Association between EBV serological patterns and lymphocytic profile of SjS patients support a virally triggered autoimmune epithelitis

Abstract

Sjögren's syndrome (SjS) is characterized by lymphocytic infiltration of exocrine glands, i.e. autoimmune epithelitis. Lymphocytes are central in SjS pathogenesis, with B-cell hyperactivity mediated by T-cells. B-cells are main targets of Epstein-Barr virus (EBV) infection, a frequently-suggested trigger for SjS. We aimed to evaluate how the EBV infection modulates B and T-cell subsets in SjS, including as controls Rheumatoid arthritis patients (RA) and healthy participants (HC). SjS patients presented decreased CXCR5+T-cells, although IL21-secreting Tfh and Tfc cells were increased. Tfc were positively correlated with ESSDAI scores, suggesting their relevant role in SjS pathogenesis. As previously described, SjS patients showed expanded circulating naïve B-cell compartments. SjS patients had a higher incidence of EBV-EA-D-IgG+ antibodies, characteristic of recent EBV-infection/reactivation. SjS patients with past infection or recent infection/reactivation showed increased CXCR3+Th1 and CXCR3+Tfh1 cells compared to those without active infection. SjS patients with a recent infection/reactivation profile presented increased transitional B-cells compared to patients with past infection and increased plasmablasts, compared to those without infection. Our results suggest EBV-infection contributes to B and T-cell differentiation towards the effector phenotypes typical of SjS. Local lymphocyte activation at ectopic germinal centres, mediated by Tfh and Tfc, can be EBV-driven, perpetuating autoimmune epithelitis, which leads to gland destruction in SjS.

Expression and regulatory characteristics of peripheral blood immune cells in primary Sjögren’s syndrome patients using single-cell transcriptomic

“…B cells are the main target of EBV infection, and EBV is one of the factors that induces pSS ( Maślińska, 2019 ). EBV infection contributes to the differentiation of B and T cells into the typical effector phenotypes observed in pSS patients ( Barcelos et al., 2021 ). There are several infectious agents that can cause disease manifestations similar to Sjogren’s syndrome, including hepatitis C virus, EBV, cytomegalovirus and HTLV-1, and these four pathogens have been found to cause persistent infection of the salivary glands after the first infection; this persistent infection subsequently leads to organ destruction and xerostomia syndrome ( Björk et al., 2020 ; Utomo and Putri, 2020 ).…”

Herpesviridae, Neurodegenerative Disorders and Autoimmune Diseases: What Is the Relationship between Them?

“…Then, it has been shown that EBV infection plays a role in B and T cell differentiation in an effector phenotype related to SS. Lymphocyte activation at ectopic germinal center, induced by follicular T helper and cytotoxic cells, and probably stimulated by EBV, might give rise to autoimmune epithelitis [ 229 ]. High levels of EBV DNA have been found in the salivary gland tissue and PBMCs of SS patients [ 230 ]; further, high levels of anti-EA have been found in SS patients [ 231 ].…”

The Meta-Analysis About The Expression and Prognosis of Anti-Ro-52, Anti-CENP-B and AMA in Sjogren's Syndrome and Systemic Sclerosis

“…In the past 20 years, nearly 14% of SS patients developed into malignant lymphomas. The mechanism of EBV infection-related SS patients may be related to excessive T cell costimulation, impaired speci c T cell response to EBV, cross-reaction of anti-EBV antibody, inhibition of B cell apoptosis, and other factors [49]. The detection rate of EB-DNA in salivary glands of anti-Ro-52(+) SS patients was signi cantly increased (78%), while the detection rate of EB-DNA in salivary glands of normal people was only 13% [50].…”