(Circulation. 1996;94:2396-2401.)
© 1996 American Heart Association, Inc.
Articles |
Anti–Endothelial Cell Antibodies in Takayasu Arteritis
Franz Volhard Clinic at the Max Delbruck Center for Molecular Medicine, Virchow Klinikum, Department of Pathology, Klinikum Buch and Charite University Hospital, Humboldt University of Berlin (Germany).
Correspondence to Friedrich C. Luft, Franz Volhard Clinic, Wiltberg Strasse 50, 13122 Berlin, FRG. E-mail fcluft@orion.rz.mdc-berlin.de.
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Abstract |
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Background Although a specific etiology for Takayasu arteritis has not been found, the bulk of evidence favors an autoimmune mechanism. We examined the sera of 19 patients with Takayasu arteritis for antineutrophil cytoplasmic antibodies (ANCA), antinuclear antibodies (ANA), anti-DNA antibodies, antibodies to extractable nuclear antigens (ENA), anti-Ro antibodies, anticardiolipin antibodies, circulating immune complexes, and anti–endothelial cell antibodies (AECA).
Methods and Results We used enzyme-linked immunoassays, immunofluorescence, counterimmunoelectrophoresis, fluorescent-activated cell sorter (FACS) analysis, and confocal microscopy. We found that although no patient had positive ANCA, ANA, anti-DNA antibodies, ENA antibodies, anti-Ro antibodies, or anticardiolipin antibodies, 18 of the 19 patients had AECA. The AECA titers of the patients were 2561±1458 compared with 126±15 arbitrary units in a normal group of control subjects (P<.001). To verify the specificity of AECA, we performed cytofluorimetry on human endothelial cells with the sera from patients and control subjects. Two entirely separate patterns of fluorescence intensity were identified. We next performed immunocytochemistry and confocal microscopy with human endothelial cells subjected to patients' sera and to sera from normal subjects. The cells subjected to sera from patients with Takayasu arteritis demonstrated specific immunofluorescent staining of their plasma membrane and cytosol.
Conclusions AECA are frequently present in patients with Takayasu arteritis. They may play a role in the pathogenesis. Furthermore, they may be useful as an additional diagnostic tool.
Key Words: arteries • vasculature • endothelium • cells • autoimmunity • collagen
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Introduction |
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Takayasu, an ophthalmologist, described a young woman with cataracts and unusual wreathlike, arteriovenous anastomoses surrounding the optic papillae. In discussing his case, Takayasu's colleagues called attention to patients with similar findings who had absent radial pulses.1 The disease affects women more commonly than men. More than half the patients develop an initial systemic illness characterized by symptoms such as fever, anorexia, malaise, weight loss, night sweats, arthralgias, pleuritic pain, and fatigue. Diminished or absent pulses, bruits, hypertension, and heart failure are late manifestations of the disease.2 3 4 A specific etiology for Takayasu arteritis has not been found. The disease has been linked to rheumatic fever, streptococcal infections, tuberculosis, rheumatoid arthritis, and other collagen vascular diseases. The overall bulk of evidence favors an autoimmune etiology.5 Antiaortic antibodies have been detected in patients with Takayasu arteritis,6 7 8 but their etiological role is uncertain. An association between Takayasu arteritis and certain HLA subtypes has been reported,9 although the importance of the association remains unclear.10 We followed 19 patients with Takayasu arteritis who were diagnosed according to the diagnostic criteria established by the American College of Rheumatology.11 12 We tested their sera for a variety of autoantibodies associated with autoimmune disease. Although conventional autoantibodies were not present in these patients, we were struck by a surprisingly high frequency of AECA.
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Methods |
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The 19 patients were admitted between 1980 and 1990. They all manifested signs or symptoms of large vessel disease accompanied by supportive aortic angiographic findings compatible with Takayasu arteritis in all patients. In 6 patients, vascular biopsy suggesting Takaysu arteritis was available. The sections were obtained during operative procedures, fixed in formalin for light microscopy, and stained by hemotoxylin and eosin, the periodic acid–Schiff reaction, or Masson's trichrome. The diagnosis was verified according to the 1990 criteria for classification of Takayasu arteritis of the American College of Rheumatology.12 All patients were followed subsequently after the diagnosis was established.
The evaluation included patient history, physical examination, aortic angiography, and laboratory tests. The laboratory evaluation included complete blood count, erythrocyte sedimentation rate, serum electrolytes, serum creatinine and urea concentrations, quantitative immunoglobulins, serum tests for rheumatoid factor, ANA, anti-DNA antibodies, ENA, anti-Ro antibodies, anticardiolipin antibodies, circulating immune complexes, ANCA, anticardiolipin antibodies, and AECA.
At our hospital, patients whose disease appears to be active are treated with prednisone, initially 1 mg/kg body wt per day for 1 month. If prednisone could not be tapered because of clinical (fever, signs of inflammation) or laboratory (erythrocyte sedimentation rate, C-reactive protein) signs of continued disease activity, azathioprine was added to the regimen. Patients with significant ischemic symptoms were considered for percutaneous transluminal angioplasty, with or without stent implantation, or vascular surgery. All 19 patients reported here showed signs of disease activity by signs, symptoms, or laboratory tests and were therefore treated as outlined above. Twenty-five healthy female blood donors served as control subjects. ANA, anti-DNA antibodies, anti-ENA, anti-Ro, and anticardiolipin antibodies were measured as described elsewhere.13 14 15 16 17 18
Human umbilical vein endothelial cells (HUVEC) were isolated from umbilical cords by chymotrypsin treatment. The cords were cleaned with isotonic saline buffer at room temperature and were incubated for 25 minutes at 37°C with 1% chymotrypsin in PBS (Seromed). Endothelial cells were then removed by centrifugation (400g for 10 minutes). The pellet was resuspended in M-199 (Seromed) with 20% fetal calf serum, 1% L-glutamine, 1% nonessential amino acids (Seromed), 1% HEPES (GIBCO), 1% Na-pyruvate, 1% Schutz medium (Seromed), as well as with streptomycin and penicillin. Primarily cultured cells were grown for 3 to 4 days and were subcultured. Subcultures 1-2 were used for the experiments.
The ELISA for AECA were done as described elsewhere.19 Briefly, the isolated cells were plated onto chemically activated microtiter plates according to methods developed by Schossler et al.20 The cells were incubated for 2 hours at 4°C with serum. We used peroxidase-labeled anti-human IgG from goat as the conjugate. We calibrated the ELISA by means of serum from a patient with extremely high AECA titers in terms of AU. All sera that were 
3 SD above the mean value (700 AU) for our normal subjects were considered positive.
For cytofluorometry, the suspension of unfixed HUVEC was incubated with sera from patients with Takayasu arteritis and healthy control subjects. The preparation was next washed thrice with PBS and was then exposed to the secondary antibody (FITC-conjugated anti-human goat IgG [Fab 2] at 1:100, 0.5% BSA/PBS; Dianova) for 30 minutes. Controls included negative controls (for autofluorescence) and antibody controls (for nonspecific binding). The cells were analyzed on a standard FACScan flow cytometer (Becton Dickinson) as described elsewhere.21
For immunocytochemistry and confocal microscopy, HUVEC were incubated with sera from patients with Takayasu arteritis and healthy control subjects for 60 minutes. The endothelial cells were washed with PBS and fixed with 3% paraformaldeyde. The preparation was next washed thrice with PBS and was then exposed to the secondary antibody (Cy-conjugated anti-human goat IgG, at 1:100, 0.1% BSA/PBS; Dianova) for 60 minutes. For confocal microscopy, the preparation was mounted with 50% glycerol under a glass coverslip on a Nikon-Diaphot microscope. A Biorad MRC 600 confocal imaging system with an argon laser was used. At least 10 to 18 cells from each of at least 3 independent experiments were examined under each experimental condition. Images were acquired in the normal scanning mode with a Kalman filter of 3 (exposure time, 3 seconds). For each set of experiments, identical settings for power of the light source, confocal aperture, gain, and beam alignment were used. The results were reproduced by two separate investigators. The observers were unaware of the experimental design and antibodies used.
Statistical analysis was carried out on a Macintosh II computer with the use of a commercially available program (Statview, Cricket Software Inc). The results (mean±SD) represent duplicate measurements. For statistical analysis, the nonparametric Wilcoxon test was used. Differences were considered to be significant when the probability value was <.05.
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Results |
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The patients ranged from 16 to 40 years of age. Eighteen of 19 patients were women, and all were white. Half the patients complained of malaise, a third had back pain, and 2 patients had had fevers lasting more than 2 weeks without a diagnosis having been made. Four patients had upper extremity claudication, while 2 had lower extremity claudication. Half the patients had neurological complaints, including headache in 5 patients, visual acuity problems in 5 patients, paresthesias in the upper extremities in 9 patients, and episodes of dizziness in 4 patients. On physical examination, 7 of 19 patients had arterial hypertension as determined in one extremity. Twelve patients had audible bruits over the subclavian arteries, 16 patients had cervical bruits, and 2 patients had abdominal bruits. Ten patients had weak or absent radial pulses in at least one arm, and blood pressure values differed substantially between the two arms.
The aortic arch was involved in 89% of our patients, while the common carotid arteries were affected in 37%. In 21% of cases, the disease was manifest in the abdominal aorta. In Fig 1
(top), a pathological section from the left subclavian artery of an operated patient is shown. The wall of the artery is markedly thickened with infiltrate extending throughout the vascular layers. All layers of the vascular wall are involved with chronic inflammation, the elastic lamina is fractured, and round cell infiltrate is apparent. The arterioles (vasa vasorum) supplying this large vessel also showed signs of perivascular infiltration. Fig 1 (bottom) is a representative angiogram from a patient with a critical stenosis in the remaining common carotid artery supplying the brain. She had been operated on earlier, and since the surgeons were not inclined to operate on her again, she was treated successfully with stent implantation.
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The patients' hematological characteristics and their AECA titers in relative units are shown individually in the Table. All but one patient had positive AECA titers by our definition. That patient was a 37-year-old woman whose disease appeared to be entirely inactive. None of the patients had positive rheumatoid factors, ANA, anti-DNA antibodies, anti-ENA, ANCA, anticardiolipin antibodies, or circulating immune complexes. Furthermore, the patients' other laboratory values, electrolytes, tests of renal function, liver function tests, and urinalyses were also normal.
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Twenty-five female blood donors served as control subjects. The age of the control subjects ranged from 18 to 40 years. All control subjects were negative for AECA. The results of the other laboratory tests, including hematological tests, electrolytes, renal and liver function test, as well as rheumatoid factors, ANA, anti-DNA antibodies, anti-ENA, ANCA, anticardiolipin antibodies, and circulating immune complexes, were within normal limits.
The AECA values of 25 normal individuals and the values of the 19 patients with Takayasu's arteritis expressed in relative units are given at the bottom of the Table
and are graphically displayed in Fig 2. The groups differed significantly (P<.001). Fig 3 shows a typical FACS analysis comparing a patient (patient 12) with highly positive AECA titers and a normal subject. The two patterns differ markedly. That same patient's serum was exposed to human endothelial cells, stained with a secondary antibody against human IgG, and compared with control serum. Fig 4 shows the highly positive fluorescence associated with the patient's serum compared with control serum. The confocal micrograph shows a weak staining of the plasma membrane and homogeneous cytoplasmic staining; the nucleus is spared. When multiple sections were made with the confocal microscope, the homogeneous cytoplasmic pattern was maintained.
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Discussion |
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We present 19 patients with Takayasu arteritis diagnosed according to the American Rheumatology Association criteria12 and with clinical features similar to those described in a recent series of 60 patients from the National Institute of Allergy and Infectious Diseases in the United States.10 The marked female preponderance, the young age of onset, the presence of hypertension in the lower extremities, the unreliable erythrocyte sedimentation rate, and the response to treatment were similar.
Takayasu arteritis is presumably the result of idiopathic autoimmune mechanisms as supported by nonspecific signs of inflammation and favorable response to immunosuppressive treatment.2 3 4 5 6 7 8 9 10 The latter conclusion is admittedly anecdotal, since no studies have been performed in which the patients were randomized to treatments. Kerr et al10 performed HLA typing on their 60 patients and found no significant differences in the distribution of any HLA antigens in their patients and the normal population. An autoimmune pathogenesis has been considered for Takayasu arteritis by others. The search for rheumatoid factor, antinuclear antibodies, and other antibodies associated with collagen diseases has been negative or inconsistent in the past.5 Gyotoku et al22 searched for circulating immune complexes in patients with Takayasu arteritis and found such complexes in 7 of 29 patients that bound to Fc receptors of peripheral blood lymphocytes. However, we found no circulating immune complexes in the patients reported here.
The new information we report is the presence of AECA in our patients, which we verified by three different methods. We used unfixed endothelial cells for FACS analysis and ELISA since it was reported that test systems with fixed endothelial cells do not specifically detect AECA.23 Furthermore, FACS and ELISA performed with fixed endothelial cells were negative, indicating that the autoantibodies directed against endothelial cells bind primarily to membrane-bound molecules. AECA was a uniform feature in our patients, while no other antibodies generally associated with vasculitis could be identified. We found no correlation between AECA titers and erythrocyte sedimentation rate and did not observe a correlation between AECA and the clinical activity of the disease. However, all our patients had markedly advanced disease, which would make the identification of such associations more difficult. Nevertheless, the separation between Takayasu patients and normal subjects by AECA values was striking. Ours is not the first report of antibodies to vascular cells in Takayasu arteritis. Ueda et al6 prepared antigen from fresh human and dog aortas and used a complement fixation reaction, which they then verified with a precipitation reaction with Ouchterlony plates. They were able to detect antiaorta antibodies in 12 of 14 patients with Takayasu aortitis. They also examined 113 patients with various other diseases including atherosclerosis, renal disease, collagen vascular diseases, and essential hypertension and discovered a positive test on only 6. Patients studied by Ueda et al demonstrated features very similar to those described here including a female preponderance, similar angiographic findings, erythrocyte sedimentation rate, and C-reactive protein elevations that only marginally correlated with disease activity and similar histological findings. They commented on nonspecific inflammation involving all layers of the aorta, fibrous thickening of the intima, fragmentation of the elastic fibers, and periarteriolar round cell infiltration in the media and adventitia.
We have not yet identified the antigen on endothelial cells to which the antibody in sera from Takayasu arteritis patients is directed. Since resting human endothelial cells react with the antibody, we conclude that epitopes expressed through cell stimulation, such as selectins or integrin ligands, are not responsible. Recently, we observed that integrins are upregulated in Wegener's granulomatosis.21 We have not yet had an occasion to search for such upregulation in patients with Takayasu arteritis. We believe that AECA probably represent the antiaortic antibodies identified by Ueda et al.6 They were careful to document the specificity of the antigen-antibody response by using both complement fixation and Ouchterlony precipitation. We attempted to further characterize our ELISA reaction by performing FACS analysis to document the interaction between our antibody and endothelial cells. We were able to show a clear interaction between endothelial cells exposed to the patients' sera compared with control subjects in every instance. The laser confocal microscope permits visualization of cell sectioning. Our photomicrographs show a weak staining of the plasma membrane and a bright homogeneous cytoplasmic staining, thus suggesting that the antibodies are not merely involved in a surface reaction but rather that the antigen to these antibodies is stored within the cytoplasm, as known from other transmembrane molecules, such as ß2-integrins. However, for the purpose of confocal microscopy, it was technically necessary to fix the endothelial cells. The fixation was performed between the incubations with the first and second antibody since we could not show AECA binding to primarily fixed endothelial cells. Therefore, we cannot exclude a cross-reaction of those autoantibodies with intracellular components, such as cytoskeletal proteins, due to the fixation process.
Antibodies to endothelial cells may be important in other vasculitides. Kawasaki disease is an acute inflammatory disease of early childhood that is associated with coronary aneurysms and thrombotic occlusion. Leung et al24 found that when endothelial cells were first exposed to interleukin-1 or tumor necrosis factor, they were promptly lysed by IgG and IgM antibodies present in the sera from children with Kawasaki disease. The cytokines presumably induced endothelial cell antigens that were recognized by cytotoxic antibodies. Similar lytic antibodies were reported in children with the hemolytic uremic syndrome.25 Furthermore, Van der Zee et al26 described AECA in patients with lupus erythematosis and vasculitis. The binding of these antibodies to endothelium was enhanced by interleukin-1 stimulation. Finally, Brasile et al27 identified autoantibodies to vascular endothelial cell–specific antigens in patients with systemic vasculitis. Wegener's granulomatosis, polyarteritis nodosa, and temporal arteritis were represented. Interestingly, their study included a single patient with Takayasu arteritis. Eighteen of 21 patients reported had autoantibodies to vascular endothelial cell antigens. We were able to show AECA in patients with systemic lupus erythematosus (n=96), progressive systemic sclerosis (n=129), and Buerger's disease (n=32)28 ; however, only 60% of patients with systemic lupus erythematosus, 58% of patients with progressive scleroderma, and 53% of patients with Buerger's disease were tested positive for AECA compared with 95% of patients with Takayasu arteritis. The mean value of AECA in patients was significantly lower in patients with Buerger's disease (1449±1370) and systemic lupus erythematosus (1440±3077) compared with the patients with Takayasu arteritis (2561±1458; P<.05) reported here. In addition, we found no AECA in 20 patients with essential hypertension, which suggests that the occurrence of AECA is not due to hemodynamic alterations.
Conclusions
We found AECA in 18 of 19 patients with Takayasu arteritis. The AECA were documented by ELISA, by fluorescent antibody cell sorting, and by confocal microscopy. These findings are consistent with earlier observations that Takayasu arteritis patients exhibit antiaortic antibodies. They support the participation of immune mechanisms in the disease and are consistent with the reported involvement of AECA in Kawasaki arteritis, the hemolytic uremic syndrome, and the vasculitis of lupus erythematosus. We have not elucidated the significance of AECA in the pathogenesis of Takayasu arteritis. Thus, it is entirely possible that the presence of AECA in patients' sera is a marker of vasculitis rather than a cause of vessel damage or dysfunction of the vascular endothelium. Detection of AECA may be diagnostically useful. Other surrogate markers of disease activity (endothelins, von Willebrand factor antigen, factor VII) have either not been adequately studied or have not been found to be superior to erythrocyte sedimentation rate or C-reactive protein in monitoring patients.29 30 31 Although we have not yet had the opportunity to conduct long-term clinical observations to determine the prognostic significance of our findings, we believe AECA may have diagnostic utility.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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Dr Eichhorn was supported in part by the DAAD (Deutsche Akademische Austauschdienst). Dr Eichhorn and Dr Sima contributed equally to this report. We thank Dr Uhlig and Dr Schroder for the angiogram.
Received April 15, 1996; revision received June 4, 1996; accepted June 7, 1996.
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References |
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