4 DISCUSSION
Infection, particularly viral infection, is a significant factor in the
development of angiitis, which is directly related to the occurrence and
development of angiitis. Our study using MR analysis revealed a clear
link between CLA and HHV-6, a member of the herpesvirus family. HHV-6
infection directly contributes to the development of CLA, while other
viruses such as EBV, HSV-1, HSV-2, varicella virus, zoster virus, and
CMV are not causally related to CLA.
Previous studies have indicated the association between HHV-6 and
leukocytoclastic angiitis, specifically CLA. Serology tests showed
positive HHV-6 IgG and IgM antibodies in patients with CLA, while tests
for other viruses were negative (19). Research shows
that over 90% of individuals are infected with HHV-6B during early
childhood, and the virus remains dormant in the body throughout their
lifetime. Thus, we believe that the occurrence of CLA should be related
to the primary infection or reactivation of HHV-6. However, subsequent
observational studies did not include HHV-6 infection as part of their
examinations. Additionally, around half of CLA cases do not have an
underlying cause (20, 21).
One of the possible mechanisms of CLA is the formation and deposition of
immune complexes in and around vessel walls (22).
Studies have shown a higher presence of IgA, IgM, and IgG in the
affected skin of CLA patients compared to unaffected skin(23). A comparative study also proposed that Helper T
cells and granzyme B may also play a role in the inflammatory process of
CLA (24). HHV-6 primarily infects CD4+T cells and
upregulates the expression of granzyme B in these cells, leading to
disruption of the body’s antiviral immunity and potentially contributing
to inflammation. It plays an important role in various inflammations. In
addition, HHV-6 infection induces the release of cytokines,like tumor
necrosis factor-alpha (TNF-α) and interleukin 1-β, which may further
contribute to inflammation and autoimmune
reactions(25). TNF- α can induce the expression of
protease-3 (PR3) and myeloperoxidase (MPO) on the cell membrane, leading
to angiitis (26). Further research is needed to
determine whether similar mechanisms exist in CLA.
Various studies have explored the connection between the herpesvirus
family and different types of angiitis. For example, EBV may be
associated with anti-neutrophil cytoplasmic antibody-associated angiitis
(AAV), Henoch-Schönlein purpura (HSP) and systemic vasculitis, varicella
zoster virus causes giant cell arteritis, Acute Retinal Necrosis (ARN)
and lgA angiitis, HSV infection is linked to cerebrovascular disease,
and CMV infection can cause skin necrotizing angiitis(4, 6, 27-31). However, our MR analysis did not find a
causal relationship between these viruses and CLA. It is important to
investigate the relationship between the herpesvirus family and
angiitis, including other forms of angiitis, through further research.
This study had several strengths, including the use of two-sample MR
analysis, which helps overcome limitations in conventional
epidemiological studies. Sensitivity analyses were conducted, and
consistent estimates from different models increased confidence in the
associations identified. However, there were also limitations to
consider. More genetic variations as IVs were for sensitivity analysis
and pleiotropy detection. The SNPs used in the analysis did not meet the
traditional GWAS significance threshold, but this was deemed acceptable(32). Additionally, the GWAS databases used were
limited to individuals of European ancestry, reducing the universality
of our results. Further studies should investigate whether our results
hold for other ancestries. Finally, the limited number of SNPs
associated with other viruses (HSV-1, HSV-2, CMV, Anti-EBV VCA IgG
levels, Anti-EBV EA IgG levels and Anti-EBV IgG seropositivity could
introduce weak instrument bias.