Original Article

Polymyositis Mediated by T Lymphocytes That Express the γ/δ Receptor

Reinhard Hohlfeld, M.D., Andrew G. Engel, M.D., Kunio Ii, M.D., and Michel C. Harper, M.D.

N Engl J Med 1991; 324:877-881March 28, 1991

Abstract

Abstract

Background.

The invasion and destruction of nonnecrotic muscle fibers by CD8+ cytotoxic T cells is considered a hallmark of polymyositis. In the cases of polymyositis reported so far, the autoinvasive CD8+ T cells expressed the common form of T-cell receptor for the recognition of antigen, the so-called α/β T-cell receptor. We describe a 69-year-old man with polymyositis mediated by CD4—, CD8— T cells expressing the recently discovered, uncommon γ/δ T-cell receptor.

Full Text of Background....

Methods.

We used immunofluorescence or immunoperoxidase techniques to study frozen sections of muscle from our patient, who had mild weakness of cervical and proximal limb muscles, and from control patients with polymyositis, inclusion-body myositis, dermatomyositis, or granulomatous myopathy with monoclonal antibodies against T-cell-related antigens (CD2, CD3, CD4, CD8, and γ/δ T-cell receptor), B cells (CD22), major histocompatibility complex (MHC) and MHC-related antigens (MHC Class I, CD1a, CD1b, and CD1c), and the 65-kd heat-shock protein. The membrane contacts between the autoinvasive cells and the sarcolemma were investigated by electron microscopy.

Full Text of Methods....

Results.

In the patient described here, but not in 28 others with inflammatory myopathies, myriad γ/δ T cells surrounded and invaded nonnecrotic muscle fibers. All muscle fibers were highly reactive for MHC Class I antigen and the 65-kd heat-shock protein. Treatment with prednisone improved the clinical and histologie findings.

Full Text of Results....

Conclusions.

Polymyositis can be mediated by γ/δ T cells. This new form of polymyositis appears to be highly responsive to steroids. (N Engl J Med 1991; 324:877–81.)

Full Text of Conclusions....

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Media in This Article

Figure 1Biopsy Specimen of the Left Triceps Muscle Obtained in April 1988 (Hematoxylin and Eosin, ×220).

Figure 2Paired Localization of the T-Cell Receptor δ1 Antigen with Red (Rhodamine) Immunofluorescence and of the CD8 Antigen with Green (Fluorescein Isothiocyanate) Immunofluorescence (×350).

Article Activity

49 articles have cited this article

Article

AHISTOLOGIC hallmark of polymyositis and inclusion-body myositis is the invasion of nonnecrotic muscle fibers by autoaggressive CD8+ cytotoxic T cells.1 The vast majority of CD8+ cells use the common α/β T-cell receptor for the recognition of antigen.2 , 3 Recently, a second type of T cell, which expresses a γ/δ but not the α/β T-cell receptor, has been discovered.4 , 5

The physiologic and potentially pathologic role of γ/δ T cells is still a mystery.6 7 8 They represent about 5 percent of all T cells in blood and lymphoid organs.9 , 10 The majority of γ/δ T cells are CD3+, CD4—, and CD8—.4 , 5 They may accumulate in cutaneous granulomas in leprosy and leishmaniasis11 and in synovial fluid in rheumatoid arthritis.12 Some γ/δ T cells recognize heat-shock proteins expressed by mycobacteria and stressed mammalian cells.13 , 14 Heat-shock proteins, a highly conserved group of proteins, can be found in all organisms. The expression of these proteins is enhanced in response to various forms of stress, including heat, irradiation, viral infection, anoxia, and various chemical agents.15 Theoretically, γ/δ T cells reacting against heat-shock proteins could participate in autoimmune reactions.8 , 15 , 16

The γ/δ T cells have a cytotoxic potential in vitro.4 , 5 Therefore, they could mediate the destruction of cells recognized by the γ/δ T-cell receptor. The cytotoxic activity of the γ/δ T cells could be restricted by major histocompatibility complex (MHC) Class I molecules, Class II molecules (a less likely possibility), or different but MHC-related molecules, such as CD1.5 , 8 , 17 18 19

We describe an inflammatory muscle disease clinically resembling pure polymyositis and highly responsive to prednisone that was mediated by CD4—, CD8— T cells expressing the γ/δ receptor. The pathological features were dominated by cell-mediated destruction of muscle fibers. All muscle fibers were highly reactive on tests for MHC Class I antigens and the 65-kd heat-shock protein, but not for CD1. Mycobacteria or intracellular parasites could not be implicated in the pathogenesis. The findings provide evidence of immunologic and etiologic heterogeneity of the "idiopathic" inflammatory muscle diseases.

Case Report

A 69-year-old man began to have difficulty climbing stairs and doing push-ups and had had several falls since the age of 65. In 1988, at the age of 67, he had mild weakness involving the cervical and proximal limb muscles. The deep-tendon reflexes were hypoactive. Vibration sense was slightly diminished in the feet. The electromyographic findings were consistent with a chronic inflammatory myopathy. The serum creatine kinase level was eight times the upper limit of normal. serologic tests for human immunodeficiency virus, human T-cell lymphotropic virus Type I, Lyme disease, and connective-tissue disease were negative. A biopsy specimen of the left triceps muscle, obtained in April 1988, demonstrated an active inflammatory myopathy with a massive mononuclear inflammatory infiltrate throughout the endomysium and at perivascular sites (Fig. 1Figure 1Biopsy Specimen of the Left Triceps Muscle Obtained in April 1988 (Hematoxylin and Eosin, ×220).). Stains for acid-fast organisms were negative.

Treatment was begun with 60 mg of prednisone per day, and the muscle weakness and creatine kinase elevation resolved over a period of two months. Over the next eight months the dose of prednisone was tapered to 7.5 mg on alternate days, leading to a reelevation of the serum creatine kinase level to three times normal; however, the patient noticed only minimal muscle weakness. Subsequent treatment with 20 to 30 mg of prednisone per day alternating with 5 mg per day resulted in a decrease in serum creatine kinase levels to twice normal or less (normal to mildly elevated). In June 1990, the patient had only trace weakness of the scapular, pectoral, iliopsoas, and hamstring muscles. A biopsy of the left biceps femoris muscle showed only sparse inflammatory cells at a few endomysial and perimysial sites, rare necrotic and regenerating fibers, and mild atrophy of Type II fibers.

Methods

A cryostat was used to obtain 4-μm sections of muscle for single or paired immunofluorescence and immunoperoxidase studies. Table 1Table 1Antibodies Used in the Study.* lists the source, specificity, and concentration for tissue application of the antibodies employed in these studies.

The mouse monoclonal primary antibodies were detected by a biotin-labeled second antibody followed by treatment with either rhodamine—avidin or fluorescein isothiocyanate—avidin, or with peroxidase-labeled streptavidin followed by Karnovsky's diaminobenzidine medium. The rabbit polyclonal anti-CD3 primary antibody was detected with rhodamine-labeled goat antirabbit IgG. Counts of endomysial inflammatory cells of a given phenotype were obtained in five to nine randomly selected fields. The proportion of T cells accounted for by a given T-cell phenotype was evaluated in single sections by the paired immunofluorescence localization of the CD3 antigen with rabbit polyclonal anti-CD3, and of the CD4, the CD8, or a γ/δ T-cell antigen with a mouse monoclonal antibody. The total number of cells in a given field was determined by phasemicroscopical examination. Macrophages were identified in adjacent sections by their positive reaction for acid phosphatase. Isotype-matched IgG at identical concentrations was substituted for primary antibody for negative controls. Smears of peripheral-blood mononuclear cells and thymocytes were used as positive controls for antibodies against subsets of γ/δ T cells and CD1. Tissue samples used as controls included sections of muscle from patients with dermatomyositis, polymyositis, inclusion-body myositis, or granulomatous myopathies and from subjects without muscle disease. For electron microscopy, specimens were processed according to established methods.25

Results

In the first biopsy specimen, obtained before prednisone treatment, myriad endomysial mononuclear cells surrounded, invaded, and replaced many muscle fibers (Fig. 1). Close to 70 percent of all endomysial cells were CD2+, CD3+ T cells, and most of the autoaggressive cells invading the muscle fibers were δ1+ T cells (Fig. 2Figure 2Paired Localization of the T-Cell Receptor δ1 Antigen with Red (Rhodamine) Immunofluorescence and of the CD8 Antigen with Green (Fluorescein Isothiocyanate) Immunofluorescence (×350). and 3Figure 3Paired Immunolocalization of the CD3 Antigen with Red (Rhodamine) Immunofluorescence and of the T-Cell Receptor δ1 Antigen with Green (Fluorescein Isothiocyanate) Fluorescence (×350).). The invading cells also included CD8+ T cells and macrophages, but these were less common than the δ1+ T cells. The δ1+ T cells and CD8+ T cells accounted for 54 percent and 29 percent of all endomysial T cells, respectively. The remaining T cells were CD4+. All δ1+ T cells were CD4—, CD8—. Macrophages accounted for about 14 percent and B cells for about 9 percent of all endomysial inflammatory cells. The B cells were either diffusely scattered among other cells or concentrated in small nodules (not shown).

The γ/δ T cells in muscle did not react with the monoclonal antibodies BB3, T_iγA, or A13. These antibodies define the major subsets of γ/δ T cells normally present in peripheral blood.26 The proportion of γ/δ T cells in blood was determined repeatedly before and during prednisone treatment and remained constant at about 10 percent of all mononuclear cells. Ninety percent of the γ/δ cells in blood had the phenotype δ1+BB3+T_iγA+.

The expression of MHC Class I antigen was markedly increased on the surfaces and intermyofibrillar components of all muscle fibers, and all inflammatory cells were positive for this antigen. Essentially all muscle fibers showed intense surface reactivity and frequently intermyofibrillar and subsarcolemmal reactivity with a monoclonal antibody against the 65-kd heat-shock protein (Fig. 4Figure 4Immunoperoxidase Localization of the Antigen to 65-kd Heat-Shock Protein in the Biopsy Specimen Shown in Figure 1 (Light Hematoxylin Counterstain, ×220).). Some of the inflammatory cells, capillary endothelial cells, and the mural elements of larger blood vessels also reacted with this antibody. In muscle specimens from normal subjects, blood vessels but not muscle fibers expressed heat-shock protein. The MHC-related CD1 antigens were not expressed by muscle fibers or inflammatory cells.

The ultrastructural features of the cell-mediated destruction of muscle fibers in this case were like those previously described in inclusion-body myositis or polymyositis.27 In the early stages of muscle-fiber destruction, the invading cells were positioned beneath the basement membrane of the muscle fiber and sent spikelike projections into the fiber (Fig. 5Figure 5Electron Micrograph of Early Muscle-Fiber Invasion.). As increasing numbers of cells traversed the basal lamina, the muscle fiber became honeycombed by the invading cells, which displaced, replaced, or compressed the fiber (Fig. 6Figure 6Electron Micrograph of Muscle Fiber Honeycombed by Numerous Projections (Arrows) Arising from the Autoaggressive Cells Positioned above the Fiber.).

In the second biopsy specimen, taken after prednisone treatment, about 70 percent of the sparse inflammatory cells were accounted for by T cells; of these, 9 percent were δ1+, 70 percent CD8+, and 21 percent CD4+. The expression of MHC Class I antigen was still increased on the surfaces of all muscle fibers, but only the fibers invaded by mononuclear cells, regenerating fibers, and a few other fibers showed surface and sometimes cytoplasmic reactivity for the 65-kd heat-shock protein.

To assess the frequency of γ/δ T cells in muscle in other cases, we examined 28 control specimens (5 from patients with granulomatous myopathy, 6 from patients with dermatomyositis, 8 from patients with polymyositis, and 9 from patients with inclusion-body myositis). Substantial numbers of δ1+ T cells were detected in only four biopsy specimens (one sample of granulomatous myopathy, 6 percent; one sample of polymyositis, 2.5 percent; and two samples of inclusion-body myositis, 6.9 and 5.3 percent); very few δ1+ T cells were noted among T cells surrounding and invading nonnecrotic muscle fibers.

The expression of heat-shock protein was studied in 25 control muscle specimens (5 from patients with granulomatous myopathy, 6 from patients with dermatomyositis, 6 from patients with polymyositis, 6 from patients with inclusion-body myositis, and 2 from subjects without muscle disease). In all control specimens, immunostaining was detected on capillary endothelial cells and mural elements of larger vessels. In all specimens from patients with inflammatory myopathies, immunostaining was detected on some of the inflammatory cells and on regenerating fibers. In the specimens from patients with inclusion-body myositis and polymyositis, marked surface immunoreactivity and frequently cytoplasmic immunoreactivity were detected on nonnecrotic muscle fibers invaded by mononuclear cells. In specimens from patients with dermatomyositis, the abnormal fibers positioned at the periphery of the fascicles displayed strong cytoplasmic and surface immunoreactivity.

Discussion

The case reported here demonstrates that autoaggressive γ/δ T cells can attack muscle fibers in polymyositis. This case provided us with the opportunity to study cytotoxic γ/δ T cells and their muscle-fiber targets using immunocytochemical techniques in situ.

Very little is known about the physiologic and pathologic role of γ/δ T cells. In vitro studies have shown that γ/δ T cells have cytotoxic potential.4 , 5 Our observation that γ/δ T cells, like CD8+ cytotoxic T cells, actively invaded nonnecrotic muscle fibers in vivo is consistent with the in vitro observations. At the ultrastructural level, the membrane contacts between the γ/δ T cells and the sarcolemma closely resembled the membrane contacts between CD8+ cytotoxic T cells and sarcolemma described previously.27

Recent evidence indicates that some γ/δ T cells recognize highly conserved stress or heat-shock proteins.8 , 13 14 15 16 Heat-shock proteins can be expressed by parasites, bacteria (notably mycobacteria), and stressed mammalian cells.16 Furthermore, it has been proposed that γ/δ T cells recognizing autologous heat-shock proteins play an important part in autoimmunity.8 , 15 , 16 There was no indication of a local or systemic parasitic or mycobacterial infection in our patient. The prompt and sustained response to prednisone is additional evidence against an infectious cause. We therefore examined the expression of heat-shock protein in muscle. Intense surface expression of heat-shock protein was detected on essentially all muscle fibers. Although this would be consistent with the hypothesis that γ/δ T cells can recognize self determinants of heat-shock protein, the antigen specificity of the autoaggressive γ/δ T cells can only be established by functional studies. Furthermore, many muscle fibers that were intensely positive for heat-shock protein were not invaded by γ/δ T cells. Finally, in a number of tissue samples from controls with muscle diseases, heat-shock protein was expressed on muscle fibers even in the absence of endomysial γ/δ T cells. These observations demonstrate that the expression of heat-shock protein in and of itself is not a sufficient condition for a muscle fiber to become the target of γ/δ T cells. Furthermore, the pattern of expression of heat-shock protein in the various disorders closely resembled that of MHC Class I antigen expression.28

Recently, subsets of γ/δ T cells have been defined with several monoclonal antibodies against monomorphic and polymorphic determinants of the T-cell receptor γ and δ chains.26 The γ/δ T cells that we identified in muscle did not react with any of the monoclonal antibodies defining the major subsets of γ/δ T cells in peripheral blood. This indicates that the autoaggressive endomysial γ/δ T cells belonged to a specialized subpopulation of γ/δ T cells, which was not detectable in the patient's blood. A preference of subsets of γ/δ T cells for selected tissues has been noted previously in mice.5 , 8 , 15 , 18 , 19

The α/β T cells recognize antigenic peptides bound to "antigen-presenting" MHC molecules.2 , 3 It is not known whether γ/δ T cells also recognize antigens in association with antigen-presenting molecules, and if they do, whether the antigen-presenting molecules are classic MHC Class I or Class II molecules or distinct but MHC-related molecules, such as CD1.5 , 8 , 17 18 19 All muscle fibers were positive for MHC Class I antigen, but very few were positive for MHC Class II antigen (data not shown). There was no evidence of the expression of CD1a, CD1b, or CD1c. These findings seem inconsistent with the action of either MHC Class II or CD1 as the antigen-presenting molecules for the autoinvasive γ/δ T cells in this case. Furthermore, the expression on all muscle fibers of MHC Class I antigen does not prove that the γ/δ T cells are restricted by these antigens, because Daudi—Burkitt's lymphoma cells, which do not express MHC Class I, Class II, or other MHC-related molecules, can be killed by a major subset of γ/δ T cells recognizing the 60-kd heat-shock protein.29

In most of the control patients with polymyositis and inclusion-body myositis that we studied, γ/δ T cells were exceedingly rare. The case described here supports the concept that "idiopathic" polymyositis is a heterogeneous group of disorders. Further studies should help us define the full clinical spectrum and understand the pathogenesis of this new form of polymyositis.

Supported by a grant (NS-6277) from the National Institutes of Health and a Research Center grant from the Muscular Dystrophy Association. Dr. Hohlfeld was the recipient of a Heisenberg grant from the Deutsche Forschungsgemeinschaft.

We are grateful to Drs. J. Ivanyi, W. Knapp, T. Hercend, and L. Moretta for the generous gift of monoclonal antibodies.

Source Information

From the Neuromuscular Research Laboratory and Department of Neurology, Mayo Clinic and Mayo Foundation, Rochester, Minn. Address reprint requests to Dr. Engel at the Neuromuscular Research Laboratory, Guggenheim Bldg. 801, Mayo Clinic, Rochester, MN 55905.

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