Soluble CD27 a biomarker of T cell activity in intrathecal inflammation in patients with relapsing-remitting multiple sclerosis
ECTRIMS Online Library. Cencioni M. 09/13/19; 279549; 287
Maria Teresa Cencioni
Maria Teresa Cencioni
Contributions
Abstract

Abstract: 287

Type: Scientific Session

Abstract Category: Pathology and pathogenesis of MS - Biomarkers

M.T. Cencioni1, S. Yusuf2, I. Palmisano1, S. Boyeon Lee1, R. Ali1, N.D. Mazarakis1, R. Nicholas1, L. Costa_Frossard3, L.M. Villar Guimerans3, P.A. Muraro1

1Brain Sciences, Imperial College London, London, 2NDORMS, Kennedy Institute of Rheumatology, Oxford University, Oxford, United Kingdom, 3Immunology, Hospital Ramon y Cajal, Madrid, Spain

Background: An increasing number of disease modifying treatments are available for Multiple Sclerosis (MS) and patient stratification towards personalised therapy would be an important improvement over current treatment algorithms. MRI is routinely used as a biomarker of inflammatory disease but it is insensitive to the ongoing inflammation in the CNS, particularly of low grade inflammation occurring without blood-brain barrier disruption. Sensitive biomarkers of ongoing inflammatory activity in the CNS are lacking. Soluble CD27 (sCD27) has been demonstrated as being abnormally high in the cerebrospinal fluid (CSF) of patients with clinically isolated syndrome as well as in adult and paediatric MS and it is also associated with higher relapse frequency after diagnosis. The levels of sCD27 were found to correlate with the presence of oligoclonal bands (OCBs) and the IgG index.
Goal: We aimed to further investigate sCD27 levels in CSF and serum in respect of their association with MS diagnosis and clinical features. We attempted to elucidate the cellular origin and modelled, in vitro, the mechanism of CD27 release.
Methods: CSF samples were collected from 80 relapsing-remitting MS (RRMS) patients and 12 controls. Serum samples were obtained from 58 RR-MS patients and 9 controls.
Lymphocytes were isolated from peripheral blood of healthy donors and CD27 knockdown CD4 T cells were produced by lentiviral shRNA vectors. These cells were used for proliferation assays and activated for 24, 48 and 96 hrs and the supernatants were collected for further analysis.
ELISA and Meso Scale Discovery Scale were performed to quantify analytes in the CSF, serum and culture medium.
Results: We detected a significant increase of sCD27 in both CSF and serum of RR-MS patients compared to controls and an association with MS disease activity. We demonstrate that purified CD4+ and CD8+ T cells are the main source of sCD27; this is released upon cell activation. We also demonstrate that CD27 knockdown in CD4 T cells release less IFNg and show a reduced proliferation as compared to wild-type CD4+T cells.
Conclusions: Our results show that sCD27 is an indicator of T cell activation in the intrathecal compartment in RR-MS patients but that it is also detectable at increased levels in the serum suggestive of concomitant systemic activation. Our results also suggest a direct implication of CD27 in inflammatory T cell effector function which warrants further investigation.
Disclosure: Nicholas R: reports non-financial support from Roche, personal fees and non-financial support from Novartis, personal fees and non-financial support from Biogen, grants from UK MS Society, outside the submitted work;

Abstract: 287

Type: Scientific Session

Abstract Category: Pathology and pathogenesis of MS - Biomarkers

M.T. Cencioni1, S. Yusuf2, I. Palmisano1, S. Boyeon Lee1, R. Ali1, N.D. Mazarakis1, R. Nicholas1, L. Costa_Frossard3, L.M. Villar Guimerans3, P.A. Muraro1

1Brain Sciences, Imperial College London, London, 2NDORMS, Kennedy Institute of Rheumatology, Oxford University, Oxford, United Kingdom, 3Immunology, Hospital Ramon y Cajal, Madrid, Spain

Background: An increasing number of disease modifying treatments are available for Multiple Sclerosis (MS) and patient stratification towards personalised therapy would be an important improvement over current treatment algorithms. MRI is routinely used as a biomarker of inflammatory disease but it is insensitive to the ongoing inflammation in the CNS, particularly of low grade inflammation occurring without blood-brain barrier disruption. Sensitive biomarkers of ongoing inflammatory activity in the CNS are lacking. Soluble CD27 (sCD27) has been demonstrated as being abnormally high in the cerebrospinal fluid (CSF) of patients with clinically isolated syndrome as well as in adult and paediatric MS and it is also associated with higher relapse frequency after diagnosis. The levels of sCD27 were found to correlate with the presence of oligoclonal bands (OCBs) and the IgG index.
Goal: We aimed to further investigate sCD27 levels in CSF and serum in respect of their association with MS diagnosis and clinical features. We attempted to elucidate the cellular origin and modelled, in vitro, the mechanism of CD27 release.
Methods: CSF samples were collected from 80 relapsing-remitting MS (RRMS) patients and 12 controls. Serum samples were obtained from 58 RR-MS patients and 9 controls.
Lymphocytes were isolated from peripheral blood of healthy donors and CD27 knockdown CD4 T cells were produced by lentiviral shRNA vectors. These cells were used for proliferation assays and activated for 24, 48 and 96 hrs and the supernatants were collected for further analysis.
ELISA and Meso Scale Discovery Scale were performed to quantify analytes in the CSF, serum and culture medium.
Results: We detected a significant increase of sCD27 in both CSF and serum of RR-MS patients compared to controls and an association with MS disease activity. We demonstrate that purified CD4+ and CD8+ T cells are the main source of sCD27; this is released upon cell activation. We also demonstrate that CD27 knockdown in CD4 T cells release less IFNg and show a reduced proliferation as compared to wild-type CD4+T cells.
Conclusions: Our results show that sCD27 is an indicator of T cell activation in the intrathecal compartment in RR-MS patients but that it is also detectable at increased levels in the serum suggestive of concomitant systemic activation. Our results also suggest a direct implication of CD27 in inflammatory T cell effector function which warrants further investigation.
Disclosure: Nicholas R: reports non-financial support from Roche, personal fees and non-financial support from Novartis, personal fees and non-financial support from Biogen, grants from UK MS Society, outside the submitted work;

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