Exosomes From Subjects With Multiple Sclerosis Express EBV-Derived Proteins and Activate Monocyte-Derived Macrophages

Abstract

ObjectiveTo investigate in a cross-sectional study the effect of serum-derived exosomes on primary human blood monocyte-derived macrophages (MDMs) comparing exosomes from healthy donors vs patients with relapsing-remitting multiple sclerosis in remission and in relapse and to assess whether the response correlates with exosomal Epstein-Barr virus (EBV) protein expression.MethodsA total of 45 serum-derived exosome preparations were isolated from patients and healthy controls and verified for the expression of exosomal and EBV markers. MDMs were differentiated from monocytes for 7 days and incubated for 24 hours with exosomes, and then, cell supernatants were collected for cytokine measurement by cytometric bead array. Cells were immunophenotyped before and after differentiation.ResultsSerum-derived exosomes of patients with multiple sclerosis (MS) expressed higher levels of EBV proteins than healthy controls. Of interest, expression of EBV nuclear antigen EBNA1 and latent membrane proteins LMP1 and 2A was higher on exosomes derived from patients with active RRMS compared with healthy controls and stable patients. After data normalization, we observed that incubation with EBV(+) exosomes induced CXCL10 and CCL2 secretion by MDMs. MDMs differentiated from patients with active disease were better secretors of CXCL10 and other interferon-γ–inducible chemokines, including CCL2 and CXCL9, than MDMs from healthy and stable MS groups. MDMs from active patients had a higher frequency of a CD14(++) subset that correlated with the secreted CXCL10.ConclusionExosomes expressing EBV proteins correlate with disease activity and induce an inflammatory response in MDMs that is compounded by the origin of the responder cells.

The Expression of Tax and HBZ Genes in Serum-Derived Extracellular Vesicles From HTLV-1 Carriers Correlates to Proviral Load and Inflammatory Markers

“…In naive PBMCs, the data suggest an increase in protein levels and transcription of IFN-γ after co-cultivation with EV tax+ HBZ+, though this is not statistical significant. Recent studies have shown that EVs are able to induce a pathogen-specific response in immune cells in studies regarding Salmonella typhimurium (Hui et al, 2021 ), human immunodeficiency virus (Sampey et al, 2016 ), hepatitis B virus (Kouwaki et al, 2016 ), and Epstein-Barr virus (Mrad et al, 2021 ).…”

Extracellular vesicles, the emerging mirrors of brain physiopathology

“…The results found in this study revealed that the expression of latent membrane proteins LMP1 and 2A and EBV nuclear antigen EBNA1 was higher on exosomes derived from patients with active MS compared with healthy controls and stable patients. Moreover, MDMs differentiated from patients with active disease were better secretors of CXCL10, CCL2 and CXCL9, than MDMs from healthy and stable MS groups (147). Thus, the authors suggest that EBV(+) exosomes could promote a proinflammatory response in MS patients by antigen-presenting cells and may contribute to ongoing immune activation.…”

Epstein-Barr Virus and Neurological Diseases

“…Monoclonal MBP-specific antibodies in MS patients interact with EBV encoded LMP1 to suppress CD4 + T cell activation, leading to elevated antibody concentrations against CTARs and the development of MS ( Lomakin et al, 2017 ). In addition, exosomes containing viral proteins (LMP1) from EBV-infected human oligodendrocyte lines were found to reduce MBP expression and promote demyelination ( Sampey et al, 2014 ; Wu et al, 2020 ; Mrad et al, 2021 ). EBV-encoded membrane protein LMP2A in B cells is abnormally sensitive to TLR9 activation.…”