Pathophysiology of Microscopic Polyangiitis
Microscopic polyangiitis (MPA) is an autoimmune small-vessel vasculitis driven primarily by anti-myeloperoxidase (MPO) ANCA antibodies that activate neutrophils, causing necrotizing inflammation of capillaries, venules, and arterioles without granuloma formation. 1, 2
Core Autoimmune Mechanism
The pathogenic cascade begins with autoantibody formation against myeloperoxidase (MPO), a neutrophil enzyme normally sequestered in primary granules. 1 The fundamental question in MPA pathogenesis is why the immune system develops antibodies against this self-antigen that is typically hidden from immune surveillance. 1
Autoantigen Exposure and Antibody Development
Defective neutrophil apoptosis or impaired clearance of apoptotic cell fragments leads to prolonged exposure of MPO to the immune system, breaking tolerance. 1
Infection may trigger disease through molecular mimicry, where microbial antigens structurally resemble MPO, initiating cross-reactive antibody production. 1
MPO becomes abnormally expressed on cell surfaces when complexed with HLA class II molecules (particularly HLA-DR), creating novel epitopes that are recognized by autoantibodies. 3
This MPO/HLA-DR complex presentation exposes cryptic autoantibody epitopes not normally accessible when MPO is properly sequestered intracellularly. 3
Neutrophil Activation and Vascular Injury
Once MPO-ANCA antibodies form, they bind to and activate primed neutrophils, triggering a destructive inflammatory cascade. 1, 4
Direct Neutrophil-Mediated Damage
ANCA binding to neutrophils causes release of oxygen radicals, lytic enzymes, and inflammatory cytokines that directly damage vessel walls. 1
MPO-ANCA can activate MPO enzymatically to generate hypochlorous acid (HOCl), a highly reactive oxidant species that causes severe endothelial cell damage. 4
This oxidative burst is specifically triggered by anti-MPO antibodies and can be blocked by antioxidants like N-acetylcysteine, confirming the pathogenic role of the antibodies. 4
Activated neutrophils degranulate at sites of tissue injury, releasing MPO that is then rapidly eliminated by specific inhibitors under normal circumstances. 1
Immune Complex Formation
ANCA may induce immune complex formation that deposits in vessel walls, though MPA is characterized by pauci-immune (few or no immune deposits) glomerulonephritis. 1, 2
The relative absence of immunoglobulin deposits distinguishes MPA from immune complex-mediated vasculitides like Henoch-Schönlein purpura. 5
Direct Endothelial Injury
- ANCA can directly adhere to and kill endothelial cells, causing necrotizing vasculitis independent of neutrophil activation. 1
Vessel-Specific Pathology
MPA predominantly affects small vessels—capillaries, venules, and arterioles—though small and medium arteries may occasionally be involved. 2, 5
Histopathologic Features
Necrotizing vasculitis with fibrinoid necrosis of vessel walls is the hallmark finding, occurring without granulomatous inflammation. 2, 5
The absence of granulomas is the key distinguishing feature from granulomatosis with polyangiitis (GPA), as the vasculitis itself is pathologically identical. 5
Pauci-immune necrotizing and crescentic glomerulonephritis is the characteristic renal manifestation, reflecting capillary inflammation with minimal immune complex deposition. 2, 5
Pulmonary capillaritis with hemorrhagic alveolar damage occurs commonly, making MPA the most frequent cause of pulmonary-renal vasculitic syndrome. 2, 5
Clinical Implications of Pathophysiology
Understanding that MPA is primarily MPO-ANCA driven (in contrast to PR3-ANCA in GPA) has direct clinical relevance for diagnosis and monitoring. 1, 2
ANCA Serology Patterns
Approximately 70% of MPA patients have detectable MPO-ANCA (perinuclear pattern), though a subset remains ANCA-negative. 2, 4
The minority of MPA patients may have PR3-ANCA rather than MPO-ANCA, though MPO predominates. 2
ANCA-negative MPA exists and presents a diagnostic challenge, as the pathophysiology in these cases may involve alternative mechanisms not yet fully elucidated. 1
Age and Severity Correlation
- Patients with MPA are typically older at presentation and have more severe kidney disease compared to GPA patients, reflecting the predilection for renal capillary involvement. 1
Common Pitfalls in Understanding MPA Pathophysiology
Do not confuse MPA with polyarteritis nodosa—MPA involves capillaries and venules while polyarteritis nodosa affects only medium-sized arteries without capillary involvement. 5
Do not assume all ANCA-associated vasculitis has the same pathophysiology—while MPA, GPA, and EGPA share ANCA positivity, their distinct clinical features reflect different underlying mechanisms (MPO vs PR3 antibodies, presence/absence of granulomas, eosinophil involvement). 1, 5
Recognize that the pathogenic role of MPO-ANCA is supported by both in vitro studies showing direct neutrophil activation and endothelial damage, and clinical evidence that B-cell depletion (rituximab) effectively treats disease by reducing antibody production. 1, 4