Analysis of anti-neutrophil cytoplasmic antibodies (ANCA):: frequency and specificity in a sample of 191 homozygous (PiZZ) alpha1-antitrypsin-deficient subjects

Background. ANCA are autoantibodies directed. against polymorphonuclear cell antigens, mainly proteinase 3 (PR3) and myeloperoxidase (MPO), which are implicated in the pathogenesis of small-vessel necrotizing vasculitis. Alpha1-antitrypsin is the main inhibitor of neutral serine proteinase [i.e. human leukocyte elastase (HLE) and PR3] present in PMN alpha-granules (alpha Gr). An association first reported by us between PR3 ANCA and the deficient PiZZ phenotype in ANCA-positive systemic vasculitis, now widely confirmed by others, led us to study the incidence and specificity of ANCA among PiZZ subjects. Methods. We tested a population of 191 PiZZ (273 sera) for ANCA activity versus 272 PiMM matched control subjects using aGr or antigen-specific ELISA [PR3, PILE, MPO, lactoferin (LF) and bactericidal/permeability increasing protein (BPI)]. Results. The incidence of antibodies directed against alpha Gr and HLE but not PR3, MPG, LF or BPI was increased in the PiZZ as compared to the PiMM group (Fisher probability respectively P < 0.0001 and P < 0.05). Conclusions. ANCA not directed against classical antigens (MPO and PR3) may be found in PiZZ patients. However, these patients do not develop systemic vasculitis features. Therefore, alpha1-antitrypsin deficiency is not sufficient to induce ANCA positive vasculitides, and may only act as a second hit amplifying factor.