020 – ADAPTIVE NATURAL KILLER CELLS IN MULTIPLE SCLEROSIS
Bernat Bertran Recasens (1) – Antia Moreira (2) – Jose-Enrique Martinez-Rodriguez (2)
Hospital del Mar, Neurology Department, Barcelona, Spain (1) – Neurology Department, Hospital del Mar Medical Research Institute (IMIM), Neurology Department, Barcelona, Spain (2)
Background: Multiple Sclerosis (MS) is an immune-mediated disease of the central nervous system with a role of herpesvirus in its pathogenesis. Whereas Epstein-Barr virus (EBV) is consistently related to MS based on seroepidemiological studies, human cytomegalovirus (HCMV) has been recently associated with lower disease susceptibility. HCMV has been reported to induce a persistent adaptive reconfiguration of natural killer (NK) cells, lymphocytes with immunoregulatory properties involved in MS immunophatology.
Objective: To evaluate the immunophenotype and function of adaptive NK cells in MS patients according to HCMV serostatus and clinical characteristics.
Methods: A cross sectional study of MS patients (n=86) and controls (n=26) was performed analysing adaptive NK cell markers (NKG2C, FcR_ and PLZF) by flow cytometry, evaluating their co-expression by multidimensional t-SNE analysis. Antibody-dependent cell activation (degranulation measured by CD107 expression, and TNF-_ production) was studied evaluating NK cell response to the HLA class I-defective 721.221 cell line in the presence of rituximab.
Results: HCMV seropositivity was associated with an NKG2C(+) FcR_(-) PLZF(-) phenotype in CD56dim NK cells both in control and MS patients, observing a higher PLZF loss in HCMV(-) MS patients as compared to controls. A multidimensional analysis showed a HCMV-related expression of NKG2C, more pronounced in controls than in MS patients, contrasting with an increased numbers of NKG2C(-) FcR_(-) PLZF(-) NK cells in MS patients. In functional experiments, CD56dim NK cells from MS patients and controls did not differ in antibody-depending cell functions. However, significant differences were found according to MS form, with a higher degranulation capability in relapsing-remitting MS and lower TNF_ secretion in primary-progressive MS. A positive correlation was found between proportions of adaptive markers and NK cell activation in controls, whereas a higher PLZF and FcRy downregulation inversely correlated with degranulation in MS patients.
Conclusions: Adaptive features of NK cells in MS patients are characterized by higher FcR_ and PLZF downregulation and less effectiveness in antibody-dependent NK cell functions as compared to controls, with additional differences according to clinical form that could provide further insights on the putative implication of NK cells in MS.