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Brain Advance Access published online on March 26, 2004
Brain, doi:10.1093/brain/awh148
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© 2004 The Guarantors of Brain

Article

Upregulated inducible co-stimulator (ICOS) and ICOS-ligand in inclusion body myositis muscle: significance for CD8+ T cell cytotoxicity

Jens Schmidt 1*, Goran Rakocevic 1, Raghavanpillai Raju 1, and Marinos C. Dalakas 1*

1 Neuromuscular Diseases Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA

* Corresponding author. E-mail: DalakasM{at}ninds.nih.gov.

Received 9 September 2003 ; revised 16 December 2003 ; accepted 27 January 2004

Abstract

Interactions between inducible co-stimulatory molecule (ICOS) and ICOS-ligand (ICOS-L) are crucial for T-cell co-stimulation, effector cell differentiation and memory CD8+ T-cell activation. Because in the muscle of patients with sporadic inclusion body myositis (sIBM) clonally expanded CD8+ T cells invade major histocompatibility complex (MHC) class I-expressing muscle fibres, we investigated ICOS·ICOS-L interactions and correlated their expression with perforin, a marker for cytotoxic effector function by autoinvasive CD8+ T cells. The mRNA from 20 muscle biopsies of sIBM, 20 non-inflammatory or dystrophic controls, two dermatomyositis (DM) and two polymyositis (PM) patients was reverse transcribed and reamplified by semi-quantitative and quantitative reverse transcription-polymerase chain reaction (RT-PCR), using primers for ICOS, ICOS-L and perforin. The glyceraldehyde 3-phosphate dehydrogenase (GAPDH)-normalized ratio of ICOS, ICOS-L and perforin expression was compared with the degree of endomysial inflammation. Protein expression of ICOS, ICOS-L and perforin was confirmed by immunohistochemistry. We demonstrate that ICOS-L mRNA was upregulated in sIBM (arbitrary units, median ± SEM: 48.6 ± 14.9) compared with controls (6.2 ± 17.8, P < 0.05) and significantly correlated with the expression of ICOS (53.9 ± 16.6 versus 6.7 ± 8.9 in controls, P < 0.001). By triple labelling immunohistochemistry, the CD8+ T cells in sIBM and PM were found to invade ICOS-L- and MHC class I-co-expressing muscle fibres. Among the autoinvasive CD8+ T cells, however, only a subset of ~5-10% were ICOS positive, and thereby perceptive for ICOS·ICOS-L signalling at the immunological synapse. In contrast, in Duchenne muscular dystrophy and DM, although ICOS and ICOS-L mRNA expression was also increased, the majority of ICOS-L- and ICOS-positive cells were in the perimysial regions and connective tissue. The mRNA for perforin was increased in sIBM (28.1 ± 8.7) compared with controls (4.3 ± 11.2, P = 0.18), and significantly correlated with mRNA of ICOS, ICOS-L and the degree of endomysial inflammation as assessed in coded haematoxylin/eosin tissue sections. By triple immunohistochemical staining and cell counting, perforin granules were found in 71% of the autoinvasive CD8+ T cells that were also ICOS positive. Our data indicate that in sIBM there is upregulation of ICOS·ICOS-L co-stimulatory signalling in association with enhanced perforin expression by the autoinvasive CD8+ T cells. The findings support previous suggestions that in IBM, the muscle fibres have the capacity for antigen presentation, thereby activating a specific subset among the autoinvasive CD8+ T cells to exert a cytotoxic effect. The observations strengthen the immunopathogenesis of sIBM, and offer the basis for future therapeutic interventions targeting ICOS·ICOS-L co-stimulatory interactions.

Keywords: inclusion body myositis; co-stimulation; autoimmunity; muscle inflammation; perforin
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