Immunohistochemical analysis of perforin and granzyme A in inflammatory myopathies

Orimo, Satoshi; Koga, Ritsuko; Goto, Kanako; Nakamura, Koichiro; Arai, Masanobu; Tamaki, Mikio; Sugita, Hideo; Nonaka, Ikuya; Arahata, Kiichi

doi:10.1016/0960-8966(94)90022-1

Cited by 52 publications

(36 citation statements)

References 32 publications

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“…Previous immunohistochemical data on perforin expression in inflammatory myopathies differ from our results (26). Using a mAb raised against an amino-terminal synthetic peptide of perforin, the authors observed faint immunoreactivity in about 10% of endomysial CD8ϩ T cells in PM, but found only very few immunoreactive T cells in DM (26).…”

Section: Discussioncontrasting

confidence: 54%

“…Using a mAb raised against an amino-terminal synthetic peptide of perforin, the authors observed faint immunoreactivity in about 10% of endomysial CD8ϩ T cells in PM, but found only very few immunoreactive T cells in DM (26). In contrast, our immunohistochemical data were obtained with a mAb raised against recombinant perforin and were corroborated by PCR, confirming perforin expression both in PM and DM.…”

Section: Discussioncontrasting

confidence: 54%

See 1 more Smart Citation

Differential expression of perforin in muscle-infiltrating T cells in polymyositis and dermatomyositis.

Goebels

Michaelis²,

Engelhardt³

et al. 1996

J. Clin. Invest.

239

137

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Polymyositis (PM) and dermatomyositis (DM) are the prototypical inflammatory diseases of skeletal muscle. In PM, CD8 ϩ T cells invade and destroy muscle fibers, whereas humoral effector mechanisms prevail in DM. We studied the expression of the cytotoxic mediator perforin in inflammatory cells in PM and DM muscle by semiquantitative PCR, immunohistochemistry and confocal laser microscopy. Similar levels of perforin mRNA were expressed in PM and DM, and abundant perforin-expressing CD3 ϩ CD8 ϩ and CD3 ϩ CD4 ϩ T cells were observed in both diseases. However, there was a striking difference in the intracellular localization of perforin. In DM, perforin was distributed randomly in the cytoplasm of the inflammatory T cells. In contrast, 43% of the CD8 ϩ T cells that contacted a muscle fiber in PM showed perforin located vectorially towards the target muscle fiber. The results suggest ( a ) that the random distribution of perforin in the cytoplasm of muscle-infiltrating T cells observed in DM reflects nonspecific activation, and ( b ) that the vectorial orientation observed only in PM reflects the specific recognition via the T cell receptor of an antigen on the muscle fiber surface, pointing to a perforin-and secretion-dependent mechanism of muscle fiber injury. ( J. Clin. Invest. 1996. 97:2905-2910.)

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Section: Discussioncontrasting

confidence: 54%

Section: Discussioncontrasting

confidence: 54%

Differential expression of perforin in muscle-infiltrating T cells in polymyositis and dermatomyositis.

Goebels

Michaelis²,

Engelhardt³

et al. 1996

J. Clin. Invest.

239

137

View full text Add to dashboard Cite

show abstract

“…The infiltrating CD8 T cells express activation markers such as CD45RO and ICAM-1, whereas the invaded myocytes overexpress HLA class I molecules on their cell surface (2)(3)(4). In addition, these CD8 T cells express cytotoxic effector molecules including perforin and granzyme B (5,6). Furthermore, it has been found that the perforin molecules in the CD8 T cells are oriented toward the target muscle fibers (7).…”

Section: P Olymyositis (Pm)mentioning

confidence: 99%

Clonal Biases of Peripheral CD8 T Cell Repertoire Directly Reflect Local Inflammation in Polymyositis

Nishio

Suzuki

Miyasaka

et al. 2001

The Journal of Immunology

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Polymyositis (PM) involves destruction of striated muscles by autoaggressive CD8 T cells, which accumulate and secrete cytotoxic effector molecules in the affected muscles. Previous studies of peripheral T cell repertoires from normal individuals and patients with viral infections have shown that primed CD8 T cells, unlike CD4 T cells, are prone to expand clonally and persist as large populations in the peripheral blood. These facts made us assume that autoaggressive myocytotoxic CD8 T cells would expand clonally in the peripheral blood from patients with PM. By clonal analyses of peripheral T cells from patients and age-matched controls, we show here that clonal expansion of CD8 T cells was more frequent in patients. This was not significant in CD4 T cells. In analogy to virus-specific T cells, the expanded T cells persisted as large populations over time. Analysis of the muscle biopsy specimens revealed that some of the expanded clones were infiltrating in the affected muscles from the same patients. These results provide the first evidence that local autoimmune reaction directly elicits significant biases in peripheral T cell repertoire. The expanded cells, which should be candidate autoaggressive T cells, were readily isolated from the peripheral blood for analysis of expressed genes including perforin. Thus, our findings should give us an immediate clue to analysis of the pathogenic T cells in PM.

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“…Although macrophages constitute only a minor fraction of the mononuclear infiltrates invading nonnecrotic muscle fibers, they account for up to 80% of the infiltrates surrounding necrotic fibers 44. Distinct from DM but consistent with lymphocytic infiltrates observed in PM, muscle‐invading CD8 + T cells stain positive for pore‐forming and cytolytic molecules such as perforin, granzyme A, and granulysin 46, 47, 48. It has been demonstrated that perforin‐polarization within endomysial CD8 + T cells occurs toward target myofibers indicative of immunosynapse formation and arguing strongly for a possible recognition of specific antigens presented via MHC class I expressing myofibers 49.…”

Section: Pathomechanisms In Ibmmentioning

confidence: 86%

Immune and myodegenerative pathomechanisms in inclusion body myositis

Keller

Schmidt

Lünemann

2017

Ann Clin Transl Neurol

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Inclusion Body Myositis (IBM) is a relatively common acquired inflammatory myopathy in patients above 50 years of age. Pathological hallmarks of IBM are intramyofiber protein inclusions and endomysial inflammation, indicating that both myodegenerative and inflammatory mechanisms contribute to its pathogenesis. Impaired protein degradation by the autophagic machinery, which regulates innate and adaptive immune responses, in skeletal muscle fibers has recently been identified as a potential key pathomechanism in IBM. Immunotherapies, which are successfully used for treating other inflammatory myopathies lack efficacy in IBM and so far no effective treatment is available. Thus, a better understanding of the mechanistic pathways underlying progressive muscle weakness and atrophy in IBM is crucial in identifying novel promising targets for therapeutic intervention. Here, we discuss recent insights into the pathomechanistic network of mutually dependent inflammatory and degenerative events during IBM.

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Immunohistochemical analysis of perforin and granzyme A in inflammatory myopathies

Cited by 52 publications

References 32 publications

Differential expression of perforin in muscle-infiltrating T cells in polymyositis and dermatomyositis.

Differential expression of perforin in muscle-infiltrating T cells in polymyositis and dermatomyositis.

Clonal Biases of Peripheral CD8 T Cell Repertoire Directly Reflect Local Inflammation in Polymyositis

Immune and myodegenerative pathomechanisms in inclusion body myositis

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