Goebles N, Behrens L. Cellular immune mechanism in inflammatory myopathies. Curr Opin Rheumatol 1997;9:520 –6. w16x Yagita H, Hanabuchi S, Asano Y, Tamura T, Nariuchi H, Okumura K. Fas-mediated cytotoxicity—a new immunoregulatory and pathogenic function of Th1 CD4q cells. Immunol Rev 1995;146:223 –39. w17x Sugiura T, Murakawa Y, Nagai A, Kondo M, Kobayashi S. Fas and Fas ligand interaction induces apoptosis in inflammatory myopathies. CD4q T cells cause muscle cell injury directly in polymyositis. Arthritis Rheum 1999;42:291 –8. w18x Kikuchi Y, Koarada S, Toda Y, et al. Difference in B cell activation between dermatomyositis and polymyositis: analysis of the expression of RPI05 on peripheral blood B cells. Ann Rheum Dis 2001;60:1137 –40. w19x Emslie-Smith AM, Engel AG. Microvascular changes in early and advanced dermatomyositis: a quantitative study. Ann Neurol 1990;27:343 –56. w20x De Bleeker JL, Engel AG. Expression of cell adhesion molecules in inflammatory myopathies and Duchenne dystrophy. J Neuropathol Exp Neurol 1994;53:369 –76. w21x Cid MC, Grau JM, Casademont J, et al. Leukocytey endothelial cell adhesion receptors in muscle biopsies from patients with idiopathic inflammatory myopathies (idiopathic inflammatory myopathy). Clin Exp Immunol 1996;104:467 –73. w22x O’Hanlon TP, Miller FW. T cell-mediated immune mechanism in myositis. Curr Opin Rheumatol 1995;7:503 –9.
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w23x Lundberg I, Ulfgren AK, Nyberg P, Andersson U, Klareskog L. Cytokine production in muscle tissue of patients with idiopathic inflammatory myopathies. Arthritis Rheum 1997;40:865 –74. w24x Confalonieri P, Bernasconi P, Cornelio F, Mantegazza R. Trasforming growth factor-1 in polymyositis and dermatomyositis correlates with fibrosis but not with mononuclear cell infiltrate. J Neuropathol Exp Neurol 1997;56:479 –84. w25x Tews DS, Goebel HH. Cytokine expression profile in idiopathic inflammatory myopathies. J Neuropathol Exp Neurol 1996;55:342 –7. w26x Lundberg I, Kratz AH, Alexanderson H, Patarroyo M. Decreased expression of interleukin-1alpha, interleukin1beta, and cell adhesion molecules in muscle tissue following corticosteroid treatment in patients with polymyositis and dermatomyositis. Arthritis Rheum 2000;43(2):336 –48. w27x Schwartz SM, Bennet MR. Death by any author name. Am J Pathol 1995;147:229 –34. w28x Dalakas ME. Polymiositis, dermatomyositis and inclusion body myositis. N Engl J Med 1991;325:1487 –98. w29x Mountz JD, Wu J, Cheng J, Zhou T. Autoimmune disease. A problem of defective apoptosis. Arthritis Rheum 1994;37:1415 –20. w30x Waldner H, Sobel RA, Howard E, Kuchroo VK. Fas and FasL-deficient mice are resistant to induction of autoimmune encephalomyelitis. J Immunol 1997;159:3100 –3. w31x Inukai A, Kobayashi Y, Honda H, Sobue G. Fas antigen is expressed in human diseased muscles, but does not link to apoptosis. Nippon Rinsho 1996;54:1992 –6. w32x Sugiura T, Murakawa Y, Nagai A, Kondo M, Kobayashi S. Fas and Fas ligand interaction induces apoptosis in inflammatory myopathies. Arthritis Rheum 1999;42:291 –8. w33x Schneider C, Gold R, Dalakas MC, et al. MHC class-I mediated cytotoxicity does not induce apoptosis in muscle fibers nor in inflammatory T cells: studies in patients with polymyositis, and inclusion body myositis. J Neuropathol Exp Neurol 1996;55:1205 –9. w34x Falcini F, Calzolari A, Generini S, et al. Bcl-2, p53 and c-myc expression in juvenile dermatomyositis. Clin Exp Rheumatol 2000;18:643 –6. w35x Nagaraju K, Casciola-Rosen L, Rosen A, et al. The inhibition of apoptosis in myositis and normal muscle cells. J Immunol 2000;164:5459 –65. w36x Li M, Dalakas MC. Expression of human IAP-like protein in skeletal muscle: a possible explanation for the rare incidence of muscle fiber apoptosis in T-cellmediated inflammatory myopathies. J Neuroimmunol 2000;106:1 –5. w37x Vattemi G, Tonin P, Filosto M, Spagnolo M, Rizzuto N, Tomelleri G. T-cell anti-apoptotic mechanism in inflammatory myopathies. J Neuroimmunol 2000;111:146 –51.
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w38x Rosen A, Casciola-Rosen I. Autoantigens as substrates for apoptotic process: implication for the pathogenesis of systemic autoimmune disease. Cell Death Differentiation 1999;6:6 –12.
w39x Chang-Chirgh , Ahearn JM. Skeletal muscle cells and the pathogenesis of myositis: a prospective. Curr Rheumatol Rep 2001;3:325 –33.
The World of Autoimmunity; Literature Synopsis Self-Reactive Antibody Repertoires in CLL The association between cancer and autoimmunity is bi-directional, and is more obvious in neoplasms of the hematopoietic system. Stahl et al. (Leukemia Lymphoma 2001;42:163) studied the self-reactive antibody repertoires of plasma IgG and IgM in B-cell chronic lymphocytic leukemia (B-CLL) patients. Using quantitative immunoblotting that allows screening of antibody reactivities in complex antibody mixtures towards a large panel of antigens, they found that the self-reactive antibody repertoires of plasma IgM and IgG are broadly altered in patients having B-CLL. Moreover, these alterations were not restricted to B-CLL patients exhibiting autoimmune disease, and the target-restricted autoimmunity in B-CLL patients was associated with altered antibody repertoires not restricted to the target organ. These findings suggest broad defects of self-reactive antibody repertoires in B-CLL patients. The use of intravenous immunoglobulin in B-CLL patients could thus have an additive effect as it might restore normal self-reactive antibody repertoires in these patients’ plasma. Do ANCA have a pathogenic role in drug-induced neutropenia? The mechanism of action of autoantibodies and whether they are pathogenic is not always clear. This is also the case with respect to anti-neutrophil cytoplasmic antibodies (ANCA) characterizing mainly vasculitides. Akamizu et al. (Clin Exp Immunol 2002;127:92) report a patient with Graves’ disease who developed ANCA after propylthiouracil treatment and exhibited neutropenia. The patient’s serum bound specifically to neutrophils and HL-60 cells differentiated into granulocytes, and lysed the HL-60 cells via a complementmediated mechanism. Both proteinase 3 and myeloperoxidase, classical targets for cytoplasmic and perinuclear ANCA, significantly inhibited both the binding and cytotoxicity of the serum. On the other hand, tumor necrosis factor-alpha, that can up-regulate cell surface expression of several ANCA antigens, enhanced both the binding and cytotoxicity of the serum. These findings support a pathogenic role for ANCA in druginduced neutropenia. The mystery still remains regarding the mechanism leading to ANCA production. TNF-alpha Blockade in Vasculitis Blockade of TNF-alpha is an accepted treatment in several autoimmune and inflammatory conditions such as rheumatoid arthritis and Crohn’s disease. Booth et al. (Ann Rheum Dis 2002;61:559) reported of 6 patients having vasculitis that were successfully treated with infliximab, a chimeric monoclonal antibody against TNF-alpha. The patients had either Wegener’s granulomatosis or microscopic polyangiitis, they had at least 3 clinical relapses and received prolonged treatment with corticosteroids and at least 4 immunosuppressive agents. The therapeutic protocol consisted of 3 intravenous does of infliximab 200 mg monthly which was well tolerated. Five of these 6 patients had remission of their disease, allowing steroid withdrawal or dose reduction by more than 50%. In addition, disease activity assessed by the Birmingham Vasculitis Activity Scores improved from a mean of 6.3 to 0.8 at three months. ESR and C reactive protein levels also decreased. These results provide hope for establishing this therapy for vasculitis patients and thus to reduce exposure to immunosuppressive agents and corticosteroids.
The pathogenesis of inflammatory muscle diseases: On the cutting edge among the environment, the genetic background, the immune response and the dysregulation of apoptosis Alberto Pignone*, Ginevra Fiori, Angela Del Rosso, Sergio Generini, Marco MatucciCerinic Department of Medicine, Section of Rheumatology, University of Florence, Viale Pieraccini 18, Villa Monna Tessa, 50139 Florence, Italy Received 7 May 2002; accepted 25 May 2002
Abstract Inflammatory muscle diseases (IMD), including dermatomyositis (DM) and polymyositis (PM), affect skeletal muscle, leading to profound tissue modification. The etiology of IMD is unknown, but multiple steps of the disease pathogenesis have been identified. The main alterations involve the immune response. Cellular infiltrates found in the muscle provide strong evidence for the involvement of a preferential immune mechanism of muscle damage. The pathologic differences found between PM and DM indicate a different role played by cell-mediated and humoral immune alterations. It is well accepted that in the pathogenetic pathway both host genes and environmental factors are involved. Apoptosis, or programmed cell death, is a complex process that plays a key role in many physiological events. It regulates the turnover of immune cells and is one of the mechanisms involved in ensuring a competent, non-autoreactive repertoire of lymphocytes. Apoptosis as a mechanism of muscle fibre death has been described in several neuromuscular disorders and muscular dystrophies, and evidence of a lack of apoptosis in IMD suggests a failure of apoptotic clearance of inflammatory cells playing a role in the maintenance of chronic cytotoxic muscle fibre damage. Most likely, the failure of apoptosis seems to be the main hallmark of the pathogenesis of IMD. 䊚 2002 Elsevier Science B.V. All rights reserved. Keywords: Inflammatory muscle diseases; Polymyositis; Dermatomyositis; Apoptosis
*Corresponding author. Tel.yfax: q39-055-4279271. E-mail address: [email protected] (A. Pignone), [email protected] (G. Fiori), [email protected] (M. MatucciCerinic). 1568-9972/02/$ - see front matter 䊚 2002 Elsevier Science B.V. All rights reserved. PII: S 1 5 6 8 - 9 9 7 2 Ž 0 2 . 0 0 0 5 5 - 1
A. Pignone et al. / Autoimmunity Reviews 1 (2002) 226–232
1. Introduction Inflammatory muscle diseases (IMDs), including dermatomyositis (DM) and polymyositis (PM), affect skeletal muscle, leading to profound tissue modification. Inflammatory cells surround, invade and destroy muscle fibres, usually resulting in symmetrical muscle weakness, slowly progressing over weeks to months or even years. The etiology of IMDs is unknown, but multiple steps of the disease pathogenesis have been identified. The main alterations involve the immune response, either for the cellular or the humoral system, but it is well accepted that in the pathogenetic pathway both host genes and environmental factors are involved. All these factors may contribute to increase the susceptibility to autoimmunity by affecting the overall reactivity and quality of the cells of the immune system that are restricted in the pathogenic process w1x. The current hypothesis is that IMDs result from immune-mediated damage occurring in genetically susceptible individuals in response to environmental stimuli. The aim of this review is to focus the current knowledge about the main potential factors contributing to the pathogenesis of IMDs and to address the hypothesis that dysregulation of apoptosis may play a pivotal role in the disease pathogenesis. 2. Genetics In IMDs, and in particular in PM, family members may be affected with other systemic rheumatic diseases or even organ-specific autoimmune diseases w2x. The presence of PMyDM in omozygotic twins and the major risk in developing the disease in the patient’s relatives support the hypothesis for a genetic background for PMyDM w3,4x. It has been reported that IMDs occur in individuals with a restricted background of major histocompatibility complex (MHC) genes. Indeed, the clinical features of IMDs are linked to the presence of other MHC genes that are involved in the production of myositis-specific antibodies. The significance of the genetic background is stressed by the evidence that: (a) an association exists between PM, DM and the MHC class I and II antigens; (b) ancestral haplotype human leucocyte antigen (HLA)-B8,
227
DR3 is associated with other autoimmune diseases w5x; and (c) sufficient data suggest that the supertype specificity DR52 is linked to the production of various antibodies anti-histidyl-tRNA synthetase w6 x . 3. Environmental factors Reports of geographic clustering of myositis cases and the observation that subsets of patients, defined by different myositis-specific antibodies, who develop the disease in different periods of the year suggest that PMyDM might be triggered by environmental factorsyinfectious agents w7x. Among these, Coxsackie viruses, for their muscle tropism, are considered as potential inducers of PMyDM. Increased levels of serum antiviral antibodies and the isolation of the virus from patients’ stools supports this link w8,9x. The infection of neonatal mice by Coxsackie virus B1 leads to the development of acute viral myositis, which changes from an acute to a chronic inflammatory process in 60% of cases. In this experimental model, chronic inflammation, as well as fibre necrosis and regeneration, and focal accumulation of mononuclear cell infiltrates are similar to human PM w10x. Virus persistence may perpetuate an inflammatory response against muscle, but others factors are also required for full induction of the disease w11x. Animal models provide clear evidence that viral infection can cause chronic muscle inflammation and that a variety of autoimmune phenomena might be involved in the pathogenesis. An infectious or environmental agent may represent a target against which an immune reaction is directed in the muscle or cross-react with muscle, evolving to a chronic, self-perpetuating process that eventually leads to an autoimmune process. It is also possible that the different subsets of disease (PM or DM) could be the result of different environmental agent stimuli. 4. Immune-mediated alterations The cellular infiltrates found in muscle in IMDs provide strong evidence for the involvement of a preferential immune mechanism of muscle damage. However, the pathologic differences found
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between PM and DM indicate a different role played by cell-mediated and humoral alterations. In PM, the inflammatory infiltrate, characterised by the presence of T-cells focused on the muscle fibres w12–14x, is most prominent in the endomysial area. Cytotoxic CD8q T-lymphocytes largely outnumber macrophages and B-lymphocytes. Tcells and macrophages surround and invade nonnecrotic muscle fibres, suggesting the involvement of cell-mediated cytotoxicity in muscle damage. Thus, CD8q T-lymphocytes, the primary cells capable of carrying out antigen-directed cytotoxicity, are the dominant cells at the site of muscle fibre damage in PM. This pathologic observation demonstrates that the muscle damage is immunemediated w15x. The T-cell cytotoxic activity is mainly due to the release of intracellular granules containing tumour necrosis factor (TNF)-b, granzymes and perforin. In particular, perforin creates pores in the target cell membrane, leading to osmotic lysis and death by necrosis. The evidence that Th1 CD4q T-cells may also have a direct cytotoxic effect w16x has led some authors to investigate other possible killing modes responsible for muscle cell death. Recently, Sugiura and co-workers have demonstrated in PM that Th1 clones of CD4q T-cells may exert strong cytotoxicity on muscle cells through the FasyFasL pathway w17x. In contrast to PM, in DM the cellular infiltrate is primarily characterised by B-lymphocytes and CD4q T-cells, suggesting that fibre damage could be mediated through humoral immune mechanisms. The cellular infiltrate is most prominent in the perivascular areas. In DM, when compared to PM, B-lymphocytes are much more prominent in different areas, macrophages are approximately equally distributed, and the ratio of CD4qyCD8q T-lymphocytes is highest in the perivascular and lowest in the endomysial areas. B-lymphocyte activation is characterised by the increased expansion of RPI05 negative cells, which represents a hallmark differentiating DM from PM w18x. In DM, CD8q T-lymphocytes are present at the surface of the muscle fibres, but they are much less prominent than in PM; an invasion of muscle fibres by these cells is rarely observed in DM. This pattern is compatible with a process in which antigen-driven CD4q helper T-lymphocytes pro-
vide help to B-lymphocytes to generate antibodies that, together with complement, participate in damage of the muscular vessels. The hypothesis that vascular damage is the key process leading to muscle damage in DM is supported by the reduction of capillaries per muscle fibre compared with controls and PM. This change occurs very early in the disease process and is related to the perifascicular atrophy commonly observed in biopsies of DM muscle w19x. Thus, capillary damage may be the initial lesion in DM. Indeed, the deposition of immunoglobulin and complement in muscle arterioles and capillaries suggests that these vascular changes are mediated by an immune mechanism. Muscle cells normally express only low levels of MHC class I. In PM and DM, MHC class I molecules are up-regulated, probably as a result of the release of cytokines from the infiltrating lymphocytes and macrophages. CD8q T-cells require recognition of class I molecules on the target cell to exert their cytotoxic function. Although the expression of MHC class I molecules is not sufficient to initiate a cytotoxic attack, the up-regulation of these molecules on myocytes in these patients favours T-cell-mediated muscle damage. The intracellular adhesion molecule (ICAM)-1 and the complementary adhesion molecules lymphocyte function-associated antigen-1 (LFA-1) are also expressed on cytotoxic CD8q T-cells and on adjacent muscle fibres w20,21x, enabling cytotoxic lymphocytes to target muscle fibres. The up-regulation of these molecules seems to be directly involved in cytotoxic activity. In PM, the activation marker HLA-DR is present on approximately onethird of all lymphocytes found in the muscle and on approximately half of the other cells invading muscle cells. Almost all lymphocytes in the muscle express the CD45RO surface marker, indicating antigen-primed memory T-cells. The ratio of ¨ uncommitCD45R yCD45RA, a marker of naıve ted T-cells, is increased in muscle compared to the circulating ratio, providing further evidence that most lymphocytes are actively committed directly to the muscle in an inflammatory process. Immunopathology studies have also identified a small subpopulation of the infiltrating lymphocytes bearing the Ki-67 nuclear antigen associated with cellular proliferation; this suggests that a portion
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of the T-cells found in the muscle have proliferated in situ, likely as an antigen-driven response taking place directly in the muscle w22x. Cytokines are highly potent low-molecular-weight proteins that regulate the intensity and duration of the immune response. Unfortunately, their low concentration, and often-transient secretion, makes them difficult to identify in tissue. In the literature there is agreement that TGF-b is present in almost all biopsies of IMD w23–25x, even if it does not appear to be specific. Lundberg et al. hypothesised a central role for IL-1a in the pathogenetic mechanism of IMD w26x. This is supported by other data demonstrating that IL-a up-regulates the expression of MHC class I molecules and effects muscle cells metabolism, both by blocking the action of insulin-like growth factor, and by inhibiting glucose transport and lactate production, with consequent nutritional disturbances. In DM, both a reduction in the number of capillaries and microvascular injury heavily impair muscle perfusion and cause hypoxia, thus potentially up-regulating IL-1a. The same contradictory results exist for the role exerted by IL-1, IL-2, IL-4 and TNF-a. Few investigators found the presence of chemokines, a group of small polypeptides that act as chemoattractants and regulate the expression of integrins in leukocyte membrane wmacrophage inhibiting protein-a and -b (MIP-1ay1b) and RANTESx. Their role is, at the moment, not known in the pathogenesis of IMDs. 5. Apoptosis Apoptosis or programmed cell death is a complex process that plays a key role in many physiological events, such as embryogenesis and immunologic tolerance. It regulates the turnover of immune cells and is one of the mechanisms involved in ensuring a competent, non-autoreactive repertoire of lymphocytes. Indeed, apoptosis seems to have a crucial role in regulating the immunologic process w27x. Morphologically, apoptosis is characterised by nuclear condensation and fragmentation, and biochemically, by cleavage of DNA into oligonucleosomal fragments. Programmed cell death is the result of a very complex, genetically determined program, which is associated with a
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large number of specific gene expressions and protein syntheses. The Bcl-2 proto-oncogene encodes a specific protein that is one of the main protective cellular systems against apoptosis, whereas the expression of the Fas ‘death receptors’ (CD95yAPO-1) is one of the main pathways responsible for the induction of apoptosis. The final process is the result of a balance between apoptosis-inhibiting and -promoting factors. In IMDs, the necrotic process of muscle cells is considered to be immune-mediated w28x. Thus, the process of cell death has always had a central role in the pathogenesis of IMDs. However, a profound difference exists among the necrotic and apoptotic mechanisms leading to cell death. While the necrosis of muscle cell is a well-known event, there is now a great debate on the role played by apoptosis in the pathogenesis of IMDs. Dysregulated apoptosis seems to be linked to the development of many autoimmune disorders w29x, including those developed in animal models, such as experimental allergic encephalomyelitis w30x. Apoptosis as a mechanism of muscle fibre death has been described in several neuromuscular disorders and muscular dystrophies, as well as under experimental conditions in denervated and reinnerveted rat muscle w31x. In this perspective, many authors investigated whether in IMDs, in addition to necrosis, apoptosis might be considered as an alternative form of cell death, both for muscle and inflammatory cells. Fas antigen was not detected in healthy human muscle, while in IMDs it has been found expressed on the surface of invaded muscle fibres w32x. Despite these observations, it is surprising that no evidence has been put forward to support an enhancement of the apoptotic pathway as a possible mechanisms of muscle cell death. In particular, no features of muscle fibre apoptosis, such as DNA fragmentation as expression of apoptosis-related proteins, have been detected w33x. A possible explanation for this apparently contradictory result is provided by the same report, demonstrating that both Fas and the protective molecule Bcl-2 are co-expressed in inflamed muscle cells. In the juvenile form of DM, an overexpression of the Bcl-2 protective system has been shown w34x. More recently, other researchers demonstrated the expression of other molecules with
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its failure. This evidence is contrary to the other hypothesis that apoptotic cells may break immune tolerance to autoantigens, triggering an autoimmune reaction w38x in IMDs w39x. Thus, the potential pathogenetic impact of an alteration of such a complex physiologic regulatory system such as apoptosis in the inductionymaintenance of autoimmune diseases still requires further studies on a large number of patients with all the clinical and histopathological subsets of IMDs. Take-home messages
Fig. 1. Apoptosis and inflammatory muscle disease. IMDs, inflammatory muscle diseases; PM, polymyositis; DM, dermatomyositis.
antiapoptotic effect in IMD, such as Fas-associated death domain-like IL-1-converting enzyme (FLICE)-inhibitory protein (FLIP) w35x and human IAP-like protein, an inhibitor of caspase activity w36x. All these data suggest a prevalent inhibition of the apoptotic pathway, with consequent muscle resistance to Fas-mediated apoptosis. In addition, for the T-cell apoptotic pathway, an up-regulation of the FasyFas ligand system without the corresponding presence of DNA fragmentation has recently been shown w37x. The immunoreactivity for promoting cell survival proteins, such as bcl-x and cyclin-dependent kinase inhibitors (p16 and p57), has been proposed as a possible explanation for the absence of the apoptotic process in IMDs. The evidence for a lack of apoptosis in IMDs (Fig. 1) suggests that failure of apoptotic clearance of inflammatory cells plays a role in the maintenance of chronic cytotoxic muscle-fibre damage. 6. Summary The pathogenesis of IMDs is the result of a complex interaction between the environment, the genetic background and the immune response. In this scenario, apoptosis is dysregulated, and the body of the literature indicates that apoptosis most likely contributes to the pathogenesis of IMDs by
● Inflammatory muscle diseases include dermatomyositis and polymyositis. ● DM and PM result from immune-mediated damage. ● Apoptosis is a mechanism of muscle fibre death. ● A failure of apoptotic clearance of inflammatory cells may contribute to the perpetuation of chronic cytotoxic damage of muscle fibre.
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The World of Autoimmunity; Literature Synopsis Self-Reactive Antibody Repertoires in CLL The association between cancer and autoimmunity is bi-directional, and is more obvious in neoplasms of the hematopoietic system. Stahl et al. (Leukemia Lymphoma 2001;42:163) studied the self-reactive antibody repertoires of plasma IgG and IgM in B-cell chronic lymphocytic leukemia (B-CLL) patients. Using quantitative immunoblotting that allows screening of antibody reactivities in complex antibody mixtures towards a large panel of antigens, they found that the self-reactive antibody repertoires of plasma IgM and IgG are broadly altered in patients having B-CLL. Moreover, these alterations were not restricted to B-CLL patients exhibiting autoimmune disease, and the target-restricted autoimmunity in B-CLL patients was associated with altered antibody repertoires not restricted to the target organ. These findings suggest broad defects of self-reactive antibody repertoires in B-CLL patients. The use of intravenous immunoglobulin in B-CLL patients could thus have an additive effect as it might restore normal self-reactive antibody repertoires in these patients’ plasma. Do ANCA have a pathogenic role in drug-induced neutropenia? The mechanism of action of autoantibodies and whether they are pathogenic is not always clear. This is also the case with respect to anti-neutrophil cytoplasmic antibodies (ANCA) characterizing mainly vasculitides. Akamizu et al. (Clin Exp Immunol 2002;127:92) report a patient with Graves’ disease who developed ANCA after propylthiouracil treatment and exhibited neutropenia. The patient’s serum bound specifically to neutrophils and HL-60 cells differentiated into granulocytes, and lysed the HL-60 cells via a complementmediated mechanism. Both proteinase 3 and myeloperoxidase, classical targets for cytoplasmic and perinuclear ANCA, significantly inhibited both the binding and cytotoxicity of the serum. On the other hand, tumor necrosis factor-alpha, that can up-regulate cell surface expression of several ANCA antigens, enhanced both the binding and cytotoxicity of the serum. These findings support a pathogenic role for ANCA in druginduced neutropenia. The mystery still remains regarding the mechanism leading to ANCA production. TNF-alpha Blockade in Vasculitis Blockade of TNF-alpha is an accepted treatment in several autoimmune and inflammatory conditions such as rheumatoid arthritis and Crohn’s disease. Booth et al. (Ann Rheum Dis 2002;61:559) reported of 6 patients having vasculitis that were successfully treated with infliximab, a chimeric monoclonal antibody against TNF-alpha. The patients had either Wegener’s granulomatosis or microscopic polyangiitis, they had at least 3 clinical relapses and received prolonged treatment with corticosteroids and at least 4 immunosuppressive agents. The therapeutic protocol consisted of 3 intravenous does of infliximab 200 mg monthly which was well tolerated. Five of these 6 patients had remission of their disease, allowing steroid withdrawal or dose reduction by more than 50%. In addition, disease activity assessed by the Birmingham Vasculitis Activity Scores improved from a mean of 6.3 to 0.8 at three months. ESR and C reactive protein levels also decreased. These results provide hope for establishing this therapy for vasculitis patients and thus to reduce exposure to immunosuppressive agents and corticosteroids.