Address for correspondence:
Naim Mahroum MD
International School of Medicine, Istanbul Medipol University,
Kavacık, Göztepe Mah, Atatürk Cd. No:40, 34810 Beykoz, Istanbul, Turkey
E-MAIL: naim.mahroum@gmail.com
Tel: +90-216 681 51 00
Fax: +90-212 531 75 55
Dear Editor,
The relation between infectious agents, particularly viruses, with
autoimmunity and autoimmune diseases, has been extensively studied
during the last decades. Recently, the association was shown to be even
stronger during the pandemic of COVID-19, as the causative virus,
SARS-CoV-2 (severe acute respiratory syndrome corona virus 2) has been
linked to severe autoimmune sequela in infected individuals. The
concerned consequences in patients with COVID-19 were documented during
the acute viral infection, throughout the long recovery phase (so-called
post-COVID syndrome), as well as secondary to the vaccines of COVID-19
[1]. Actually, the autoimmune nature of SARS-CoV-2 has been vastly
reported in the medical literature and it is beyond the scope of our
current paper [2]. However, it shows the strong bond between
infection and autoimmunity. Subsequently, with a deep interest in the
field, we analyzed the article of Chang et al [3] concluding that
there is no correlation between herpes simplex viral infections and
systemic lupus erythematosus (SLE) in terms of causality using Mendelian
randomization.
In fact, SLE as a syndrome represents a spectrum of chronic systemic
autoimmune conditions affecting almost every organ system and
characterized by the production of a wide variety of autoantibodies. In
terms of etiology, or more precisely, triggers of the disease, various
infectious agents especially viruses were linked to the emergence of
SLE. We have previously shown, by a real-life bigdata analysis, a strong
and significant correlation between SLE and hepatitis C virus (HCV)
compared to controls [4]. Moreover, infections in general were found
in remarkable association with SLE besides increasing the mortality
rated in hospitalized patients with SLE [5]. When it comes to herpes
viruses and autoimmunity, the topic can be addressed in two main levels.
The first is related to the correlation between herpes viruses and
autoimmunity in general, whereas the second level concerns SLE and
herpes viruses.
Human Herpes Viruses (HHVs) are widely spread DNA viruses infecting high
proportion of the general population. The family is well known of
causing latent and active infection determined by the competency of the
immune system of the infected individual. Epstein–Barr virus (EBV) was
demonstrated to serve as a risk factor for developing multiple sclerosis
(MS) in certain age groups whilst Human Herpes Virus 6 (HHV-6), another
HHV, inferred a risk for the disease in all age groups [6]. In fact,
the mechanisms regarding the role of HHV-6 in MS has been considerably
investigated [7]. For instance, HHV-6 was found to provoke
autoimmunity through several mechanisms like its capability of lysing
infected cells, and hence exposing high amounts of cell antigens
presenting to the immune system. HHV-6 can also cause an irregular
expression of the histocompatibility molecules resulting in the
presentation of self-antigens. Another hypothesized mechanism by which
HHV-6 contributes to autoimmune diseases is through molecular mimicry
where viral proteins produced are similar, in various degrees, to
self-proteins. The latter results in cross-reactive T cells with the
ability of recognizing both viral and self-antigens.
Meanwhile, HHVs are responsible for a significant number of aspects in
SLE. In terms of susceptibility to developing SLE, both EBV and CMV
serve as important players in this regard [8]. Structural proteins
of the viruses were shown to modulate the risk of SLE in genetically
predisposed individuals. Interestingly, other members of the HHVs were
directly and indirectly linked to SLE including Herpes Simplex Virus
(HSV). In contrast to the findings presented by Chang et al [3];
Reis and colleagues illustrated a significant importance of both primary
and reactivation of HHVs in patients with SLE [9]. By enrolling 71
SLE patients classified into active and non-active disease, serum
samples were evaluated by PCR for the detection of HHVs including HSV-1
and HSV-2. Based on the results, the authors emphasized the need to
check for the presence of HSV-1 and HSV-2 in patients with SLE
presenting with atypical symptoms.
Having said that, we do agree that HSV-1 and HSV-2 are not as common as
other members of the HHVs, particularly EBV, in terms of etiology,
pathogenesis, and exacerbation of SLE. Nevertheless, their implication
in SLE should not be underestimated. This association comes to a greater
attention due to the critical importance of CNS infection in SLE, as it
carries a high mortality rate and constitutes a clinical challenge in
the differential diagnosis of SLE-related CNS disease (termed
neuropsychiatric lupus) [10]. While the latter is treated with high
doses of immunosuppression, the high mortality in the former could be
worse under immunosuppressive treatment.