SUMMARYAnnexin V has an important role in the regulation of apoptosis and antibodies directed against it have been shown to lead to apoptosis of vascular endothelial cells. To evaluate the role of anti-annexin V antibodies (AA5A) in Takayasu's arteritis (TA), we investigated these antibodies in the sera of 66 TA patients, 50 healthy controls and in the follow-up sera of 12 active TA patients by enzyme-linked immunosorbent assay. The AA5A-positive patients were analysed further for the presence of anti-endothelial cell antibodies (AECA) and anticardiolipin antibodies (ACLA) to determine the relationship of AA5A with these autoantibodies. AA5A were observed in 36% (24/66) of the patients versus 6% (3/50) of the controls ( P < 0·001) and in 53% (19/36) of patients with active TA versus 17% (5/30) of those with inactive disease ( P < 0·01). Levels of AA5A were also observed to be significantly higher in patients with TA compared to controls (0·557 ± 0·362 versus 0·259 ± 0·069; P < 0·0001) and in patients with active disease compared to those with inactive disease (0·700 ± 0·403 versus 0·385 ± 0·205; P < 0·0001). In the followup study, 6/12 patients who became inactive during follow-up also showed normalization of AA5A levels. AECA and ACLA were detected in 54% (13/24) and 12% (3/24) of the AA5A-positive patients, respectively. Our results show that a significant proportion of TA patients have AA5A, which exhibit an association with AECA and because they have a correlation with disease activity thus appear to be involved in the disease pathogenesis.
SUMMARYExpression of heat shock protein (HSP)-65 as well as infiltration of T-cells in arterial lesions and raised levels of circulating antibodies against mycobacterial HSP65 (mHSP65) led us to the concept that mHSP65 or its human homologue (hHSP60) might be involved in the etiopathogenesis of Takayasu's arteritis (TA). Therefore, we investigated mHSP65 and hHSP60 reactive peripheral blood T-cell subsets by BrdU incorporation assay and flow cytometry as well as investigating the different isotypes of antimHSP65 and hHSP60 antibodies by ELISA. Eighty-four percent (22/26) of the TA patients were observed to show T-cell proliferation to mHSP65 and hHSP60 whereas only 16% (3/18) healthy controls showed such proliferation ( P < 0·001). Both HSPs induced proliferation of exclusively CD4 + T-cells and not CD8 + T-cells. We also observed a significantly higher prevalence of only the IgG isotype reactive to mHSP65 and hHSP60 in TA as compared to HC (mHSP65: 92% TA versus 11% HC, P < 0·0001 and hHSP60: 84% versus 22%, P < 0·001). Our data show a significant correlation between mHSP65 and hHSP60 reactive T-cells (CD3 + : r = 0·901; CD4 + : r = 0·968) as well as anti-mHSP65 and anti-hHSP60 IgG antibodies ( r = 0·814) suggesting an infection induced autoimmunity in TA, possibly induced by molecular mimicry between mHSP65 and hHSP60 or other tissue specific antigens.
SUMMARYWe have investigated constitutive and phytohaemagglutinin (PHA) + phorbol 12-myristate 13-acetate (PMA)-induced gene expression of tumour necrosis factor (TNF)-a , interferon (IFN)-g , interleukin (IL)-2, IL-3, IL-4, IL-10, IL-12 and granulocyte macrophage colony-stimulating factor (GM-CSF) in peripheral blood mononuclear cells (PBMCs) of 10 patients with Takayasu's arteritis (TA) and 10 healthy controls by semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR). The constitutive mRNA expression of TNF-a (69·0 ± 4·0% versus 27·5 ± 18·0%; P = 0·001) and IL-4 (60·0 ± 10·0% versus 0%; P = 0·001) was significantly higher in patients than controls; that of IL-3 was comparable in both groups (38·0 ± 6·0% versus 32·0 ± 5·0%; P = 0·651) while no constitutive mRNA expression was observed for the other cytokines studied. The stimulated PBMCs of patients, as compared with the controls, had higher mRNA gene expression of TNF-a (127·0 ± 16·0% versus 54·0 ± 6·0%; P = 0·001), IFN-g (93·0 ± 13·0% versus 57·0 ± 5·0%; P = 0·032), IL-2 (109·0 ± 13·0% versus 68·0 ± 6·0%; P = 0·015), IL-3 (60·0 ± 8·0% versus 21·2 ± 3·0%; P = 0·045) and IL-4 (68·0 ± 7·0% versus 27·0 ± 7·2%; P = 0·01) The mRNA expression of IL-10 was lower in patients than controls (35·0 ± 8·0% versus 75·0 ± 12·0%; P = 0·022). The GM-CSF mRNA was similar (102·0 ± 6·0% versus 89·0 ± 5·0%; P = 0·475) in both groups. Stimulation of cells with PHA + PMA showed no IL-12 expression but stimulation with lipopolysaccharide induced higher IL-12 mRNA in patients than controls (83·0 ± 14·0% versus 33·0 ± 4·0%; P = 0·005). Our data suggest that an inflammatory cytokine signature exists in TA with a key role for TNF-a , IL-4, IL-10 and IL-12 in different pathological processes of the disease.
Objective. Anti-endothelial cell antibodies are considered to have an important role in the pathogenesis of Takayasu arteritis (TA). Previously, these antibodies were detected using human umbilical vein endothelial cells, which do not completely represent the antigenicity/functions of aortic endothelial cells, the specific targets in TA. To delineate the precise role of antigenic targets, we investigated such targets as well as the pathogenic mechanism of antibodies directed against aortic endothelial cells (AAECAs) in TA.Methods. AAECAs were detected using a cellular enzyme-linked immunosorbent assay (ELISA), and their antigenic targets were detected by immunoblotting. AAECA-mediated induction of endothelial adhesion molecule expression and cytokine production was studied by ELISA, and apoptosis was studied using the TUNEL method.Results. AAECAs were detected in 86% of patients with TA and in 9% of controls. Sera obtained from AAECA-positive patients with TA recognized a total of 9 antigens ranging in size from 18 kd to 200 kd, of which the 60-65-kd triplet was recognized most often. The aortic endothelial cell reactivity of Hsp60-absorbed sera was reduced by ϳ50% as compared with that of unabsorbed sera (mean ؎ Conclusion. Our data show that the AAECAs that are present in patients with TA are directed mainly against 60-65-kd antigen(s) and may cause vascular dysfunction by inducing expression of endothelial adhesion molecules, cytokine production, and apoptosis.SD
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