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  • Anti-neutrophil cytoplasmic antibody are ANCA for short.
  • Vasculitis is inflammation of the blood vessels. Diseases involving vasculitis are called vasculitides.
  • While there are a variety of vasculitides, Granulomatosis with polyangiitis (GPA) aka Wegener’s granulomatosis (WG), microscopic polyangiitis, Eosinophilic granulomatosis with polyangiitis (EGPA) aka Chrug-Strauss Syndrome (CSS) are the vascular inflammation diseases characterized by ANCA (1, 2; see figure below).
  • ANCA-associated vasculitides are rare autotimmune diseases, affecting ~12 to 18 per million per year (3, 4).


History of the discovery of ANCA (Anti-neutrophil cytoplasmic antibody)

  • In 1982, David Davies, an Australian pathologist observed that ‘a subset of patients with focal necrotizing and crescentic glomerulonephritis had circulating antibodies that bound to the cytoplasm of normal neutrophils‘ (5, 6).
  • Davies’ team’s observation got little attention until 1985 when a Dutch-Danish collaboration (7) independently confirmed that patients with GPA/WG had autoantibodies that reacted with cytoplasmic components of neutrophils and monocytes.
  • These antibodies were called c-ANCA, the c for the characteristic cytoplasmic staining pattern associated with the antibodies binding to their targets. What were they binding?
    • Turned out to be the 29-kiloDalton slightly cationic serine protease, PR-3 (proteinase 3), found inside the neutrophil’s azurophilic or alpha-granules.
    • It’s synthesized as a pre-enzyme and appears early in neutrophil differentiation from myeloid progenitor cells.
  • Other groups identified p-ANCA, i.e., anti-neutrophil antibodies with a perinuclear staining pattern in patients suspected of having vasculitis, specifically glomerulonephritis and/or necrotizing vasculitis (8, 9).
    • These ANCA turned out to bind MPO (Myeloperoxidase).
    • Also found inside the azurophilic or alpha-granules, MPO is a highly cationic, 146-kiloDalton, two-chain protein.
    • MPO has an important role in reactive oxygen species’ generation, specifically by catalyzing hypochlorite from hydrogen peroxide and chloride anion.
  • Over time, research showed the c-ANCA and p-ANCA designations were irrelevant since these staining patterns are artifacts, generated as a result of fixatives used in the cell staining process.
  • Role of ANCA and neutrophils in ANCA-associated vasculitis (AAV) are summarized in the tables below (10, 11).

  • Different types of vasculitis involve different types of blood vessels. Over the decades, experts in the field used the latest research data to generate a consensus classification system to aid more accurate diagnosis (see figures below from 1, 11). As such AAVs tend to be around small and medium blood vessels.



  • Consensus-driven definition of AAV and confirmation of the pathogenic role of ANCA in the disease processes followed (see figures below from 11, 12).

Triggers and Symptoms of ANCA-Associated Vasculitis (AAV)

  • Obviously AAVs are complex, multi-factorial diseases (13).
    • Genetic components include HLA (Human Leukocyte Antigens) (14, 15).
    • Environmental include air pollutants such as silica (16).
    • Infections include Staphylococcus aureus or Ross River virus (6).
      • For e.g., all the patients in the original Davies’ et al ANCA study (5) had serologic evidence of Ross River virus infection.
      • And S. aureus nasal carriage is associated with GPA/WG (17).
    • Drugs include propylthiouracil and cocaine contaminated with the anti-helminthic drug, levamisole (18, 19).
  • Disease usually starts with acute-onset tingling in the extremities (20).
  • Disease can be limited to one organ, most frequently kidney or lung, or involve multiple sites such as upper and lower respiratory tract, kidneys, skin and peripheral nerves (11; see figures below from 21, 22).
  • Symptoms vary based on the blood vessels involved,
    • If dermal veins (dermal veniculitis), then Purpura.
    • If lung alveolar capillaries, then Pulmonary hemorrhage.
    • If kidney glomerular capillaries, then glomerular capillaritis.
    • If peripheral nerves (peripheral neuropathy), then epineural arteritis.
    • If eye and orbit blood vessels, then ocular inflammation.
    • Muscle weakness and atrophy are also possible.

Rx of ANCA-Associated Vasculitis (AAV)

  • Treatment largely consists of immunosuppression (cyclophosphamide, glucocorticoids, methotrexate), and more recently depletion of B cells using the monoclonal antibody (mAb), Rituximab, see figure below from 12.

Immunology of ANCA and ANCA-associated vasculitis (AAV)

  • Target of ANCA are proteins synthesized by neutrophils.
  • In EGPA/CSS, the target for the pathologic ANCA response is the neutrophil protein MPO while in GPA/WG, it’s the neutrophil protein PR-3.
  • Research over the years implicates feed-back loop involving ANCA, neutrophils and complement in driving blood vessel inflammation in AAV (ANCA-Associated Vasculitis). Figure below from 23 suggests how.



  • In AAVs, pathogenic ANCAs are IgG antibodies, i.e., class-switched from IgM. This requires T cell help. So back-tracking from the anti-neutrophil antibodies made by B cells (ANCA), we come to T cells, which need to have seen the pieces of the same protein (antigen) presented by and on the surface of dendritic cells. This is the principle of cognate recognition, i.e., in-built check and balance in immune function to ensure that helper T cells help B cells specific for the same, and not other, antigens.
  • Following activation, T cells that help cognate B cells need to differentiate into follicular helper T cells in order to
    • Be able to gain access to the B cell follicles inside lymph nodes.
    • Secrete specific cytokines such as IL-21, IL-5 and many others.
    • Express cell-surface molecules such as CD40 ligand and ICOS.
    • These are necessary to help mediate antibody affinity maturation and class switch.
  • In turn, the helped cognate B cells
    • Expand clonally, i.e., oligoclonal expansion.
    • Increase the affinity of their antigen-specific antibodies, i.e., affinity maturation.
    • Switch from IgM to IgG antibodies, i.e., antibody class-switching.
  • Thus, in order for a B cell to make IgG antibodies against a neutrophil protein, T cell tolerance to that neutrophil protein needs to have broken down (24). How this happens is still unclear though the consensus hypothesis in the field is molecular mimicry with infection(s), i.e., that certain microbes have peptides whose sequences overlap with those of the neutrophil proteins, MPO and PR-3.
  • Important to note that healthy people also have circulating ANCA antibodies (25). Differences include
    • Lower titers.
    • Lower avidity (strength of antibody binding to its antigen).
    • Less subclass diversity.
    • Less capacity to activate neutrophils in vitro (26, 27).

How does ANCA (anti-neutrophil cytoplasmic antibodies)-driven blood vessel inflammation start?

  • ANCA means breakdown in tolerance to neutrophil proteins.
  • One hypothesis suggests
    • Patients got infections with specific microbes, Staphylococcus aureus or Ross River virus.
    • These microbes and the neutrophil proteins MPO and PR-3 have overlapping peptides, i.e., molecular mimicry.
  • Problem with the infection-molecular mimicry hypothesis:
    • S. aureus is a common even normal inhabitant of human nasal cavities.
    • Yet only a tiny proportion of people get ANCA-associated vasculitis (AAV).
    • Something else is necessary to trigger the full vicious cycle of autoimmune blood vessel inflammation.
    • Also infection doesn’t explain role of environmental pollutants and drugs in AAVs.
    • So infection can only explain disease cycle partially, not fully.
  • Unaddressed questions:
    • How does T cell tolerance to neutrophil proteins break down in AAV patients, i.e., why does the break down happen only in AAV patients, not in everyone who gets those infections?
    • Is there something different about neutrophils in these patients?
    • The blood vessels that are the targets of the damaging immune responses
      • In different AAVs.
      • In different subsets of AAV patients with the ‘same‘ disease.
        • Why those particular ones?
        • What, if anything, is different about them?
    • These are as-yet-unanswered, even unasked questions.


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  14. Cao, Yali, et al. “DRB1* 15 allele is a risk factor for PR3-ANCA disease in African Americans.” Journal of the American Society of Nephrology 22.6 (2011): 1161-1167. DRB1*15 Allele Is a Risk Factor for PR3-ANCA Disease in African Americans
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