ANCA associated vasculitis – new insight into pathogenesis, diagnostics and therapy**
Nowe spojrzenie na patogenezę, diagnostykę i leczenie układowego zapalenia naczyń związanego z przeciwciałami ANCA
Department of Nephrology and Transplantation Medicine, Wrocław Medical University
Head of Department: Professor Marian Klinger MD, PhD
ANCA (anti-neutrophil cytoplasmic antibodies) associated vasculitis is according to Chapel-Hill Consensus necrotizing vasculitis, vasculitis with few or no immune deposits, predominantly affecting small vessels (i.e. capillaries, venules, arterioles and small arteries), that is associated with MPO (myeloperoxidase)-ANCA or PR3 (proteinase3)-ANCA. These kinds of antibodies are connected with three types of vasculitis: granulomatosis with polyangiitis-GPA (earlier Wegener’s granulomatosis), microscopic vasculitis-MPA and eosinophilic granulomatosis with polyangiitis-EGPA (earlier Churg-Strauss syndrome) (1). This review summarizes current information about ANCA associated vasculitis concerning epidemiology, pathogenesis, diagnostics and therapy.
Vasculitis type depends on geographical region. Granulomatosis with polyangiitis is more frequent in the northern Europe. Microscopic vasculitis is more common in southern Europe, Japan (2) and in Peru (3), Asians and Maoris in New Zealand (4). Granulomatosis with polyangiitis frequency doubled in Germany between 1994 and 2006. The reasons were probably: increase of disease awareness and more often diagnosis of this disease, increase in survival of patients (5). Frequency of microscopic polyangiitis also increases in Germany (5), Australia (6). The frequency of biopsy proven ANCA (+) vasculitis among people over 18 years old was more than 13.2 million per year. 36 from 82 patients (44%) have died for 12 years of observation (7).
There are many antigens associated with susceptibility to ANCA associated vasculitis. Full list of them may be found in one of the newest publications (8). Very important are also environmental factors, especially infections. Associations between infections: Pseudomonas, Klebsiella, Escherichia coli (9), Staphylococcus aureus (10), Enterococcus (11), Ross-River virus (12), Epstein-Barr virus (13), exposure to mRNA in influenza vaccine (14), Rickettsiae (15) infections and development of ANCA associated vasculitis in human were found. Molecular mimicry between fimbrie FimH of Escherichia coli, Klebsiella and human LAMP (lysosome associated membrane protein) antibodies was also described (16). There was also found that granulomatosis with polyangiitis appearance is cyclical with a period 7.6 years. There was suggested that this disease might be connected with cyclical infection (17). Connections between ambient UVR (ultraviolet radiation) and incidence of granulomatosis with polyangiitis and eosynophilic granulomatosis with polyangiitis were also found (18). Silica is other postulated risk factor of granulomatosis with polyangiitis and microscopic vasculitis (19). Other potential risk factors of c-ANCA positive vasculitis are heavy metal and pesticides exposure, atopy (20), farm exposure (21), drugs. There was also found that microscopic vasculitis is more common in rural than in urban area in Australia (6).
ANCA associated vasculitis accordingly with current knowledge develops as a result of neutrophils activation by autoantibodies directed to neutrophils antigens myeloperoxidase and proteinase 3 or against human lysosome-associated membrane protein-2 which is present in neutrophils and vascular endothelium (22). Genetic background promotes development of the disease. At the beginning many environmental factors (infections, stress, lipopolisaccharides and others) may cause priming of neutrophils and complement system activation. As a result of epigenetic changes primed neutrophils exhibit more than normal myeloperoxidase and proteinase 3 on their surface (23) and adhere to endothelium. After that production of ANCA antibodies begins. ANCA antibodies increase priming of neutrophils through Fab and Fc receptor. Primed neutrophils excrete many factors like properdine, B factor, proteases, ROS (reactive oxygen species) and myeloperoxidase. Indicators of neutrophils apoptosis were diminished in the course of ANCA positive systemic vasculitis in comparison with healthy persons (24). As a result vascular endothelium dysfunction appears and alternative complement pathway activation begins including C5a production (25). C5a strongly attracts neutrophils what cause an influx of this kind of cells and induction of severe necrotic vasculitis (26). Moreover in the course of ANCA vasculitis development of NETs (neutrophil extracellular traps) formation appears (27). Products of granulocytes priming especially free radicals promote NETs formation (28). NETs may bind different antigens in chromatin web and activate TLRs (Toll-like receptors) directly (29). TLRs activate lymphocytes Th: TLR9-Th1, and TLR2-Th17 (30). Treg cells function is also impaired in the course of ANCA vasculitis (31). Breg number is diminished without impaired function (in terms of Il-10 production) in the course of ANCA associated vasculitis (32). There is a large number of memory B cells relatively to other B cells during remission in patients with ANCA associated vasculitis. This imbalance may promote big percentage of disease relapses, especially in PR-3 ANCA systemic vasculitis (33). Changes in other kinds of cells function in the course of ANCA associated vasculitis also appear. There was also found that serum from patients with ANCA (+) vasculitis stimulates M2c macrophages podtype to fagocytosis (34). CD14 expression correlated with ANCA autoantigen expression in ANCA vasculitis on monocytes and there were suggestions that it may reflect cell activation (35). Macrophages and dendritic cells were the cells producing chemokine CCL18, antigen that expression is high in crescentic ANCA associated vasculitis and correlates with crescent formation, interstitial inflammation, and impairment of renal function (36). The biomarkers of ANCA positive systemic vasculitis in urine are also searched. It was found that in the course of the disease relapses: alfa-1 acid glycoprotein, KIM-1 (kidney injury molecule 1), MCP-1 (monocyte chemoattractant protein-1), NGAL (neutrophil gelatinase-associated lipocalin) levels increased. MCP-1 levels were the best differentiator of active disease and remission: 1.3 fold increase of MCP-1 was highly associated with relapse of disease (94% sensitivity and 89% of specificity) (37).
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