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Journal article
Uncovering the significance of expanded CD8 + large granular lymphocytes in inclusion body myositis: Insights into T cell phenotype and functional alterations, and disease severity
Frontiers in immunology, Vol.14, Art. 1153789
2023
PMID: 37063893
Abstract
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.
Details
- Title
- Uncovering the significance of expanded CD8 + large granular lymphocytes in inclusion body myositis: Insights into T cell phenotype and functional alterations, and disease severity
- Authors/Creators
- Emily McLeish - Murdoch UniversityAnuradha Sooda - Centre for Molecular Medicine and Innovative Therapeutics, Murdoch University, Murdoch, WA, AustraliaNataliya Slater - Murdoch UniversityBarbara Kachigunda - Murdoch University, Centre for Biosecurity and One HealthKelly Beer - Perron Institute for Neurological and Translational ScienceShereen Paramalingam - Fiona Stanley HospitalPhillipa J Lamont - Neurogenetic Unit, Department of Neurology, Royal Perth Hospital, Perth, WA, AustraliaAbha Chopra - Murdoch University, Centre for Molecular Medicine and Innovative TherapeuticsFrank Louis Mastaglia - Perron Institute for Neurological and Translational ScienceMerrilee Needham - Fiona Stanley HospitalJerome David Coudert - University of Notre Dame
- Publication Details
- Frontiers in immunology, Vol.14, Art. 1153789
- Publisher
- Frontiers Media SA
- Identifiers
- 991005571669907891
- Copyright
- © 2023 McLeish et al.
- Murdoch Affiliation
- Centre for Molecular Medicine and Innovative Therapeutics; Institute for Immunology and Infectious Diseases
- Language
- English
- Resource Type
- Journal article
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- 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