The development of autoimmune disorders requires a combination of genetic, immunological, and environmental factors. Infectious agents, such as viruses and bacteria, can trigger autoimmunity through different mechanisms, and for systemic vasculitis in particular, microbial agents have been suggested to be involved in its pathogenesis. Although the exact mechanisms have not been fully elucidated, different theories have been postulated. This review considers the role of infections in the etiology of primary vasculitis, emphasizing their related immunological events.
Primary systemic vasculitides are a complex group of disorders that involve multiple organs, often with a severe clinical course. Although uncommon, they require prompt management and adequate handling. Early diagnosis is required to preserve the function of the affected organs and to decrease mortality. Clinical manifestations are varied and nonspecific and may be related to those occurring in other systemic diseases, such as infections or malignancies. Although the origin of primary vasculitis is not fully understood, there is a combination of genetic, immunological, and environmental factors, like infections, which could trigger some of them. In the latest revision of the Chapel Hill Consensus Conference (CHCC), vasculitis associated with hepatitis B (HBV) and hepatitis C (HCV) viruses were included [
The most important microbial agents presumed to be involved in the development of primary systemic vasculitis.
Microbial agent | Reference | |
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Type of vasculitis | ||
Takayasu arteritis |
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Giant cell arteritis |
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Polyarteritis nodosa | Hepatitis B virus, hepatitis C virus, and HIV infection | [ |
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Immune complex vasculitis | ||
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Increased incidence during influenza epidemics | [ |
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HCV | [ |
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Many bacteria, viruses, and even protozoa (e.g., |
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Few associations with infections | [ |
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ANCA-associated vasculitis | ||
Microscopic polyangiitis |
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Granulomatosis with polyangiitis |
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Eosinophilic granulomatosis with polyangiitis | — |
Various mechanisms have been proposed to be involved in the relationship between infection and systemic vasculitis: molecular mimicry, superantigens, cell activation by Toll-like receptors (TLR), and more recently, the anti-idiotypic response by neutrophil extracellular traps in the antineutrophil cytoplasmic antibodies- (ANCA-) associated vasculitis (Table
Theories regarding the role of infection in the development of primary systemic vasculitis. Toll-like receptor (TLR); 3 proteinase (PR3); myeloperoxidase (MPO).
Vasculitis | Mechanism | Microbial agent | Evidence | References |
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Takayasu’s arteritis | Molecular mimicry |
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MPO-AAV | Neutrophil cell traps | Various | Immunofluorescence analyses revealed MPO located in these extracellular chromatin fibers |
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PR3-AAV | Neutrophil cell traps | Various | Immunofluorescence analyses revealed MPO located in these extracellular chromatin fibers |
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Stimulation of T lymphocytes by |
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Persistent activation of circulating T lymphocytes |
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Antigens can join to renal basement membranes by charge interaction |
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— | [ | |
Idiotype, anti-idiotype |
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Similarity of some bacterial peptides, including but not limited to |
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TLR activation |
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During active infection of AAV, TLR9 expression increased significantly compared to uninfected patients |
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Molecular mimicry |
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Anti-lysosomal-associated membrane protein-2 (hLAMP-2) | [ |
For several years, a causal link between Takayasu’s arteritis (TA) and tuberculosis (TB) has been proposed due to the granulomatous nature of both diseases. Moreover, the link is supported by the increasing frequency of TA in patients from continents with a high prevalence of TB, such as Asia, Africa, and South America [
In giant cell arteritis (GCA), the presence of certain viruses in the tissues of temporal arteries from affected patients has been suggested. However, a study conducted on 37 samples to detect
In contrast, polyarteritis nodosa (PAN) is strongly linked to hepatitis B virus (HBV) and also has been linked to hepatitis C virus (HCV), human immunodeficiency virus (HIV), group A
The association between PAN and HBV has been frequently observed (10–54% of patients); in fact, in the last CHCC, this association was grouped in a specific subset of vasculitis called vasculitis associated with probable cause [
Regarding basement membrane disease, only a description of infection (influenza outbreak) is thought to be a likely trigger [
Vasculitis associated with antineutrophil cytoplasmic antibodies (ANCA) includes a group of diseases that cause small-vessel necrosis. These diseases are characterized by the presence of ANCA which vary depending on the vasculitis type and whether they are directed against myeloperoxidase (MPO) or proteinase 3 (PR3) [
Currently, there is only one
Neutrophil extracellular traps (NETs) have recently been reported to participate in the pathogenesis of various autoimmune diseases, such as AAV (MPO-ANCA and PR3-ANCA vasculitides). Immunofluorescence analyses of NETs induced
For several years, the involvement of
Different theories have been developed regarding the relationship between GPA and
One study found that, in GPA chronic carrier patients of
More recently, another mechanism based on the similarity of some bacterial peptides was proposed. It includes (but is not limited to)
Because the aforementioned bacterial peptides have similarities with PR3c, GPA carriers of
In AAV, TLR expression on monocytes and natural killer cells in peripheral blood [
Finally, another important finding, which supports the relationship between AAV and bacterial infection, is the presence of human autoantibodies against protein 2 of the lysosomal membrane (hLAMP-2) in patients with AAV (80% of patients from three European cohorts) [
Other organisms, such as
Most infectious agents, including viruses, bacteria, and parasites, can trigger autoimmunity through various mechanisms. Infections are associated with the secondary forms of vasculitis. However, there is growing evidence that microbial agents also play a role in the induction of primary systemic vasculitis. For example, a number of infectious agents have been proposed as potential triggers; however, in most cases, the link remains hypothetical. Different mechanisms and pathogenic hypotheses have been proposed (molecular mimicry, superantigens, cell activation by Toll-like receptors, the anti-idiotypic response, and neutrophil extracellular traps); however, the pathophysiology of the complex relationship between infection and vasculitis remains not fully understood.
The authors declare no conflict of interests.