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Clinical immunology is in the Netherlands a separate clinical specialty within internal medicine and pediatrics.Clinical immunologists work closely together with nephrologists, rheumatologists and many other medical specialists. Apart from research and teaching, clinical immunologists are taking care of patients with immune-deficiencies, vasculitides and systemic auto-immune diseases. Clinical immunology in the Netherlands has always been an important contributor to basic and clinical science in the Netherlands.Major scientific contributions were made in the field of Systemic Lupus Erythematosus and ANCA associated vasculitis. These Dutch contributions will be reviewed in this article. (C) 2014 Elsevier B.V. All rights reserved.

Clinical immunology is in the Netherlands a separate clinical specialty within internal medicine and pediatrics. Clinical immunologists work closely together with nephrologists, rheumatologists and many other medical specialists. Apart from research and teaching, clinical immunologists are taking care of patients with immune-deficiencies, vasculitides and systemic auto-immune diseases. Clinical immunology in the Netherlands has always been an important contributor to basic and clinical science in the Netherlands. Major scientific contributions were made in the field of Systemic Lupus Erythematosus and ANCA associated vasculitis. These Dutch contributions will be reviewed in this article. (C) 2014 Elsevier B.V. All rights reserved.

Objective, To compare the disease spectrum of consecutive patients with antineutrophil cytoplasmic autoantibodies directed against proteinase 3 (anti-PR3) or myeloperoxidase (anti-MPO).Design. Retrospective analysis,Setting. Three teaching hospitals in the Netherlands.Main outcome measures, Clinical features at presentation, histopathological characteristics and outcome. Subjects. All consecutive patients who tested positive for anti-PR3 (n = 46) or anti-MPO (n = 46) over an X-year-period.Results, At diagnosis, patients with anti-PR3 had a higher vasculitis activity index than patients with anti-MPO (P Conclusion. A large divergence was seen in the disease spectrum between patients with anti-PR3 and those with anti-MPO. In particular, extra-renal disease manifestations, granuloma formation and relapses were more prominent in anti-PR3- than in anti-MPO-positive patients.

Objective, To compare the disease spectrum of consecutive patients with antineutrophil cytoplasmic autoantibodies directed against proteinase 3 (anti-PR3) or myeloperoxidase (anti-MPO). Design. Retrospective analysis, Setting. Three teaching hospitals in the Netherlands. Main outcome measures, Clinical features at presentation, histopathological characteristics and outcome. Subjects. All consecutive patients who tested positive for anti-PR3 (n = 46) or anti-MPO (n = 46) over an X-year-period. Results, At diagnosis, patients with anti-PR3 had a higher vasculitis activity index than patients with anti-MPO (P

Anti-neutrophil cytoplasmic autoantibodies (ANCA) have specificity for cytoplasmic proteins of myeloid cells. Many antigens recognized by ANCA have already been described. In most patients with primary forms of vasculitis such as Wegener's granulomatosis (WG), the Churg-Strauss Syndrome (CSS) and microscopic polyangiitis (MPA), ANCA with specificity for either proteinase 3 (PR3) or myeloperoxidase (MPO) can be detected. The diagnostic potential of these antibodies is now fairly well established. In a patient with signs and symptoms of vasculitis, anti-PR3 suggests a diagnosis of WG, whereas anti-MPO is associated with WG, CSS, MPA, and with idiopathic necrotizing crescentic glomerulonephritis. Anti-MPO, however, also occurs, incidentally, in other diseases. During follow-up studies, it has been shown that the persistence of ANCA or its reappearance is a risk factor for relaspe and/or poor renal outcome. In addition, rising ANCA levels are associated with recurrence in many cases. ANCA increases are, however, not invariably followed by relapse and high levels of ANCA may be found during clinical remission. So, different functional characteristics of antibodies may be of importance with respect to the development of relapses. Functional characteristics that might be important in disease reactivation include: subclass distribution, the capacity of ANCA to induce oxygen radicals, its capacity to inhibit the irreversible inactivation of proteinase 3 by al-antitrypsin, and/or its capacity to inhibit the proteolytic activity of PR3. ANCA levels may be either used to institute ''pre-emptive'' therapy, or to closely monitor patients to detect early signs of disease relapse, or to adopt an approach in which reductions of immunosuppressive treatment are postponed in those patients who remain ANCA positive. In a prospective study, relapses were prevented when treatment was started immediately after an increase in ANCA titers. These data, however, must be confirmed by studies on larger groups of patients. Hence, there is still an obvious need for more prospective studies.

Anti-neutrophil cytoplasmic antibodies (ANCA) constitute a new group of antibodies that are directed against myeloid proteins. Several antigens recognized by ANCA have been described. Antibodies directed to proteinase 3, myeloperoxidase and/or elastase are closely associated with necrotizing systemic vasculitis and/or necrotizing and crescentic glomerulonephritis. Changes in levels of anti-proteinase 3 in generally reflect disease activity in Wegener's granulomatosis. The diagnostic significance of other or still unknown specificities has not yet been definitely established. Recent data from in vitro and in vivo models suggest a role for ANCA in the pathogenesis of systemic vasculitides and/or necrotising and crescentic glomerulonephritis.

Anti-neutrophil cytoplasmic antibodies (ANCA) constitute a new group of antibodies that are directed against myeloid proteins. Several antigens recognized by ANCA have been described. Antibodies directed to proteinase 3, myeloperoxidase and/or elastase are closely associated with necrotizing systemic vasculitis and/or necrotizing and crescentic glomerulonephritis. Changes in levels of anti-proteinase 3 in generally reflect disease activity in Wegener's granulomatosis. The diagnostic significance of other or still unknown specificities has not yet been definitely established. Recent data from in vitro and in vivo models suggest a role for ANCA in the pathogenesis of systemic vasculitides and/or necrotising and crescentic glomerulonephritis.

Neutrophil activation in vitro and in vivo in kidneys in Wegener's granulomatosis. The mechanisms underlying glomerular capillary wall injury in Wegener's granulomatosis (WG) are not well understood. Anti-neutrophil cytoplasmic antibodies (ANCA), present in sera from patients with WG, are known to stimulate respiratory burst and degranulation of primed polymorphonuclear neutrophils (PMN) in vitro. Experimental studies have shown that oxygen radical production and lysosomal enzymes are important mediators of glomerular capillary wall injury. In the present study we investigated the presence of activated PMN and the extracellular localization of lysosomal enzymes in 28 consecutive renal biopsies from patients with WG. The presence of activated PMN within the renal biopsies was compared with the capacity of ANC A, isolated from simultaneously drawn serum samples, to activate primed PMN obtained from a normal donor. Both parameters were also related to renal function. Renal biopsies were obtained from newly diagnosed WG patients before therapy had started. Activation of PMN in the biopsies was assessed by measuring hydrogen peroxide production in situ. The number of activated PMN in the biopsy correlated with the extent of impairment of renal function. Proteinase 3, myeloperoxidase, and elastase, all targets of ANCA, were localized extracellularly in renal tissue and were also found within tubular epithelial cells. All ANC A positive samples were capable of activating primed PMN. The amount of activation correlated with the ANCA titer in those samples. No correlation, however, was found between the in vitro capacity of ANCA-positive IgG fractions to activate primed PMN and the number of activated PMN present in the renal biopsy. We conclude that activated PMN producing toxic oxygen metabolites and releasing lysosomal enzymes, are present in renal biopsies from patients with WG. The amount of activated PMN present within the kidney, and not the capacity of the corresponding ANCA to activate PMN, correlates with renal tissue damage as assessed by serum creatinine levels.

Antineutrophil cytoplasmic antibodies (ANCA) have been described as sensitive and specific markers for active Wegener's granulomatosis (WG). ANCA in WG produce a characteristic cytoplasmic staining pattern of neutrophils (c-ANCA) and are directed against proteinase 3 (Pr3), a serine protease from the azurophilic granules. c-ANCA, more or less equivalent to anti-Pr3, occur in more than 90% of patients with extended WG, in 75% of patients with limited WG without renal involvement, and in some 40% to 50% of patients with vasculitic overlap syndromes suggestive of WG such as microscopic polyarteritis. The presence of c-ANCA is highly specific for those diseases (greater than 98%). Changes of levels of c-ANCA precede disease activity and may be used as guidelines for treatment.Antibodies producing a perinuclear staining of ethanol-fixed neutrophils (p-ANCA) occur in a wide range of diseases. They are directed against different cytoplasmic constituents of neutrophils. Among those, antibodies to myeloperoxidase are found in patients with idiopathic crescentic glomerulonephritis, the Churg-Strauss syndrome, polyarteritis nodosa with visceral involvement, and vasculitic overlap syndromes. Their specificity for this group of necrotizing vasculitides is high (94% to 99%), although they may occur in patients with hydralazine-induced glomerulonephritis, anti-glomerular basement membrane disease, and possibly in some patients with idiopathic systemic lupus erythematosus. Antibodies to leukocyte elastase are incidentally found in patients with vasculitic disorders, whereas lactoferrin antibodies are detected in patients with primary sclerosing cholangitis with or without ulcerative colitis and in rheumatoid arthritis. Their diagnostic significance awaits further studies. p-ANCA of undefined specificity may distinguish ulcerative colitis (sensitivity of 75%) from Crohn's (sensitivity of 20%). p-ANCA also occur in autoimmune liver diseases: in 75% of patients with chronic active hepatitis, in 60% to 85% of those with primary sclerosing cholangitis, and in about 30% of patients with primary biliary cirrhosis. Finally, p-ANCA are detected in chronic arthritides and in some 5% of healthy controls. Assessment of their diagnostic value has to await further characterization of the antigens involved, allowing the development of antigen-specific assays.

Antineutrophil cytoplasmic antibodies (ANCA) have been described as sensitive and specific markers for active Wegener's granulomatosis (WG). ANCA in WG produce a characteristic cytoplasmic staining pattern of neutrophils (c-ANCA) and are directed against proteinase 3 (Pr3), a serine protease from the azurophilic granules. c-ANCA, more or less equivalent to anti-Pr3, occur in more than 90% of patients with extended WG, in 75% of patients with limited WG without renal involvement, and in some 40% to 50% of patients with vasculitic overlap syndromes suggestive of WG such as microscopic polyarteritis. The presence of c-ANCA is highly specific for those diseases (greater than 98%). Changes of levels of c-ANCA precede disease activity and may be used as guidelines for treatment. Antibodies producing a perinuclear staining of ethanol-fixed neutrophils (p-ANCA) occur in a wide range of diseases. They are directed against different cytoplasmic constituents of neutrophils. Among those, antibodies to myeloperoxidase are found in patients with idiopathic crescentic glomerulonephritis, the Churg-Strauss syndrome, polyarteritis nodosa with visceral involvement, and vasculitic overlap syndromes. Their specificity for this group of necrotizing vasculitides is high (94% to 99%), although they may occur in patients with hydralazine-induced glomerulonephritis, anti-glomerular basement membrane disease, and possibly in some patients with idiopathic systemic lupus erythematosus. Antibodies to leukocyte elastase are incidentally found in patients with vasculitic disorders, whereas lactoferrin antibodies are detected in patients with primary sclerosing cholangitis with or without ulcerative colitis and in rheumatoid arthritis. Their diagnostic significance awaits further studies. p-ANCA of undefined specificity may distinguish ulcerative colitis (sensitivity of 75%) from Crohn's disease (sensitivity of 20%). p-ANCA also occur in autoimmune liver diseases: in 75% of patients with chronic active hepatitis, in 60% to 85% of those with primary sclerosing cholangitis, and in about 30% of patients with primary biliary cirrhosis. Finally, p-ANCA are detected in chronic arthritides and in some 5% of healthy controls. Assessment of their diagnostic value has to await further characterization of the antigens involved, allowing the development of antigen-specific assays.

Objective, To compare the disease spectrum of consecutive patients with antineutrophil cytoplasmic autoantibodies directed against proteinase 3 (anti-PR3) or myeloperoxidase (anti-MPO). Design. Retrospective analysis, Setting. Three teaching hospitals in the Netherlands. Main outcome measures, Clinical features at presentation, histopathological characteristics and outcome. Subjects. All consecutive patients who tested positive for anti-PR3 (n = 46) or anti-MPO (n = 46) over an X-year-period. Results, At diagnosis, patients with anti-PR3 had a higher vasculitis activity index than patients with anti-MPO (P

Anti-neutrophil cytoplasmic antibodies (ANCA) constitute a new group of antibodies that are directed against myeloid proteins. Several antigens recognized by ANCA have been described. Antibodies directed to proteinase 3, myeloperoxidase and/or elastase are closely associated with necrotizing systemic vasculitis and/or necrotizing and crescentic glomerulonephritis. Changes in levels of anti-proteinase 3 in generally reflect disease activity in Wegener's granulomatosis. The diagnostic significance of other or still unknown specificities has not yet been definitely established. Recent data from in vitro and in vivo models suggest a role for ANCA in the pathogenesis of systemic vasculitides and/or necrotising and crescentic glomerulonephritis.

Rapidly progressive glomerulonephritis (RPGN) is a clinical syndrome characterized by rapid deterioration of renal function occurring within days or weeks together with signs of glomerulonephritis, that is, proteinuria and hematuria with cellular casts. The syndrome is, in many cases, histopathologically manifested as fibrinoid necrosis of the capillary wall with extracapillary proliferation and crescent formation [1]. This so-called necrotizing crescentic glomerulonephritis (NCGN) is seen in 5 to 15% of renal biopsies in most series [1–3]. Although it is infrequent, the importance of the condition is illustrated by the fact that most cases of NCGN, if left untreated, develop renal failure within days or weeks [1]. Based on immunohistopathology NCGN can be subdivided into three distinct categories. The first one, occurring in 2 to 20% of the cases and characterized by linear staining of the glomerular capillary wall for immunoglobulin and complement, has classically been described as anti-glomerular basement membrane (GBM) disease. It is associated with autoantibodies to structural antigens of the GBM, in particular to the first globular noncollagen domain of collagen type IV [4]. The antibodies are considered of pathogenetic significance. The second category, comprising 15 to 50% of cases, is characterized by granular deposits of immunoglobulin and complement suggesting that immune complexes are pathogenetically involved. This type occurs in conjunction with systemic autoimmune diseases such as lupus erythematosus, in cases of post-infectious glomerulonephritis, IgA nephropathy or Henoch-Schonlein purpura, or as an idiopathic variety. The third group of NCGN, occurring in 40 to 80%, demonstrates only a few or no immune deposits and is designated as pauci-immune NCGN [1–3, 5, 6]. Pauci-immune NCGN occurs as part of Wegener's granulomatosis (WG) or related conditions, or without systemic vasculitis (idiopathic NCGN). The pathophysiology of this pauci-immune type of NCGN has not been elucidated. Within the last decade, however, it has been recognized that the condition is associated with autoantibodies to cytoplasmic components of neutrophils (anti-neutrophil cytoplasmic antibodies or ANCA). ANCA were first described in 1982 by Davies et al in a few patients with segmental necrotizing glomerulonephritis [7]. Only in 1985 did it become apparent that ANCA are a sensitive and specific marker for Wegener's granulomatosis (WG) [8]. Later on, ANCA were described in patients with microscopic polyarteritis [9]. Falk and Jennette, in 1988, showed that ANCA are also associated with the idiopathic form of pauci-immune NCGN [10]. These data have now been confirmed by many groups and support the view that ANCA-associated glomerulonephritis and vasculitis is, indeed, a distinct disease category. A number of studies, in addition, have suggested that ANCA are involved in the pathophysiology of the aforementioned disorders. As ANCA, however, have recently also been detected in a wide range of inflammatory and infectious conditions, a critical reappraisal of the diagnostic significance of ANCA-testing seems justified. In this review we will evaluate the current state of ANCA-testing as well as elaborate on the pathophysiological role of the autoantibodies in necrotizing glomerulonephritis and vasculitis. Data presented recently at the Fifth International Workshop on ANCA, held in Cambridge, United Kingdom, will be included [11]. As such, it adds to previous reviews on ANCA that were published following the Second [12], Third [13], and Fourth [14] Workshops on ANCA.

Antineutrophil cytoplasmic antibodies (ANCAs) constitute a new class of autoantibodies that seem to recognise myeloid lysosomal enzymes. The occurrence of ANCAs with specificity for human leucocyte elastase (HLE) was assessed in serum samples that were routinely submitted for ANCA determination. During a study period of more than six years anti-HLE was found in only six out of 1102 serum samples that produced a perinuclear or an atypical cytoplasmic staining pattern on ethanol fixed granulocytes. These six serum samples were from four patients with a clinical diagnosis of Wegener's granulomatosis but without a definite histological diagnosis, one patient with systemic vasculitis, and one patient with Cogan's syndrome. To further evaluate the prevalence of anti-HLE we tested 315 serum samples from patients with different forms of vasculitis and related disorders. Anti-HLE was detected in two patients only. Thus autoantibodies to HLE are rarely found in serum samples from patients with vasculitic or related disorders.