Antineutrophil Cytoplasmic Antibody-Associated Vasculitides
Antineutrophil Cytoplasmic Antibody-Associated Vasculitides
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides are a heterogeneous group of diseases corresponding to necrotising inflammation of small vessels with a wide range of clinical presentations. At least two of the diseases are believed to exhibit a common ground of pathophysiological mechanisms. These are granulomatosis with polyangiitis (GPA, formerly known as Wegener's granulomatosis) and microscopic polyangiitis (MPA). ANCA directed against proteinase 3 (PR3) are preferentially associated with GPA, and anti-myeloperoxidase (MPO) ANCA are associated mainly with MPA and eosinophilic GPA (formerly known as Churg-Strauss syndrome). Anti-MPO and anti-PR3 antibodies can activate neutrophils in vitro. In vivo data are available for humans and mice on the pathogenicity of anti-MPO but it is more controversial for PR3-ANCA. A recent genome-wide association study of patients with ANCA-associated vasculitides confirmed the genetic contribution to the pathogenesis of these conditions, with significant association of PR3-ANCA and human leukocyte antigen-DP and the genes encoding α1-antitrypsin and PR3. MPO-ANCA were significantly associated with human leukocyte antigen-DQ. Thus, recent results from epidemiological studies, genome-wide association study and therapeutic trials have suggested that these entities are, in fact, distinct. We have summarised these results and discuss the idea that these two entities should be studied separately as the nature of the two auto-antigens suggests at a molecular level despite shared ANCA involvement.
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs) are clinical entities corresponding to necrotising inflammation of small vessels and include three entities: two recently renamed granulomatosis with polyangiitis (GPA) and eosinophilic GPA (EGPA), and microscopic polyangiitis (MPA). The annual incidence of systemic vasculitides as a group is estimated at about 10–20 patients per million. These diseases represent a heterogeneous group with a wide range of clinical presentations. Histological analysis revealing granulomatous formations is a key feature of GPA and EGPA, together with eosinophilic infiltration for the latter. ANCA directed against proteinase 3 (PR3) are preferentially associated with GPA, and anti-myeloperoxidase (MPO) ANCA are associated mainly with MPA and EGPA. However, among the myriad proteins stored within neutrophil granules, only two of them, namely PR3 and MPO appear to be selective and almost mutually exclusive targets of ANCA. As a result, PR3-ANCA and MPO-ANCA became useful tools to differentially diagnose GPA and MPA, although GPA may rarely be associated with MPO-ANCA. Although PR3 and MPO are neutrophil-derived proteins stored within granules, their biochemical and functional properties are very different.
A lot of actors implicated in the pathophysiology of AAV are already identified. A large number of recent reviews provide detailed reports on these results. However, the causes of AAV are still unclear and their pathophysiological mechanisms remain poorly identified. One of the explanations for this is that the classical pathophysiological scheme proposing a common paradigm for MPA and GPA might have hampered the elaboration of antigen-specific stories or scenarios. Because EGPA is already considered as a distinct entity, we will in this review focus our attention on the differences between MPA and GPA regarding epidemiology, pathophysiology, clinical presentation and treatment, in order to propose that MPO-ANCA and PR3-ANCA associated diseases should be studied separately.
Abstract and Introduction
Abstract
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides are a heterogeneous group of diseases corresponding to necrotising inflammation of small vessels with a wide range of clinical presentations. At least two of the diseases are believed to exhibit a common ground of pathophysiological mechanisms. These are granulomatosis with polyangiitis (GPA, formerly known as Wegener's granulomatosis) and microscopic polyangiitis (MPA). ANCA directed against proteinase 3 (PR3) are preferentially associated with GPA, and anti-myeloperoxidase (MPO) ANCA are associated mainly with MPA and eosinophilic GPA (formerly known as Churg-Strauss syndrome). Anti-MPO and anti-PR3 antibodies can activate neutrophils in vitro. In vivo data are available for humans and mice on the pathogenicity of anti-MPO but it is more controversial for PR3-ANCA. A recent genome-wide association study of patients with ANCA-associated vasculitides confirmed the genetic contribution to the pathogenesis of these conditions, with significant association of PR3-ANCA and human leukocyte antigen-DP and the genes encoding α1-antitrypsin and PR3. MPO-ANCA were significantly associated with human leukocyte antigen-DQ. Thus, recent results from epidemiological studies, genome-wide association study and therapeutic trials have suggested that these entities are, in fact, distinct. We have summarised these results and discuss the idea that these two entities should be studied separately as the nature of the two auto-antigens suggests at a molecular level despite shared ANCA involvement.
Introduction
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs) are clinical entities corresponding to necrotising inflammation of small vessels and include three entities: two recently renamed granulomatosis with polyangiitis (GPA) and eosinophilic GPA (EGPA), and microscopic polyangiitis (MPA). The annual incidence of systemic vasculitides as a group is estimated at about 10–20 patients per million. These diseases represent a heterogeneous group with a wide range of clinical presentations. Histological analysis revealing granulomatous formations is a key feature of GPA and EGPA, together with eosinophilic infiltration for the latter. ANCA directed against proteinase 3 (PR3) are preferentially associated with GPA, and anti-myeloperoxidase (MPO) ANCA are associated mainly with MPA and EGPA. However, among the myriad proteins stored within neutrophil granules, only two of them, namely PR3 and MPO appear to be selective and almost mutually exclusive targets of ANCA. As a result, PR3-ANCA and MPO-ANCA became useful tools to differentially diagnose GPA and MPA, although GPA may rarely be associated with MPO-ANCA. Although PR3 and MPO are neutrophil-derived proteins stored within granules, their biochemical and functional properties are very different.
A lot of actors implicated in the pathophysiology of AAV are already identified. A large number of recent reviews provide detailed reports on these results. However, the causes of AAV are still unclear and their pathophysiological mechanisms remain poorly identified. One of the explanations for this is that the classical pathophysiological scheme proposing a common paradigm for MPA and GPA might have hampered the elaboration of antigen-specific stories or scenarios. Because EGPA is already considered as a distinct entity, we will in this review focus our attention on the differences between MPA and GPA regarding epidemiology, pathophysiology, clinical presentation and treatment, in order to propose that MPO-ANCA and PR3-ANCA associated diseases should be studied separately.
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