[Granulomatous vasculitides and vasculitides with extravascular granulomatosis]. / Granulomatöse Vaskulitiden und Vaskulitiden mit extravaskulärer Granulomatose.

Vasculitides are inflammatory diseases of blood vessels caused by autoimmune or infectious processes, which are associated with alterations and destruction of the vascular wall. From a histopathological point of view, granulomatous vasculitides can be distinguished from necrotizing vasculitides with respect to the pattern of inflammation. Granulomatous vasculitides are characterized by intramural, predominantly lymphohistiocytic infiltrates with the formation of giant cells. They include giant cell arteritis (GCA) and Takayasu arteritis (TAK). By contrast, anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) belongs to the group of necrotizing vasculitides. AAV includes granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). In addition to systemic necrotizing small vessel vasculitis, GPA and EGPA are characterized by extravascular granulomatous necrotizing inflammation mainly affecting the upper and/or lower respiratory tract, in EGPA with eosinophilic infiltrates. These granulomatous lesions are part of the autoimmune process and associated with tissue damage.

Granulomatous Inflammation in ANCA-Associated Vasculitis.

ANCA-associated vasculitis (AAV) comprises granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA). While systemic vasculitis is a hallmark of all AAV, GPA is characterized by extravascular granulomatous inflammation, preferentially affecting the respiratory tract. The mechanisms underlying the emergence of neutrophilic microabscesses; the appearance of multinucleated giant cells; and subsequent granuloma formation, finally leading to scarred or destroyed tissue in GPA, are still incompletely understood. This review summarizes findings describing the presence and function of molecules and cells contributing to granulomatous inflammation in the respiratory tract and to renal inflammation observed in GPA. In addition, factors affecting or promoting the development of granulomatous inflammation such as microbial infections, the nasal microbiome, and the release of damage-associated molecular patterns (DAMP) are discussed. Further, on the basis of numerous results, we argue that, in situ, various ways of exposure linked with a high number of infiltrating proteinase 3 (PR3)- and myeloperoxidase (MPO)-expressing leukocytes lower the threshold for the presentation of an altered PR3 and possibly also of MPO, provoking the local development of ANCA autoimmune responses, aided by the formation of ectopic lymphoid structures. Although extravascular granulomatous inflammation is unique to GPA, similar molecular and cellular patterns can be found in both the respiratory tract and kidney tissue of GPA and MPA patients; for example, the antimicrobial peptide LL37, CD163+ macrophages, or regulatory T cells. Therefore, we postulate that granulomatous inflammation in GPA or PR3-AAV is intertwined with autoimmune and destructive mechanisms also seen at other sites.

Low Concentrations of C5a Complement Receptor Antibodies Are Linked to Disease Activity and Relapse in Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis.

OBJECTIVE: To examine concentrations of circulating antibodies targeting C3a and C5a complement receptors in antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) and analyze their association with disease activity. METHODS: Concentrations of antibodies against C3a and C5a complement receptors (anti-C3aR and anti-C5aR) and plasma complement fragments C3a and C5a were determined in patients with AAV (n = 110; granulomatosis with polyangiitis [GPA; n = 82] or microscopic polyangiitis [MPA; n = 28]), systemic lupus erythematosus (SLE) patients as disease controls (n = 36), and healthy donors (n = 220). C3aR and C5aR expression by circulating neutrophils, monocytes, and T cells was analyzed using flow cytometry. Clinical data were assessed at time of serum sampling and during follow-up for 60 months. RESULTS: In AAV, anti-C3aR and anti-C5aR antibodies were decreased (P = 0.0026 and P ≤ 0.0001, respectively). In remission, anti-C3aR antibody concentrations rose to values comparable to healthy donors, whereas anti-C5aR antibody concentrations did not. In GPA, anti-C5a and anti-C5aR antibody concentrations inversely correlated with each other (r = -0.6831, P = 0.0127). In newly diagnosed GPA, decreased concentrations of anti-C5aR antibodies but not anti-C3aR antibodies were associated with disease activity (P = 0.0009). Moreover, low anti-C5aR antibodies were associated with relapse in GPA (hazard ratio 3.54, P = 0.0009) and MPA (hazard ratio 4.41, P = 0.0041). The frequency of C5aR-expressing cells within T cell populations was increased in GPA (P = 0.0021 for CD4+ T cells; P = 0.0118 for CD8+ T cells), but not in MPA. CONCLUSION: Low concentrations of anti-C5aR antibodies reflect disease activity and are associated with an increased risk for relapse in AAV.

Autoimmune pre-disease.

Approximately 5% of the world-wide population is affected by autoimmune diseases. Overall, autoimmune diseases are still difficult to treat, impose a high burden on patients, and have a significant economic impact. Like other complex diseases, e.g., cancer, autoimmune diseases develop over several years. Decisive steps in the development of autoimmune diseases are (i) the development of autoantigen-specific lymphocytes and (often) autoantibodies and (ii) potentially clinical disease manifestation at a later stage. However, not all healthy individuals with autoantibodies develop disease manifestations. Identifying autoantibody-positive healthy individuals and monitoring and inhibiting their switch to inflammatory autoimmune disease conditions are currently in their infancy. The switch from harmless to inflammatory autoantigen-specific T and B-cell and autoantibody responses seems to be the hallmark for the decisive factor in inflammatory autoimmune disease conditions. Accordingly, biomarkers allowing us to predict this progression would have a significant impact. Several factors, such as genetics and the environment, especially diet, smoking, exposure to pollutants, infections, stress, and shift work, might influence the progression from harmless to inflammatory autoimmune conditions. To inspire research directed at defining and ultimately targeting autoimmune predisease, here, we review published evidence underlying the progression from health to autoimmune predisease and ultimately to clinically manifest inflammatory autoimmune disease, addressing the following 3 questions: (i) what is the current status, (ii) what is missing, (iii) and what are the future perspectives for defining and modulating autoimmune predisease.