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

Abstract

IntroductionInclusion 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). MethodsWe 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. ResultsBlood 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. ConclusionAltogether, these results suggest that T-LGL expansion occurring in IBM patients is correlated with exacerbated immune dysregulation and increased disease burden.

Identification of distinct immune signatures in inclusion body myositis by peripheral blood immunophenotyping using machine learning models

“…Recently, the presence of CD8 + large granular lymphocytes (LGLs) has been revealed in the blood and muscle of approximately 34–58% of IBM patients. 34 , 35 In line with these findings, cluster 3 further substantiates the importance of these late‐differentiated T cells in IBM. Notably, patients in this cluster also possess an abundance of CD4 + and gamma‐delta (Vδ1 and Vδ2) T cells exhibiting high expression levels of CD57.…”

Inclusion body myositis, viral infections, and TDP-43: a narrative review

“…In most such cases, the virally induced senescent, IFN-ƴ producing cytotoxic CD8+ T cells are the ones involved in IBM, in a genetically predisposed host. Immunophenotyping IBM patients to identify elevated CD8+ CD57+ populations may help stratify patients with prognostic and possibly therapeutic implications [ 84 ]. Identifying pathogenic mechanisms may lead to the identification of potential new treatments or to drug repurposing to improve the outcome in this debilitating disease.…”

“…Moreover, in some IBM patients, there is an increased population of large granular T lymphocytes (T-LGL) characterized by augmented expression of surface molecules KLRG1 and CD57 [ 1 ]. The expanded T-LGL in IBM are rather secondary, “reactive,” with a senescent-like profile, associated with inhibitory NK cell receptors and increased inflammatory and cytotoxic features [ 84 ]. Of interest, HIV-1 infection is also a risk factor for the evolution of clonal T-LGL disorders [ 85 ].…”

“…Surprisingly, HLA DRB1*13 is neuroprotective, along with apoE, against age-related brain changes [ 96 ]. HLA-C*14:02:01 allele was higher in IBM patients with high LGL T cell expression [ 84 ]. HLA-C*14:02 allele was also associated with a T cell response in HIV-1 infection, which was nevertheless non-protective for the viral infection [ 97 ].…”

“…Alemtuzumab (against CD52), natalizumab, anti-TNF alpha such as infliximab or etanercept, or IL-1 inhibitors as anakinra and canakinumab showed modest or no improvement [ 105 ], Rapamycin (sirolimus) targets mTOR important in IL-2 immune responses and protein metabolism (NCT04789070) [ 105 ]. Novel therapeutic avenues involve anti-KLRG1 antibodies, targeting a surface marker of the highly differentiated CD8T cells (NCT04659031) [ 84 , 105 ]. Moreover, in HIV, the KLRG1 expression on NK cells correlates with HIV transcription, and targeting KLRG1 on NK cells potentially aids in elimination of HIV-infected cells [ 106 ].…”