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.