Pathogens in Vasculitis: Is It Really Idiopathic?

Abstract

Vasculitis is an autoimmune disease characterized by the infiltration of leukocytes in blood vessels. An increasing number of studies on human and animal models have implicated various microorganisms in the pathogenesis of vasculitis. Previous studies have shown the presence of infectious agents, including viruses, bacteria, and fungi, in diseased vessels. However, despite continued research, the link between infection and vasculitis is not fully understood, possibly owing to the lack of appropriate animal models that mirror human disease and the technical limitations of pathogen detection in blood vessels. Among the pathogen-induced animal models, Candida albicans water-soluble fraction (CAWS)-induced coronary arteritis is currently considered one of the representative models of Kawasaki (KD) disease. Advances in metagenomic next-generation sequencing have enabled the detection of all nucleic acids in tissue, which can help identify candidate pathogens, including previously unidentified viruses. In this review, we discuss the findings from reports on pathogen-associated vasculitis in animal models and humans, with a specific focus on the investigation of the pathogenesis of vasculitis. Further studies on animal models and microbes in diseased vessels may provide important insights into the pathogenesis of vasculitis, which is often considered an idiopathic disease.

Alteration of microbial composition in the skin and blood in vasculitis

“…On the other hand, excessively activated leukocytes, including lymphocytes, macrophages, and neutrophils, damage the vessels and aggravate inflammation 12 . While the etiology of vasculitis remains incompletely understood, an increasing number of animal and human studies have suggested that it is associated with a variety of pathogenic agents including bacteria, viruses, and fungi 4 . Previous studies have indicated that viruses relate to small-vessel vasculitis in many cases, whereas bacterial infections cause vasculitis in all sizes of vessels 24 .…”

“…Among the nine different genetic variants of the SEN virus (A to I), the most predominant genotypes are SEN virus D and H, which are typically found in patients with non-A-E hepatitis 26 . HBV is associated with cryoglobulinemic small-vessel vasculitis and polyarteritis nodosa (PAN), and the relationship between PAN and HBV has been often reported 4 . Approximately 5% of patients with HCV-associated mixed cryoglobulinemia develop cryoglobulinemic vasculitis, as a consequence of the deposition of immune complex (IC) in small vessels.…”

“…The association between vasculitis and various pathogens has been widely reported 4 . For example, immunoglobulin (Ig)A vasculitis is often triggered by a prior infection, such as an upper respiratory tract infection, caused by various microorganisms, including Streptococcus , Staphylococcus aureus , and varicella-zoster virus 5 .…”

“…Studies on the association between vasculitis and pathogens have been conducted using animal models. For instance, injection of Candida albicans water-soluble fraction in mice induces inflammation of the aortic root and coronary arteries 10 – 13 , as well as in experimental models of vasculitis caused by viral, bacterial, fungal, and other pathogens 4 . Another study attempted to identify the causal microbe of the temporal arteries in patients with giant cell arteritis (GCA), and 16S ribosomal RNA gene sequencing revealed microbiome differences in temporal arteries between GCA and non-GCA.…”

Cardiovascular pathology in vasculitis

“…HIV infection is associated with vasculitis affecting the aorta and major branches, and PAN-like forms have also been described. Chronic active EBV infection is linked to medium- to large-vessel vasculitis, with coronary artery aneurysms as a typical complication 69 , 70 ; it is also linked with KD 71 . A broad spectrum of coronary changes including aneurysms, chronic vasculitis, and luminal narrowing due to myofibroblastic proliferation, have been described in a young adult suffering from KD associated with Parvovirus 19 infection 72 .…”