ANCA-Associated Vasculitis (AAV)

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of rare, autoimmune conditions characterized by widespread, multisystemic inflammation and often necrosis of the smaller blood vessels. This results in a variety of multiorgan signs and symptoms, which manifest throughout the body, making the diagnosis of AAV challenging.¹

AAV consists of 3 main subtypes: granulomatosis with polyangiitis (GPA; formerly known as Wegener granulomatosis), eosinophilic granulomatosis with polyangiitis (EGPA; formerly known as Churg-Strauss syndrome), and microscopic polyangiitis (MPA).¹

Pathogenesis of AAV

Autoantibodies produced by the immune system attack granular protein components within neutrophils in specific patterns, namely perinuclear (pANCA) or cytoplasmic (cANCA) patterns.¹ 

pANCA patterns indicate that the antineutrophil antibodies are targeting the myeloperoxidase (MPO) protein inside of neutrophils, while cANCA patterns indicate that the antineutrophil antibodies are targeting the proteinase 3 (PR3) protein within neutrophils.² 

ANCA autoantibodies may also target lysosomal-associated membrane protein 2 (LAMP2).^2,3 Autoantibodies targeting LAMP2 may develop following infection with Gram-negative bacteria, resulting in the development of AAV in people with a genetic predisposition.⁴

Read more about AAV histology

Acute vascular inflammation results when neutrophils containing these autoantigens (MPO and PR3) within cytoplasmic granules are activated by genetic factors and/or various exposures, including environmental factors or microbial infections, that stimulate complement activation. A variety of proinflammatory stimuli, including complement C5a, tumor necrosis factor-alpha (TNFα), and bacterial lipopolysaccharide (LPS), prime the neutrophils.^1,2 

Once the neutrophils are primed with these proinflammatory stimuli, ANCA autoantibody binding further activates the neutrophils, which then degranulate, releasing toxic oxygen free radicals and destructive enzymes that contribute to endothelial cell damage within the vasculature.^1,2 This endothelial cell damage may lead to destructive vascular necrosis, particularly of the smaller blood vessels. Thus, in AAV, neutrophils are both the targets of autoimmunity and effectors of endothelial damage.⁵

ANCA autoantibodies may activate intracellular signaling pathways, promoting increased transmigration and adhesiveness of neutrophils to the vascular endothelium.^1,6

Read more about AAV pathophysiology

Genetic Etiology of AAV

Although the exact triggers for the development of autoimmunity in AAV has not been identified, multiple factors, including genetic predispositions, contribute to the etiology of AAV.² 

Researchers conducting a genome-wide association study discovered that certain genetic characteristics, including major histocompatibility complex (MHC) traits, correlated with ANCA autoantigen specificity over clinical manifestations of disease subtypes. In particular, polymorphisms in the human leukocyte antigen (HLA) gene correlated with both anti-PR3 ANCAs (HLA-DP) and anti-MPO ANCAs (HLA-DQ).¹

Molecules encoded by the HLA gene are responsible for the presentation of antigens and the corresponding antigen specificities of T-cell receptors and immunoglobulin antigen-binding domains. Therefore, polymorphisms in the HLA gene may cause dysfunction of this immune cell training and targeting mechanism.²

Many studies analyzing susceptibility genes and loci have identified several genes affiliated with the development of GPA, including CTLA4, PTPN22, COL11A2, SERPINA1, and the MHC class II gene cluster.⁷

Read more about AAV genetics

Role of Environmental Exposures in AAV Etiology

Several environmental exposures have been associated with the development of AAV, such as the inhalation of silica and treatment with certain pharmaceutical agents. Exposure to silica dust activates alveolar macrophages and fibroblasts and attracts neutrophils to the lungs. Workers who process substances such as wood, grass, grain, cotton, sand, wool, soil, flint, and rock, among others, may become exposed to silica.⁸

Drug exposures are becoming increasingly recognized as a cause of AAV, especially medications used to treat hyperthyroidism (propylthiouracil, carbimazole, methimazole), hypertension (hydralazine), and bacterial infections (minocycline).^1,8

In addition to silica and drug exposures, microbial pathogen exposure has been suggested as a potential AAV contributor.^8-10

Read more about AAV risk factors

Role of Microbial Infections in AAV Etiology

Viral, bacterial, fungal, and parasitic infections may trigger the development of AAV. Growing evidence supports the association between AAV and infections.^8-10 

A systematic review of the literature reported that several types of infections have been associated with the development of MPO-AAV. Viral agents, such as Epstein-Barr virus, cytomegalovirus, and Dengue virus, and bacterial agents, such as Staphylococcus aureus resulting in infectious endocarditis, Rickettsia rickettsii, Escherichia coli, and Mycobacterium avium complex, have all been found to trigger MPO-AAV.⁹

Direct invasion of blood vessel endothelial cells of by certain bacteria, fungi, or parasites may also trigger vasculitis.¹¹

If AAV is caused by infection, it is critical to determine the exact underlying cause. This guides optimal treatment efficacy, as treatment may differ based on the type of infection.¹¹

Read more about AAV treatment

References

1. Qasim A, Patel JB. ANCA positive vasculitis. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2022. Updated May 29, 2022. Accessed March 7, 2023.
2. Xiao H, Hu P, Falk RJ, Jennette JC. Overview of the pathogenesis of ANCA-associated vasculitis. Kidney Dis (Basel). 2016;1(4):205-215. doi:10.1159/000442323
3. Kain R, Exner M, Brandes R, et al. Molecular mimicry in pauci-immune focal necrotizing glomerulonephritis. Nat Med. 2008;14(10):1088-1096. doi:10.1038/nm.1874
4. Willcocks LC, Lyons PA, Rees AJ, Smith KGC. The contribution of genetic variation and infection to the pathogenesis of ANCA-associated systemic vasculitis. Arthritis Res Ther. 2010;12(1):202. doi:10.1186/ar2928
5. Jarrot PA, Kaplanski G. Pathogenesis of ANCA-associated vasculitis: an update. Autoimmun Rev. 2016;15(7):704-713. doi:10.1016/j.autrev.2016.03.007
6. Radford DJ, Luu NT, Hewins P, Nash GB, Savage CO. Antineutrophil cytoplasmic antibodies stabilize adhesion and promote migration of flowing neutrophils on endothelial cells. Arthritis Rheum. 2001;44(12):2851-2861. doi:10.1002/1529-0131(200112)44:12<2851::aid-art473>3.0.co;2-2
7. Relle M, Föhr B, Fasola F, Schwarting A. Genetics and pathophysiology of granulomatosis with polyangiitis (GPA) and its main autoantigen proteinase 3. Mol Cell Probes. 2016;30(6):366-373. doi:10.1016/j.mcp.2016.08.009
8. Chen M, Kallenberg CGM. The environment, geoepidemiology and ANCA-associated vasculitides. Autoimmun Rev. 2010;9(5):A293-A298. doi:10.1016/j.autrev.2009.10.008
9. Karperis K, Kakoullis L, Papachristodoulou E, Panos G. Infection-induced MPO-ANCA associated vasculitis: a systematic review of published case reports. Abstract presented at: American College of Rheumatology (ACR) Convergence 2020; November 5-9, 2020; Virtual.
10. Cartin-Ceba R, Peikert T, Specks U. Pathogenesis of ANCA-associated vasculitis. Rheum Dis Clin North Am. 2010;36(3):463-477. doi:10.1016/j.rdc.2010.05.006
11. Pagnoux C, Cohen P, Guillevin L. Vasculitides secondary to infections. Clin Exp Rheumatol. 2006;24(Suppl 41):S71-S81.

Reviewed by Hasan Avcu, MD, on 3/12/2023.

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Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT

Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT is a freelance medical writer and Doctor of Physical Therapy from Maryland. She has expertise in the therapeutic areas of orthopedics, neurology, chronic pain, gastrointestinal dysfunctions, and rare diseases especially Ehlers Danlos Syndrome.