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Uncovering the significance of expanded CD8 + large granular lymphocytes in inclusion body myositis: Insights into T cell phenotype and functional alterations, and disease severity
Journal article   Open access   Peer reviewed

Uncovering the significance of expanded CD8 + large granular lymphocytes in inclusion body myositis: Insights into T cell phenotype and functional alterations, and disease severity

Emily McLeish, Anuradha Sooda, Nataliya Slater, Barbara Kachigunda, Kelly Beer, Shereen Paramalingam, Phillipa J Lamont, Abha Chopra, Frank Louis Mastaglia, Merrilee Needham, …
Frontiers in immunology, Vol.14, Art. 1153789
2023
DOI: https://doi.org/10.3389/fimmu.2023.1153789
PMID: 37063893
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Published8.53 MBDownloadView
CC BY V4.0,  Open Access

Abstract

CD8-Positive T-Lymphocytes Humans Leukemia, Large Granular Lymphocytic Muscle, Skeletal - metabolism Myositis, Inclusion Body - metabolism Patient Acuity Phenotype
Introduction: Inclusion body myositis (IBM) is a progressive inflammatory myopathy characterised by skeletal muscle infiltration and myofibre invasion by CD8+ T lymphocytes. In some cases, IBM has been reported to be associated with a systemic lymphoproliferative disorder of CD8+ T cells exhibiting a highly differentiated effector phenotype known as T cell Large Granular Lymphocytic Leukemia (T-LGLL). Methods: We investigated the incidence of a CD8+ T-LGL lymphoproliferative disorder in 85 IBM patients and an aged-matched group of 56 Healthy Controls (HC). Further, we analysed the phenotypical characteristics of the expanded T-LGLs and investigated whether their occurrence was associated with any particular HLA alleles or clinical characteristics. Results: Blood cell analysis by flow cytometry revealed expansion of T-LGLs in 34 of the 85 (40%) IBM patients. The T cell immunophenotype of T-LGLHIGH patients was characterised by increased expression of surface molecules including CD57 and KLRG1, and to a lesser extent of CD94 and CD56 predominantly in CD8+ T cells, although we also observed modest changes in CD4+ T cells and γδ T cells. Analysis of Ki67 in CD57+ KLRG1+ T cells revealed that only a small proportion of these cells was proliferating. Comparative analysis of CD8+ and CD4+ T cells isolated from matched blood and muscle samples donated by three patients indicated a consistent pattern of more pronounced alterations in muscles, although not significant due to small sample size. In the T-LGLHIGH patient group, we found increased frequencies of perforin-producing CD8+ and CD4+ T cells that were moderately correlated to combined CD57 and KLRG1 expression. Investigation of the HLA haplotypes of 75 IBM patients identified that carriage of the HLA-C*14:02:01 allele was significantly higher in T-LGLHIGH compared to T-LGLLOW individuals. Expansion of T-LGL was not significantly associated with seropositivity patient status for anti-cytosolic 5'-nucleotidase 1A autoantibodies. Clinically, the age at disease onset and disease duration were similar in the T-LGLHIGH and T-LGLLOW patient groups. However, metadata analysis of functional alterations indicated that patients with expanded T-LGL more frequently relied on mobility aids than T-LGLLOW patients indicating greater disease severity. Conclusion: Altogether, these results suggest that T-LGL expansion occurring in IBM patients is correlated with exacerbated immune dysregulation and increased disease burden.

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Collaboration types
Domestic collaboration
Citation topics
1 Clinical & Life Sciences
1.6 Immunology
1.6.1021 Natural Killer Cells
Web Of Science research areas
Immunology
ESI research areas
Immunology
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