Reactivation of human herpesvirus 6 (HHV-6) infection in patients with connective tissue diseases
Introduction
Autoimmune connective tissue diseases (ACTD) encompass many diseases, including systemic sclerosis or scleroderma (SSc), systemic lupus erythematosus (SLE), discoid lupus erythematosus (DLE), dermatomyositis (DM), vasculitis and other conditions causing chronic inflammation that can affect many organs and systems. Although the etiologies of ACTD remain unclear, clinical, epidemiological, and laboratory findings suggest that several viral infections may be involved.1
Reactivation of human herpesvirus 6 (HHV-6), as suggested by the high rates of viral isolation, occurs frequently in patients with collagen vascular diseases.2 Moreover, Hoffmann and coauthors demonstrated active HHV-6 infection in a 37-year-old woman affected by SLE and histiocytic necrotizing lymphadenitis (Kikuchi-Fujimoto disease).3 More recently, HHV-7 replication has been documented in the salivary glands of patients with adult-onset Still disease.4 Beside these two reports, little is known about the involvement of HHV-6 and 7 in the pathogenesis of ACTD. In the present study the presence and burden of these two viruses in ACTD were investigated.
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Subjects and clinical samples
Blood and skin biopsies were obtained from 58 patients with ACTD recruited at the Section of Dermatology, University of Genoa. Their characteristics, details of their therapy, and disease activity are included in Table 1. Disease activity in patients with SLE, LED, DM were assessed using different validated clinical activity tests (SLEDAI, CLASI, DSSI) based on involvement of organs systems.5, 6, 7
Blood samples from 38 healthy subjects (HS) were included as the control group. The Medical
Detection and quantification of HHV-6 and HHV-7 DNA load in serum
HHV-6 viremia was detected in a significantly higher proportion of ACTD patients than in HS (26/58 [44.8%] vs. 1/38 [2.6%], p = 0.001; χ2 test). HHV-7 DNA was not detected in sera from any of the patients or HS controls (Table 2).
The detection rates of HHV-6 DNA in patients affected by SSc, DLE, SLE and DM were 70%, 40%, 45%, 25%, respectively (Fig. 1). The levels of HHV-6 DNA load were low in the majority of cases, ranging from 7 to 165 GEq/ml (Fig. 2), with the exception of 1 patient that had
Discussion
The measurement of HHV-6 and HHV-7 in serum combined with measurement of the latently infected PBMC proved that HHV-6, but not HHV-7, is actively replicating in patients affected by ACTD. This is shown by the significantly higher percentage of HHV-6 DNA detected in sera from patients with ACTD, which is an accurate marker of active HHV-6 infection.13, 14 The measurement of HHV-6 in serum is not sufficient to prove that the viral DNA detected is not derived from passive lysis of latently
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Cited by (36)
Insights into the knowledge of complex diseases: Environmental infectious/toxic agents as potential etiopathogenetic factors of systemic sclerosis
2021, Journal of AutoimmunityCitation Excerpt :Originally classified as lymphotropic viruses, the in vivo tropism of both species is considerably broader, including T-lymphocytes, macrophages, natural killer (NK) cells, endothelial cells, neurons, epithelial cells, thyrocytes, and endometrial cells [76,77,79–84]. After primary infection, causing exanthema subitum when sustained by HHV-6B infection [85], both viruses establish latent infection [86–89], and can reactivate symptomatically in the susceptible host, where reactivation has been associated to several autoimmune diseases, including systemic sclerosis [82,90–100]. Notably, HHV-6 was found to infect endothelial cells in vivo and in vitro [75], causing loss of their angiogenetic ability [76].
Human Herpesviruses 6 and 7 (Roseola, Exanthem Subitum)
2018, Principles and Practice of Pediatric Infectious DiseasesPrevalence of HHV-8 in systemic autoimmune diseases
2015, Journal of Clinical VirologyCitation Excerpt :Nevertheless, whether EBV is the direct cause or just a consequence (i.e. reactivation) of the underlying immunological status of these individuals remains to be elucidated. Other herpesviruses have also been extensively studied in order to discern whether they could play a central role for the development of SAD [8,9]. Human Herpesvirus 8 (HHV-8), though, seems to be the virus toward which researchers working on SAD have paid less attention.
HHV-6A and HHV-6B in Autoimmune Disease
2014, Human Herpesviruses HHV-6A, HHV-6B, and HHV-7, Third EditionDetection of human herpesviruses (HHVs) DNA in blood samples: A true marker of fever of unknown origin (FUO)?
2014, Journal of Clinical VirologyOccupational trichloroethylene hypersensitivity syndrome: Human herpesvirus 6 reactivation and rash phenotypes
2013, Journal of Dermatological ScienceCitation Excerpt :Especially, blood samples taken within 5 days after the disease occurrence were not available, which made it difficult to discuss a causal relationship between the HHV6 reactivation and the increased cytokines, and which type of cytokine secretion, T-helper 1 (Th1) type (TNF-α and IFN-γ) or Th2 type (IL-5 and IL-10), was dominant at the beginning of the disease. Another possible question is whether or not the copy number of HHV6 DNA in PBMC is an accurate marker of the reactivation compared to the number in sera [36,37]. The complete HHV6 genome integrated into the host germline genome can be observed in less than 1% of populations, which is known as chromosomally integrated HHV6 [38].
- 1
Present address: Laboratory of Immunoregulation, NIAID, NIH, Bethesda, Maryland.
- 2
These authors equally contributed to this work.