Silica is one of the most abundant minerals on earth, and exposure to silica dust has been identified as a risk factor for many SARDs, including SS, RA, SLE, and AAV. Individuals working in agriculture, mills, drilling, painting, and textiles have been identified to have a greater risk of developing AAV disease. Multiple case reports have shown that continuous exposure to silica increases the risk of positive ANCA. Several studies have described cases of silica exposure and AAV. A 74-year-old patient with AAV developed fever and malaise after prolonged exposure to silica. Main and Wroe described three cases of silica-exposed patients with AAV, two of whom still required dialysis after treatment. Analysis of the occupational histories of 16 patients with AAV revealed that patients with vasculitis were more likely to be exposed to silica than controls. Previous surveys on post-earthquake disease prevalence, such as the Kobe earthquake in Japan, the Great East Japan earthquake, and the Yunnan earthquake in China, showed that the incidence of AAV was higher than before. The change was attributed to the harmful effects of air pollution on the human body due to increased atmospheric levels of silica from the earthquake. Studies have confirmed the dose-related effects of silica exposure. A meta-analysis showed that silica exposure was positively associated with AAV. A case-control study suggested a 3.4-fold increased risk of ANCA serology positivity in individuals with occupational silica exposure. Only a few studies have proposed a relationship between sustained exposure to silica and AAV. However, research on the relationship between sustained exposure to silica and severity of AAV remains inadequate.
The mechanism by which silica causes AAV is unclear. A previous study found that silica does not have a direct toxic effect on genetically susceptible individuals but rather enhances the immune response non-specifically, activates T cells and Treg cells, and leads to autoimmune dysfunction ( Figure 1 ). With continued exposure to crystalline silica, the body produces inflammatory cytokines, including interleukin-1(IL-1) and tumor necrosis factor-beta (TNF-beta), leading to inflammation and eventual fibrosis. Silica can induce apoptosis of neutrophils, macrophages, and monocytes, and damaged cells release many proteolytic enzymes, leading to chronic inflammation and tissue fibrosis. Another study suggested that silica can induce the expression of MPO in the cell membrane of neutrophils and monocytes, causing ANCA-related autoimmune responses.
A previous study found that the incidence of AAV varies significantly with latitude, further supporting the influence of geographical region on AAV disease. Epidemiological studies have shown that the risk of GPA is high in the northern hemisphere of the earth, whereas the risk of MPA is high in the southern hemisphere. Quantitative changes showed marked changes, while the incidence of GPA and EGPA increased with increasing latitude and decreasing ambient UV radiation levels. Similarly, related studies have confirmed that the positive rate of PR3-ANCA decreases with increasing latitude and ultraviolet radiation intensity.
UV radiation is a sensitive factor that varies with latitude, and related studies have found a close relationship between UV radiation and immune diseases. UV radiation, which changes with latitude, is considered to be the actual cause of AAV. UV radiation is necessary for the skin's synthesis of 1,25(OH)2 D3, which regulates immune system homeostasis. UV irradiation of the skin induces vitamin D synthesis, which in turn inhibits the proliferation of Th1 and Th17 cells and the production of cytokines. These changes cause the immune system to differentiate into Th2 cells, thereby enhancing the activity of CD24+, CD25+, and CD8+ cells. This is consistent with a mechanism mediated by Th1 and/or Th17 cells in the pathogenesis of GPA. This may explain why the association between MPA and UV light is not strong, since granulomas are not present in MPA. However, accurate estimation of the average amount of UV radiation in a region is challenging. The influence of immigration, clothing characteristics, skin color preferences, religious and cultural beliefs, and other factors need to be excluded, as well as the influence of dietary intake of vitamin D, related drugs, and other environmental factors on the final serum vitamin D level in each region. These challenges should be addressed in future studies.
Microbial infection is considered to be an important risk factor for the development of AAV. Intranasal staphylococcus aureus (S. aureus) infection is most closely associated with AAV. The early symptoms of patients with GPA are mainly runny nose, nosebleeds, and other symptoms, because the most prominent feature of the disease is the granulomatous inflammation of the respiratory tract. S. aureus infection that colonizes the respiratory tract may trigger GPA disease activity. Previous studies have found that the detection rate of S. aureus in patients with GPA is significantly higher than that in healthy individuals, and patients with GPA with chronic S. aureus infection have a significantly increased risk of recurrence. A randomized controlled trial in the Netherlands showed that patients treated with trimethoprim/sulfamethoxazole (T/S, 960 mg three times a week) had a decreased recurrence rate by 66%. In contrast, prophylactic treatment of chronic S. aureus carriers with T/S did not reduce the risk of relapse. This may be related to factors, such as drug dosage and different bacterial detection methods. Further studies found that the imbalance in the proportion of various bacteria colonized in respiratory tract may contribute to the incidence of AAV. The proportion of S. aureus colonization in nasal samples of patients with GPA increased, but the diversity of the microbiome decreased. Current studies indicate that S. aureus is only related to the pathogenesis of GPA, but no obvious relationship seems to exist between S. aureus and the pathogenesis of MPA and EGPA.
The role of S. aureus in the pathogenesis of AAV may be as follows: (1) Superantigens of S. aureus directly stimulate B cells and T cells. Among them is the polyclonal activation of B cells by S. aureus cell wall components. Additionally, S. aureus may directly initiate neutrophils, leading to surface expression of PR3. (2) S. aureus contains a highly homologous complementary form of the protein in humans. cPR-3 (105-201) acts as a protein complementary to the human autoantigen PR3 and elicits an autoimmune response. (3) The CpG motif of S. aureus may trigger B lymphocytes in the peripheral blood of patients in remission, leading to the production of ANCA and relapse of AAV. (4) The polypeptide 6-phosphogluconate dehydrogenase (6PGD) 391-410 encoded by the S. aureus plasmid is homologous to the previously determined immunodominant MPO-T cell epitope, and it is immunogenic in humans. Studies have shown that 6PGD induces MPO-related nephritis. (5) S. aureus-derived extracellular adhesion protein (EAP) and Staphylococcus peroxidase inhibitor (SPIN) can induce the body to produce ANCA. (6) S. aureus is an effective inducer of NETs, DNA extracellular complex, and antibacterial factors secreted by neutrophils. Exposure of ANCA antigens to the immune system can initiate an autoimmune response to AAV.
Epstein-Barr virus (EBV) infection is most closely related to various SARDs. Multiple case reports found that patients with AAV may develop anti-MPO antibodies following EBV infection. Treatment with glucocorticoids combined with ganciclovir can significantly relieve clinical symptoms and reduce viral load. Lidar et al. found that anti-EBV capsid antigen antibodies and anti-EBV early antigen antibodies were significantly higher in the sera of patients with AAV than in healthy individuals. Treatment with glucocorticoids in combination with ganciclovir significantly relieved clinical symptoms and reduced viral load. Hepatitis B virus (HBV) and hepatitis C virus (HCV) may be triggers for SARDs. An Egyptian study found 62.7% hepatitis C virus infection in 42 patients with AAV, and C-ANCA levels were significantly correlated with hepatitis C virus antibody levels. Lee et al. found a significantly higher risk of relapse in anti-HBc-positive patients with EGPA. Resolved HBV infection may have an important impact on vasculitis activity at diagnosis and subsequent relapse after remission in patients with EGPA. Recently, ANCA has been identified in patients with coronavirus disease 2019 (COVID-19) infections, but relatively few cases have been reported. Studies have proposed the involvement of the parvovirus B19, human herpesvirus, and hantavirus in the occurrence of AAV. However, these studies are few and have not found a significant correlation between these viruses and the development of AAV.
Few studies have been conducted on other microorganisms in AAV. A Japanese study reported that Aspergillus infections, including Candida, Candida, and Fusarium, were found in patients with both allergic bronchopulmonary mycosis (ABPM) and EGPA. Kuwabara et al. found that Mycobacterium tuberculosis infection and anti-tuberculosis drugs may be related to AAV. Fujita et al. found that the positive rate of Chlamydia pneumoniae in patients with MPO-AAV was 33%. A Japanese report described a woman who underwent total thyroidectomy, developed PR3-ANCA 3 months after surgery, and had a chronic infection with Tsukamurella pulmonis. GPA often occurs in gastrointestinal mucosal lesions, and the study detected 25 cases of Helicobacter pylori infection among 36 patients with GPA. Currently, the effect of these microorganisms on AAV is only speculative, and further large-scale studies are needed to verify.
Drug-induced small vessel vasculitis is a small group of AAV disorders that still do not have a precise definition. Drugs that may be associated include hydralazine, allopurinol, propylthiouracil, phenothiazine, nitrofurantoin, methimazole, minocycline, phenytoin sodium, penicillamine, lorazepam, levamisole, cocaine, isoniazid, montelukast, erlotinib, and tofacitinib. Among them, the incidence of AAV caused by antithyroid drugs is higher, especially propylthiouracil. The clinical manifestations of propylthiouracil-induced AAV disease are similar to those of primary AAV, whereas the disease severity is less severe and prognosis is better. After cessation of antithyroid drug use, symptoms of patients with AAV gradually resolve and ANCA titers decrease significantly. Treatment strategies for drug-induced AAV differ from those for primary AAV. In patients with mild symptoms, immediate discontinuation of the relevant drug can lead to disease remission. Patients with severe diseases should be treated aggressively. However, immunosuppressive maintenance therapy is often unnecessary. The mechanism of drug-induced AAV disease may be related to NETs. However, further studies are needed to verify the exact mechanism. NETs are associated with inflammation in various ways. NETs can directly induce endothelial damage and activate alternative complement pathways. Additionally, they are a major component of thrombosis. The relationship between NETs and ANCAs seems to be bidirectional, a vicious circle.
The efficacy of vaccines is based on the ability of the host immune response to the antigen to elicit a memory T-cell response over a period of time. The influenza vaccine is generally considered safe and effective. However, in recent years, the population after influenza vaccination has developed various autoimmune phenomena, such as Guillain-Barre syndrome, RA, pemphigus vulgaris, psoriasis, giant cell arteritis, and AAV. Several AAV cases associated with influenza vaccination have been reported, but influenza vaccination does not increase the recurrence rate of AAV disease. The exact etiology of AAV induced by influenza vaccination is unclear and may be related to molecular mimicry and autoimmune/inflammatory syndrome induced by adjuvants (ASIA syndrome). Recent studies have found that AAV may occur after receiving the COVID-19 mRNA vaccine, and patients with existing AAV may experience recurrence after receiving the COVID-19 mRNA vaccine. The mechanism of new or recurrent AAV after vaccination is still a mystery and may be similar to the mechanism of AAV caused by influenza vaccine. Additionally, the enhanced immune response and presence of monocytes after vaccination may cause MPO-ANCA and PR3-ANCA. However, this evidence originates from individual case reports, and no specific mechanism has been explored.