Antineutrophil cytoplasmic autoantibodies in inflammatory bowel disease.
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Antibodies, Antineutrophil Cytoplasmic↗
Biomedical subjects
J C Jennette
Publications and source records attributed to J C Jennette.
Do antineutrophil cytoplasmic autoantibodies cause Wegener's granulomatosis and other forms of necrotizing vasculitis?
The in vitro experimental observations support the theoretical pathogenic scenario depicted in Figure 14. A similar scenario could be portrayed for monocytes. ANCA in the circulation are unable to interact with unprimed neutrophils because the target antigens are within the cytoplasm (Fig. 14A). Synergistic priming of neutrophils, e.g., by an infection, causes small amounts of target antigens to be released at the cell surface (Fig. 14B) where they can interact with ANCA (Fig. 14C). ANCA-activated neutrophils then adhere to endothelial cells via adhesion molecule interactions that may require prior priming of the endothelial cells (Fig. 14C). These activated and adherent neutrophils then injure endothelial cells (and eventually underlying vessel wall structures) by releasing granule enzymes and toxic oxygen metabolites (Fig. 14D). Although many research groups throughout the world have been attempting to create an animal model of ANCA-induced disease based on the theoretical paradigm proposed in Figure 14, as well as on other paradigms, no one has reported complete success. Until this is accomplished, the role of ANCA in the pathogenesis of Wegener's granulomatosis and other forms of ANCA-associated vasculitides will remain conjectural.
Antibodies, Antineutrophil Cytoplasmic↗
Nephropathology consultation via digitized images.
Investigations into a digitized image communications system were prompted by a need to bring expert consultation to physicians in community practice. Pathologists desired the capability to concomitantly view, annotate, and discuss images with referring physicians at distant sites. Methods included evaluation of the human and procedural domain into which the system was to be integrated. The GDCN computer consultation system has the consultant nephropathologist first evaluate the processed biopsy slides, digitize representative images, transmit them with the diagnosis to referring nephrologist, and, finally, conduct an interactive consultation and review of the biopsy and case. Image resolution and compression variables must be set for each individual medical consulting application. For the GDCN, it was found that the 640 x 496 x unlimited color with compression ratios not exceeding 1:32 are acceptable. An obvious improvement of this computerized system over the noncomputerized review sessions is the ability to immediately share and discuss a new image that had not been previously sent. In the old noncomputerized consultation, only images that had been mailed could be discussed. The computerized sessions allow transmission (10 sec) of a new image that the consultation might demand. The computerized sessions also provide the ability to show the referring nephrologist an area of biopsy interest that the pathologist had not previously transmitted. Biopsy slides can be viewed during the consultation, an area digitized, and that image transmitted to the nephrologist during the consultation. Hardware and costs for the sending station were: [table: see text] This system far exceeds the requirements for this particular application; however, it is sufficient to support future, higher-technology computer applications. If necessary, this same system could be used with a less expensive computer, a less expensive camera, software compression, and a single monitor. These alterations could lessen the expenditures by some $8000 and result in a total cost of $10,000. Hardware and costs for the receiving station were: [table: see text] Cost of the receiving station could be reduced by using a less expensive computer and a single monitor system, thereby saving up to $5000 and resulting in a total cost of $7,400. DCCEC and GDCN have elected to use the more expensive, user-friendly and more rapid image transmission system SEND-->IT, rather than the less expensive system mainly because of experience with incorporating the system into the daily activities of the GDCN. SEND-->IT best met the essentials for GDCN.(ABSTRACT TRUNCATED AT 400 WORDS)
Biopsy↗
Prevalence and pathologic features of sickle cell nephropathy and response to inhibition of angiotensin-converting enzyme.
BACKGROUND: Nephropathy may develop in patients with sickle cell disease. We determined the prevalence of proteinuria and renal insufficiency in a group of patients with sickle cell disease and investigated the renal pathologic changes and the effects of an angiotensin-converting-enzyme inhibitor (enalapril) on protein excretion in patients found to have nephropathy. METHODS: We prospectively screened 381 patients with sickle cell disease for the presence of proteinuria and renal insufficiency. Renal biopsy and measurements of glomerular filtration rate, effective renal plasma flow, and urinary protein excretion were performed in 10 patients with mild nephropathy before and after the administration of enalapril, and again two to three weeks after its discontinuation. RESULTS: Of the 381 patients with sickle cell disease, 26 (7 percent) had serum creatinine concentrations above the normal range and 101 (26 percent) had proteinuria of at least 1+. The renal lesions in the 10 patients who had biopsies consisted of glomerular enlargement and perihilar focal segmental glomerulosclerosis. The mean (+/- SD) glomerular area in these patients was 28.7 +/- 4.1 x 10(3) micron 2, as compared with 15.8 +/- 4.3 x 10(3) micron 2 in 10 control patients without renal disease who had died of trauma (P less than 0.0001). During the administration of enalapril, the mean 24-hour urinary protein excretion decreased 57 percent (range, 23 to 79 percent) below the base-line value (P less than 0.001), and it increased to 25 percent below the base-line value after enalapril was discontinued. The glomerular filtration rate and effective renal plasma flow did not change significantly. CONCLUSIONS: Approximately 25 percent of patients with sickle cell disease have proteinuria. Treatment with enalapril reduces the degree of proteinuria in these patients, suggesting that glomerular capillary hypertension may be a pathogenic factor in sickle cell nephropathy.
Adult↗
Treatment of progressive membranous glomerulopathy. A randomized trial comparing cyclophosphamide and corticosteroids with corticosteroids alone. The Glomerular Disease Collaborative Network.
OBJECTIVE: To determine if deterioration in renal function could be ameliorated by adding cyclophosphamide to corticosteroid therapy in patients with progressive membranous glomerulopathy. DESIGN: Randomized, controlled treatment trial. Patients were followed for a mean of 29.2 +/- 17.1 months. SETTING: Collaborative network of 120 university and private-practice nephrologists. PARTICIPANTS: Patients with membranous glomerulopathy whose renal function deteriorated (as evidenced by doubling of the serum creatinine level, a 50% fall in the glomerular filtration rate, or a sustained serum creatinine level of greater than 2.0 mg/dL [reciprocal creatinine value, 0.5], or whose nephrotic range proteinuria persisted in association with morbid complications. Of 156 patients with biopsy-proven membranous glomerulopathy, 36 became eligible for randomization. Twenty-six of these 36 patients were randomly assigned to receive one of the two treatments. INTERVENTIONS: Pulse methylprednisolone, oral corticosteroids, and 6 months of intravenous cyclophosphamide or alternate-day corticosteroid therapy alone. MAIN RESULTS: At entry, no statistical differences were found between the treatment groups in duration of renal disease, age, gender, serum creatinine level, 24-hour urine protein excretion, or biopsy stage. The groups showed no difference in mean arterial blood pressure during follow-up. Four of the 13 patients receiving corticosteroids alone and 4 of the 13 patients receiving corticosteroids plus intravenous cyclophosphamide progressed to end-stage renal disease during follow-up. Reciprocal creatinine values tested at 6-month intervals showed no statistical differences between treatment groups at any time point. The log of the 24-hour protein excretion values showed no statistical differences between treatment groups after treatment. The power to detect a substantial improvement in renal function, defined as a doubling of the reciprocal of the serum creatinine, at the 0.05 significance level was 0.92. CONCLUSIONS: Combination therapy with intravenous cyclophosphamide and corticosteroids, when compared with corticosteroid therapy alone, does not improve renal function in patients with progressive membranous glomerulopathy.
Adult↗
Reactivity of antineutrophil cytoplasmic autoantibodies with mononuclear phagocytes.
Antineutrophil cytoplasmic autoantibodies (ANCA) react with proteins found in the granules of neutrophils and the peroxidase-positive lysosomes of monocytes, including myeloperoxidase (MPO), proteinase 3 (PR-3), and elastase. ANCA-associated diseases, such as Wegener's granulomatosis and polyarteritis nodosa, are characterized by necrotizing vascular inflammation. The inflammatory lesions typically contain both neutrophils and mononuclear phagocytes, with the latter sometimes predominating, for example, in the granulomatous lesions of Wegener's granulomatosis. We investigated the presence of the ANCA target antigens PR3, MPO, and elastase in mononuclear phagocyte cytoplasm during the course of differentiation in vitro and in alveolar and peritoneal macrophages. We observed that ANCA antigens were down-regulated during mononuclear phagocyte differentiation, with the loss corresponding to that of peroxidase-positive granules. This suggests that ANCA can directly interact only with monocytes and early exudative macrophages and not with mature macrophages.
Autoantibodies↗
Clinical and pathologic features of fibrillary glomerulonephritis.
A diagnosis of fibrillary glomerulonephritis was made in 31 renal biopsies from 28 patients on the basis of the electron microscopic identification of glomerular deposits of randomly arranged fibrils that resembled amyloidosis but were larger. This accounted for approximately 1% of all nontransplant renal biopsy diagnoses. Renal biopsy specimens with parallel arrays of 30 nm to 50 nm microtubules (that is, immunotactoid glomerulopathy) were not included in the study. The patients had a mean age of 49 years with a range of 21 to 75. The male to female ratio was 1:1.8 and the ratio of Whites to Blacks was 8.3:1, which differs from the 3:1 ratio in our overall biopsy population. All patients had proteinuria (mean 6.0 g/day), and most had hematuria and renal insufficiency. After a mean follow-up of 24 months, there was 48% renal survival. The light microscopic appearance of the fibrillary glomerulonephritis was quite varied. Capillary wall thickening and matrix expansion were the most frequent alterations. Nineteen percent of specimens had crescents. Morphometric ultrastructural analysis demonstrated a mean fibril diameter of 22.4 +/- 7.4 nm. Immunofluorescence microscopy revealed that IgG was the dominant and often the only immunoglobulin class in immune deposits, and subclass analysis revealed that IgG4 was the dominant or exclusive subclass in all specimens tested. We hypothesize that the relatively homogeneous nature of the immunoglobulin in the immune deposits is the basis for the fibril formation.
Adult↗
Anti-myeloperoxidase antibodies stimulate neutrophils to damage human endothelial cells.
Anti-myeloperoxidase autoantibodies are found in association with idiopathic necrotizing glomerulonephritis and systemic vasculitis. It is not known if their presence is an epiphenomen or an integral part of the pathogenic process. To further delineate their hypothesized pathogenicity, we studied their ability to stimulate neutrophils to damage human umbilical vein endothelial cells in vitro. Anti-myeloperoxidase antibodies from human, rabbit and mouse sources were utilized. These antibodies stimulated neutrophils to damage endothelial cells as determined by 51Cr release. The effect was dependent on priming the neutrophils with tumor necrosis factor-alpha, and further enhanced with the addition of endotoxin. The amount of endothelial cell damage was dependent on the dose of anti-myeloperoxidase, the source of the neutrophils, the concentration of TNF, and the presence of endotoxin. Under identical conditions, control antibodies did not stimulate neutrophils to damage endothelial cells. The effect was confirmed by labeling the endothelial cells with 3H-adenine which yielded the same results. These results provide further in vitro evidence that anti-myeloperoxidase autoantibodies may play a significant role in the pathogenesis of idiopathic pauci-immune glomerulonephritis and vasculitis.
Adenine↗
Anti-myeloperoxidase autoantibodies react with native but not denatured myeloperoxidase.
We wondered whether anti-myeloperoxidase (MPO) autoantibodies (MPO-ANCA) found in patients with systemic vasculitis react with a conformational epitope or epitopes on the MPO molecule. Sera from 15 human MPO-ANCA, and a polyclonal and a monoclonal anti-MPO antibodies were reacted with MPO in native and denatured states. Human MPO-ANCA and mouse monoclonal anti-MPO reacted with native MPO, and a 120-kD band representing the MPO hologenzyme, but not with denatured MPO fragments; however, MPO-ANCA and mouse anti-MPO did not demonstrate competitive inhibition of binding to MPO. Polyclonal rabbit anti-MPO reacted with both native and denatured MPO. All MPO-ANCA tested showed the same patterns of reactivity with native and denatured MPO in dot blot and Western blot analyses. Both polyclonal and monoclonal anti-MPO antibodies inhibited MPO's protein iodination by over 90%, whereas MPO-ANCA IgGs, normal IgGs and disease control IgGs did not. These data suggest that (i) MPO-ANCA interact with a conformational epitope on the MPO molecule; and (ii) MPO-ANCA from different patients have similar reactivity with native versus denatured MPO.
Antibodies, Antineutrophil Cytoplasmic↗
Acute renal failure secondary to leukocyte-mediated acute glomerular injury.
Acute glomerulonephritis can cause acute renal failure. Activated neutrophils and monocytes are major effectors of glomerulonephritic renal failure. Adhesion molecules, granule enzymes, reactive oxygen radicals, lipid metabolites, and cytokines of activated neutrophils and monocytes mediate glomerular capillary constriction, occlusion, and destruction. Injurious products and biologically active mediators released by activated leukocytes have profound functional effects on mesangial cells and endothelial cells, which in turn participate in the disturbance of glomerular function, for example, by altering capillary diameter and surface area. The glomerular inflammatory events result in decreased glomerular capillary ultrafiltration coefficient and glomerular filtration rate, as well as other functional perturbations.
Acute Kidney Injury↗
ANCA--diagnostic markers or pathogenic agents?
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Antibodies, Antineutrophil Cytoplasmic↗
Disease associations and pathogenic role of antineutrophil cytoplasmic autoantibodies in vasculitis.
Antineutrophil cytoplasmic autoantibodies are a useful diagnostic serologic marker for a variety of well-known vasculitic syndromes, including Wegener's granulomatosis, polyarteritis nodosa (especially microscopic polyarteritis nodosa), Churg-Strauss syndrome, and pulmonary-renal syndrome with alveolar capillaritis. Although most patients with antineutrophil cytoplasmic autoantibody-associated disease have systemic disease, disease limited to one organ does occur, eg, isolated necrotizing glomerulonephritis, isolated respiratory tract disease, or isolated orbital disease. Antineutrophil cytoplasmic autoantibody titers may be useful in modulating treatment regimens. There is in vitro evidence that antineutrophil cytoplasmic autoantibodies are directly involved in the pathogenesis of antineutrophil cytoplasmic autoantibody-associated vasculitides.
Antibodies, Antineutrophil Cytoplasmic↗
Antibodies against granule proteins activate neutrophils in vitro.
Polymorphonuclear leukocyte (PMN) respiratory burst was stimulated by heterologous antibodies against PMN granule proteins but not by control antibodies. Fluorescence-activated cell sorter (FACS) analysis of activated PMN demonstrated the presence of two primary granule proteins, proteinase 3 (PR-3) and cationic protein 57 (CAP-57) at the membrane surface. The presence of myeloperoxidase (MPO) at the cell surface of primed and unprimed PMN was confirmed by immunoelectron microscopy. Priming doses of recombinant tumor necrosis alpha (rTNF alpha) enhanced the rate of superoxide (O2-) production by these antibodies and increased the amount of surface protein accessible to these antibodies. Anti-neutrophil cytoplasmic autoantibodies (ANCA) with specificities for PMN granule proteins are present in patients with Wegener's granulomatosis, polyarteritis nodosa, and idiopathic and crescentic glomerulonephritis. The demonstration that antibodies against granule proteins activate PMN supports the hypothesis that the vasculitis seen in these diseases is due in part to PMN mediated oxidative injury following PMN stimulation by ANCA.
Antibodies, Antineutrophil Cytoplasmic↗
Antineutrophil cytoplasmic autoantibodies: disease associations, molecular biology, and pathophysiology.
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Autoantibodies↗
Serum IgA-fibronectin aggregates in patients with IgA nephropathy and Henoch-Schönlein purpura: diagnostic value and pathogenic implications. The Glomerular Disease Collaborative Network.
IgA nephropathy is a common form of glomerulonephritis that has varied clinical expressions, ranging from asymptomatic hematuria to rapidly progressive nephritis. We report the strong association (P less than 0.0001) of circulating IgA-fibronectin aggregates with IgA nephropathy. Of 30 patients with IgA nephropathy, 93.3% had serum IgA-fibronectin aggregates detected with an enzyme immunoassay using collagen as a substrate to bind the aggregates. Among the patients with IgA-fibronectin aggregates were patients with Henoch-Schönlein purpura and recurrent crescentic IgA nephropathy in transplants. Only 11.7% of 103 patients with other types of glomerular disease and 6.7% of normal controls had positive IgA-fibronectin aggregate assay levels. IgA-fibronectin aggregates also were detected in serum using an antifibronectin antibody capture assay; and could be depleted from serum by heparin-agarose affinity chromatography. The circulating IgA-fibronectin aggregates had the same unusual predominance of lambda relative to kappa light chains that is observed in the glomerular deposits of IgA nephropathy. The data indicate that IgA-fibronectin aggregates are a useful serologic marker for IgA nephropathy, Henoch-Schönlein purpura, and recurrent IgA nephropathy in transplants. The presence of fibronectin in the circulating aggregates may play an important role in the preferential deposition of nephritogenic IgA-containing immune complexes in the mesangium of patients with IgA nephropathy.
Antigen-Antibody Complex↗
Antineutrophil cytoplasmic autoantibody-associated diseases: a pathologist's perspective.
Antineutrophil cytoplasmic autoantibodies (ANCA) are a useful diagnostic serologic marker for the most common forms of necrotizing vasculitis, provide a means of categorizing vasculitides so that diagnostically useful shared pathologic and clinical characteristics can be recognized, and offer insight into the pathogenesis of previously idiopathic diseases. ANCA-associated vasculitides can be categorized into a number of distinctive clinicopathologic categories, eg, Wegener's granulomatosis, Churg-Strauss syndrome, pulmonary renal syndrome, microscopic polyarteritis nodosa, leukocytoclastic angiitis, and necrotizing and crescentic glomerulonephritis. At least the latter four syndromes can also be caused by other ANCA-negative immunopathogenic mechanisms, eg, immune complex deposition. Therefore, thorough diagnostic classification requires both an assessment of clinicopathologic category, as well as an assessment of immunopathologic category. Although different ANCA-associated vasculitic syndromes have distinctive clinical and pathologic features, all ANCA-associated vasculitides share a number of common pathologic features, ie, focal distribution, necrosis, and neutrophil infiltration. ANCA assays have very good sensitivity and specificity for ANCA-associated diseases, but the prevalence of these diseases in the patient population being analyzed must be taken into consideration when determining the predictive value of a test result. As with all serologic tests, ANCA results must be integrated with other clinical and pathologic data in order to reach the most accurate diagnostic conclusion.
Antibodies, Antineutrophil Cytoplasmic↗
Diagnostic classification of antineutrophil cytoplasmic autoantibody-associated vasculitides.
Antineutrophil cytoplasmic autoantibodies (ANCA) are in the circulation of patients with a variety of clinically and pathologically distinctive forms of necrotizing vasculitis. Some patients have classic manifestations of well-recognized clinicopathologic syndromes, such as Wegener's granulomatosis, microscopic polyarteritis nodosa, and Churg-Strauss syndrome, but many patients are difficult to assign to a diagnostic category. The Ad Hoc Nomenclature Committee of The Third International Workshop on ANCA is attempting to identify a working classification system for ANCA-associated vasculitides. This system takes into account the many shared clinical and pathologic features, and relies on prerequisite positive and negative findings for diagnostic categorization.
Antibodies, Antineutrophil Cytoplasmic↗
The pathogenic role of antineutrophil cytoplasmic autoantibodies.
Antineutrophil cytoplasmic autoantibodies (ANCA) are found in the sera of patients with systemic necrotizing vasculitis and glomerulonephritis. Their role in the pathogenesis of these diseases is not clearly understood; however, there is a growing body of data that supports a pathogenic function for these antibodies. In vitro they can activate neutrophils and monocytes to produce reactive oxygen species (ROS), degranulate, and damage target cells. The antigens to which they are directed stimulate T lymphocytes from patients with these diseases. The ANCA directed against proteinase 3 (PR3) may also play a role in growth regulation of monocytes by inactivating the enzymatic function of its antigen. The proposed model of ANCA-induced disease takes into account both the in vitro data and the natural history of these diseases.
Antibodies, Antineutrophil Cytoplasmic↗