Catherine Limas

Autoantibodies against beta-adrenoceptors in human idiopathic dilated cardiomyopathy.

Although it is recognized that the number of cardiac beta-adrenoceptors is reduced in human dilated cardiomyopathy, the mechanisms involved have not been defined. We examined the possible role of altered humoral immunity by comparing the effect of sera from patients with idiopathic dilated cardiomyopathy (n = 20), ischemic or valvular heart disease (n = 28), or controls with no known cardiac disease (n = 18) on the binding of radioligands to cardiac beta-receptors. The ability of sera from cardiomyopathic patients to inhibit the binding of [3H]dihydroalprenolol to rat cardiac membranes was significantly higher than that of the other two patient groups (40 +/- 5% at 50-fold serum dilution compared to 14 +/- 3% for the ischemic/valvular heart disease group, and 14 +/- 4% for the normal control group, p less than 0.001). A similar inhibition was exerted by IgG from cardiomyopathic patients. Only the number, not the affinity, of the beta-receptors was decreased by cardiomyopathic sera. This decrease could be prevented by preincubating the sera with anti-human IgG, indicating the presence of autoantibodies. Furthermore, the sera were ineffective against cardiac alpha 1-adrenoceptors and considerably less effective against lung beta 2-receptors. In addition to ligand binding inhibition, sera from cardiomyopathic patients could immunoprecipitate beta-adrenoceptors quantitatively from solubilized cardiac membranes. Positive sera inhibited significantly isoproterenol-stimulated adenylate cyclase with no effect on basal or NaF-stimulated activities. These results document the presence in sera from patients with idiopathic dilated cardiomyopathy of autoantibodies directed against the cardiac beta 1-adrenoceptor which may play an important role in the regulation of inotropic responsiveness to beta-agonists.

Tissue Blood-Group Antigens and Prognosis in Low Stage Transitional Cell Carcinoma of the Bladder

The loss of A, B or H blood-group antigens from the surface of neoplastic epithelial cells has been correlated with aggressive tumor behavior. We examined this phenomenon in low stage transitional cell carcinoma of the bladder. In an analysis of biopsy material from 37 patients the absence of these antigens on the original or recurrent tumors correlated with the subsequent development of invasive disease (stage B or greater), while the presence of antigens correlated with failure to develop invasive disease. Analysis of transitional cell surface antigens may help improve the therapy of bladder cancer.

Soluble Interleukin-2 Receptor Levels in Patients With Dilated Cardiomyopathy Correlation With Disease Severity and Cardiac Autoantibodies

BACKGROUND There is evidence that autoimmunity plays an important role in the initiation and progression of myocardial injury in dilated cardiomyopathy. Abnormalities of both cellular and humoral immunity have been described in this disease. Soluble interleukin-2 receptor (sIL-2R) levels in the serum reflect activation of T lymphocytes in the periphery or in tissues. The present study explored the possibility that activation of cellular immunity is frequent in patients with idiopathic dilated cardiomyopathy and may have functional consequences. METHODS AND RESULTS Serum sIL-2R levels were determined with an enzyme-linked immunosorbent assay in 50 dilated cardiomyopathy patients, 30 patients with ischemic heart disease, and 22 normal control subjects. In addition, the presence of anti-beta-receptor and antimyosin antibodies was sought in the serum of cardiomyopathy patients. High sIL-2R levels (> 1400 pg/mL) were found in 38% of the dilated cardiomyopathy patients but only 6% of the ischemic heart disease patients. The group of sIL-2R-positive patients was characterized by higher average age, a higher percentage of women, and more severe disease (lower ejection fraction, higher left ventricular filling pressures, and lower cardiac output). Although the prevalence of cardiac autoantibodies did not correlate with the presence of high sIL-2R levels, higher titers of autoantibodies were found predominantly in the sIL-2R-positive group. CONCLUSIONS T-lymphocyte activation, as reflected in elevated sIL-2R levels, is frequent in patients with dilated cardiomyopathy and is associated with more severe disease. Cellular and humoral immune activation may correlate with progression of the disease process.

Anti-beta-receptor antibodies in human dilated cardiomyopathy and correlation with HLA-DR antigens

The mechanisms responsible for the decline in the density of beta-adrenoceptors in the failing myocardium have not been adequately defined. It is a possibility that the nature of the process leading to heart failure may determine, in large part, the pathogenesis of this decline. Sera of some patients with dilated cardiomyopathy contain antibodies directed against the beta-adrenoceptor, as judged by ligand binding inhibition, immunoprecipitation and immunoblotting assays. Because deranged immune function is thought to play a role in dilated cardiomyopathy, immunogenetic markers of the propensity to develop anti-beta-receptor antibodies were sought. The prevalence of HLA-DR4 was significantly higher in dilated cardiomyopathy patients (40 vs 24% in 511 normal subjects, pc less than 0.001). In contrast, no association was found between HLA phenotypes and alcoholic cardiomyopathy. Furthermore, 72% (13 of 18) of the HLA-DR4 dilated cardiomyopathy patients had anti-beta-receptor antibodies compared to 22% (7 of 33) HLA-DR4-negative patients; in the latter, presence of antibody was linked to the HLA-DR1 phenotype. Conversely, 67% (15 of 23) of the antibody-positive patients were typed as HLA-DR4 compared to only 10% of the antibody-negative patients. Interestingly, none of the 23 antibody-positive patients were typed as HLA-DR3 while 37% of the antibody-negative did. Only 25% of alcoholic cardiomyopathy patients had anti-beta-receptor antibodies and no preponderant HLA association could be demonstrated. These results suggest that the presence of anti-beta-receptor antibodies in patients with idiopathic dilated cardiomyopathy may be under the control of the major histocompatibility locus.

Effect of salt on the vascular lesions of spontaneously hypertensive rats.

SUMMARY High salt intake accelerates hypertension in humans and increases cardiovascular morbidity and mortality. The temporal relation between blood pressure (BP) deration and appearance of vascular lesions during salt-loading was studied in the spontaneously hypertensive rat (SHR). Starting at 5 weeks of age, SHRs and normotensive Wistar-Kyoto rats (WKYs) were given 1% NaCl in their drinking water; SHRs and WKYs on tap water served as controls. Animals from each group were sacrificed at 10 and 20 weeks of age, and the aorta and Intrarenal vessels were studied by light and electron microscopy.

Lichen Planus in Children: A Possible Complication of Hepatitis B Vaccines

Abstract: Lichen planus (LP) has been reported as a complication of hepatitis B vaccination in both adults and children. According to published observations, an autoimmune reaction may be triggered by the viral S epitope. In children, LP is uncommon and, because of its atypical clinical presentation, definitive diagnosis may require biopsy. We investigated the possible association of recombinant hepatitis B virus (HBV) vaccines with childhood LP or LP‐like eruptions seen in our hospital over the last 3 years. Only biopsy‐confirmed cases in which the clinical history could be thoroughly scrutinized were included. We report five patients less than 16 years of age in whom such an association could be supported by relevant data. Thirteen similar pediatric and 15 adult cases have been reported from various countries in the last 5 years. The data indicate that LP is a complication that rarely occurs in children receiving the HBV vaccine. It appears without known predisposing factors and has variable clinical presentations while the␣histologic findings are consistent and, with minor variations, typical of LP.

Influence of anti-beta-receptor antibodies on cardiac adenylate cyclase in patients with idiopathic dilated cardiomyopathy

Autoantibodies against the cardiac beta 1-adrenoceptor are present in the sera of patients with idiopathic dilated cardiomyopathy and may modulate the responsiveness of cardiac beta-adrenergic pathways to agonists. The regulation of cardiac adenylate cyclase activity by autoantibodies was examined in 50 patients with dilated cardiomyopathy. Inhibition of isoproterenol-sensitive adenylate cyclase activity could be demonstrated by serum dilutions or IgG in 52% (26 of 50) of the patients; basal and NaF-stimulated activities, in contrast, were unaffected. In 14 patients, both ligand binding to beta-receptor and isoproterenol-sensitive adenylate cyclase activity were inhibited by 100-fold serum dilutions. Pretreatment of cardiac membranes with pertussis toxin did not affect inhibition of adenylate cyclase indicating that the effect of sera does not depend on Gi. The immunogenetic control of antireceptor antibodies was examined by comparing the distribution of HLA antigens in antibody-positive and antibody-negative patients. HLA-DR4 and HLA-DR1 were strongly associated with antibodies inhibiting ligand binding and adenylate cyclase activity (71% of patients with such antibodies typed as either DR4 or DR1). Conversely 58% of patients with HLA-DR4 and 71% of patients with HLA-DR1 antibodies showed inhibition of adenylate cyclase activity compared to 46% of those who lacked both HLA-DR4 and HLA-DR1 antibodies. These results strongly suggest that cardiac beta-adrenergic receptors and adenylate cyclase activity in dilated cardiomyopathy can be modulated by circulating autoantibodies, the presence of which is under the control of the major histocompatibility complex.

Decreased number of beta-adrenergic receptors in hypertensive vessels.

Responsiveness to inotropic agents is altered in hypertension and may contribute to its initiation and maintenance. A biochemical basis for this change was provided by the observation that the number of beta-adrenergic receptors, as reflected in specific [3H]dihydroalprenolol binding, was diminished in both arteries and veins of spontaneously hypertensive rats. There was no change in the affinity of dihydroalprenolol for the binding sites or in the capacity of isoproterenol to displace dihydroalprenolol. The decline in beta-adrenergic receptor numbers is not secondary to blood pressure elevation but may, instead, contribute to the pathogenesis of hypertension.

Analysis of Fixation Effects on Immunohistochemical Localization of Prostatic Specific Antigen in Human Prostate

We studied human prostatic specific antigen (PSA) localization in human prostate to investigate the possibility that the previously reported variations in the intensity of antigen staining were due to fixation and embedding methods. We have evaluated the effects of physical and several chemical fixatives on prostate samples obtained immediately after prostatectomies and radical cystectomies. Our analysis of fixation effects and immunohistochemical staining of polyclonal antibody to PSA indicates that the formalin fixation and paraffin embedding methods used previously did provide optimum localization of the antigen and the variations in the intensity of PSA staining could not be attributed to the methodology. Although PSA staining was relatively uniform in the lower grade neoplastic tumors, the higher grade, moderately to poorly differentiated tumors showed intense-through-weak PSA localization or no PSA staining suggesting that PSA staining intensity was not uniformly related to tumor differentiation.

T‐Antigen in normal and neoplastic urothelium

The expression of the Thomsen‐Friedenreich antigen (T‐antigen) in normal and neoplastic urothelium was investigated using paraffin‐processed and fresh frozen tissue sections obtained by biopsy from 56 patients. The T‐antigen was detected through its binding to the peanut agglutinin (PNA) with two methods: a biotin‐avidin‐peroxidase system or a modified red cell adherence test. In vitro treatment of the tissue sections with neuraminidase induced PNA binding in the normal and neoplastic urothelium as well as the red blood cells and the vascular endothelium. Spontaneous PNA binding was absent in normal bladder epithelium, but was observed in 10% of the noninvasive and 65% of the invasive transitional cell carcinomas (TCC). The positive reactions were seen in the cytoplasm, cell surface, and mucin. These results were correlated with the light and electron microscopic findings and with the detectability of the A, B, H blood group antigens in the same tissues. Ultrastructurally, the PNA binding sites frequently corresponded to the Golgi apparatus and to secretory products which stained with Alcian blue. About 90% of TCCs with spontaneous PNA binding did not express the expected blood group antigen. The latter was also undetectable in 54% of TCCs lacking spontaneous PNA binding. It appears, therefore, that the expression of T‐antigen occurs later in the evolution of aggressive TCCs, usually when they have advanced to invasive stages. The finding of spontaneous T‐antigen unmasking correlates with the presence of invasion and a higher risk for metastatic involvement of regional lymph nodes.