A Paradigmatic Interplay between Human Cytomegalovirus and Host Immune System: Possible Involvement of Viral Antigen-Driven CD8+ T Cell Responses in Systemic Sclerosis.

Maria-Cristina Arcangeletti,Dilia Giuggioli,Gianluca Sighinolfi,Adriana Calderaro,Clodoveo Ferri,Flora De Conto,Clara Maccari,Rosanna Vescovini,Carlo Chezzi,Riccardo Volpi

doi:10.3390/v10090508

Maria-Cristina Arcangeletti, Dilia Giuggioli + Show 8 more

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https://doi.org/10.3390/v10090508

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Abstract

Human cytomegalovirus (HCMV) is a highly prevalent opportunistic agent in the world population, which persists as a latent virus after a primary infection. Besides the well-established role of this agent causing severe diseases in immunocompromised individuals, more recently, HCMV has been evoked as a possible factor contributing to the pathogenesis of autoimmune diseases such as systemic sclerosis (SSc). The interplay between HCMV and immune surveillance is supposed to become unbalanced in SSc patients with expanded anti-HCMV immune responses, which are likely involved in the exacerbation of inflammatory processes. In this study, blood samples from a cohort of SSc patients vs. healthy subjects were tested for anti-HCMV immune responses (IgM, IgG antibodies, and T cells to peptide pools spanning the most immunogenic HCMV proteins). Statistically significant increase of HCMV-specific CD8+ T cell responses in SSc patients vs. healthy subjects was observed. Moreover, significantly greater HCMV-specific CD8+ T cell responses were found in SSc patients with a longer disease duration and those with higher modified Rodnan skin scores. Given the known importance of T cells in the development of SSc and that this virus may contribute to chronic inflammatory diseases, these data support a relevant role of HCMV-specific CD8+ T cell responses in SSc pathogenesis.

Highlights

Systemic sclerosis (SSc) is an autoimmune disease characterized by immunological abnormalities, vasculopathy, and excessive extracellular matrix deposition, which leads to fibrosis of the skin and internal organs [1,2,3,4,5,6]
It has been shown that an increased IL-13 production by peripheral blood CD8+ T cells homing to the skin of systemic sclerosis (SSc) patients correlates with the extent of skin fibrosis, which is a typical feature of this autoimmune disease [23,24]
Viruses that persist in the infected subject after primary infection such as Human cytomegalovirus (HCMV), Epstein-Barr virus (EBV), and parvovirus B19 [28,29] have been proposed as possible triggering or worsening factors of SSc

Summary

Introduction

Systemic sclerosis (SSc) is an autoimmune disease characterized by immunological (both humoral and cellular) abnormalities, vasculopathy, and excessive extracellular matrix deposition, which leads to fibrosis of the skin and internal organs [1,2,3,4,5,6]. An increasing body of evidence highlights a critical role for T cell responses in the pathogenesis of systemic sclerosis (SSc), which contributes to fibrosis modulation and vascular damage [8,9,10,11,12]. Recent studies highlight a predominant role of CD8+ T cell infiltrates with a typical CD28− phenotype in the lesional skin of SSc patients already in the early stages of the disease [2,22]. It has been shown that an increased IL-13 production by peripheral blood CD8+ T cells homing to the skin of SSc patients correlates with the extent of skin fibrosis, which is a typical feature of this autoimmune disease [23,24]. Other interesting observations rely on the fact that CD8+ T cells found in peripheral blood of patients with SSc present an antigen-driven oligoclonal expansion even though antigen specificity is not yet known [8,25,26,27]

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