Angiotensin receptor agonistic autoantibodies and hypertension: preeclampsia and beyond.

Hypertensive disorders are life-threatening diseases with high morbidity and mortality, affecting billions of individuals worldwide. A multitude of underlying conditions may contribute to hypertension, thus the need for a plethora of treatment options to identify the approach that best meets the needs of individual patients. A growing body of evidence indicates that (1) autoantibodies that bind to and activate the major angiotensin II type I (AT1) receptor exist in the circulation of patients with hypertensive disorders, (2) these autoantibodies contribute to disease pathophysiology, (3) antibody titers correlate to the severity of the disease, and (4) efforts to block or remove these pathogenic autoantibodies have therapeutic potential. These autoantibodies, termed AT1 agonistic autoantibodies have been extensively characterized in preeclampsia, a life-threatening hypertensive condition of pregnancy. As reviewed here, these autoantibodies cause symptoms of preeclampsia when injected into pregnant mice. Somewhat surprisingly, these auto antibodies also appear in 3 animal models of preeclampsia. However, the occurrence of AT1 agonistic autoantibodies is not restricted to pregnancy. These autoantibodies are prevalent among kidney transplant recipients who develop severe transplant rejection and malignant hypertension during the first week after transplantation. AT1 agonistic autoantibodies are also highly abundant among a group of patients with essential hypertension that are refractory to standard therapy. More recently these autoantibodies have been seen in patients with the autoimmune disease, systemic sclerosis. These 3 examples extend the clinical impact of AT1 agonistic autoantibodies beyond pregnancy. Research reviewed here raises the intriguing possibility that preeclampsia and other hypertensive conditions are autoimmune diseases characterized by the presence of pathogenic autoantibodies that activate the major angiotensin receptor, AT1. These pathogenic autoantibodies could serve as presymptomatic biomarkers and therapeutic targets, thereby providing improved medical management for these conditions.

Anti-centromere antibody-positive subjects presenting with hypertensive emergency and renal dysfunction in the absence of skin manifestations: a variant of systemic sclerosis or a novel entity?

Two patients with anti-centromere antibody (ACA), hypertensive emergency, and acute renal failure, mimicking scleroderma renal crisis, without Raynaud's phenomenon and typical skin manifestations of systemic sclerosis (SSc), are reported. A review of 26 ACA-positive patients between March 2003 and March 2011 in Yokosuka Kyosai Hospital identified four additional patients with similar manifestations. All patients were Japanese women between 41 and 84 years of age at presentation. Human leukocyte antigen (HLA) genotyping tests revealed the absence of the HLA-DQB1*0501 and DRB1*0101 alleles, which are associated with disease susceptibility to ACA-positive SSc among Japanese. These subjects' manifestations may represent a novel entity.

[Innate and acquired immunity in angiotensin-induced malignant hypertension]. / Native und induzierbare Immunität bei der angiotensininduzierten malignen Hypertonie.

Participation of the immune system in angiotensin (Ang) II-induced endorgan damage is not a conventionally accepted idea. Nevertheless, we have evidence from a double-transgenic rat model of malignant hypertension that Ang II leads not only to activated innate immunity via NF-kB, but also to activated acquired immunity via dendritic cells. By means of surface markers, we observed dendritic cell maturation, migration, and contact with CD4 and CD8 lymphocytes in hearts and kidneys of double-transgenic rats. Treatment with dexamethasone or etanercept provides protection in this model, independent of arterial blood pressure-related effects. Our preliminary data implicate innate immunity and acquired immunity. Both cell-mediated and antibody-mediated effects are involved in the latter in this model.

Autoantibodies against the angiotensin receptor (AT1) in patients with hypertension.

Sera from patients with malignant essential hypertension (n = 14), malignant secondary hypertension mainly attributable to renovascular diseases (n = 12) and renovascular diseases without malignant hypertension (n = 11) and from normotensive healthy blood donors (n = 35) were studied for the presence of autoantibodies against G-protein-coupled cardiovascular receptors. Autoantibodies against the angiotensin II receptor (AT1) were detected in 14, 33, 18 and 14% of patients with malignant essential hypertension, malignant secondary hypertension, renovascular diseases and control patients, respectively. Sensitivity of the enzyme immunoassay was assessed as 5 microg/ml IgG. Patients did not show antibodies against bradykinin (B2) or angiotensin II subtype 2 (AT2) receptors. Autoantibodies affinity-purified from positive patients localized AT receptors in Chinese hamster ovary transfected cells, and displayed a positive chronotropic effect on cultured neonatal rat cardiomyocytes. These results demonstrate the existence of autoantibodies against a functional extracellular domain of human AT1 receptors in patients with malignant hypertension, and suggest that these autoantibodies might be involved in the pathogenesis of malignant hypertension.

Functional autoimmune epitope on alpha 1-adrenergic receptors in patients with malignant hypertension.

Because of the growing evidence that hypertensive disease is accompanied by immunological dysfunction, we have investigated autoimmunity in patients with malignant hypertension. Peptides corresponding to the sequence of the second extracellular loops of the human alpha 1-adrenergic receptor and the M2-muscarinic receptor were used as antigens in an ELISA. Serum from 4 (12%) of 33 healthy controls, 3 (20%) of 15 patients with malignant essential hypertension, and 7 (64%) of 11 with secondary hypertension showed positive responses in the ELISA for the alpha 1-adrenergic receptor peptide. Positive responses were significantly more common among the patients with secondary hypertension than in the other two groups (p < 0.01). By contrast, no autoantibodies against the M2-muscarinic receptor peptide were detected in either hypertensive group. Autoantibodies against the alpha 1-adrenergic receptor, affinity-purified from patients with positive responses, specifically recognised bands with molecular masses of 68, 40, and 37 kDa on immunoblotted membrane proteins of rat ventricles. The patients' autoantibodies caused a decrease in tritiated prazosin binding sites and an increase in heart beating frequency of neonatal cultured rat cardiomyocytes; antibodies purified from the controls had no effect. Circulating autoantibodies against the alpha 1-adrenergic receptor are present in a subgroup of patients with malignant hypertension. These autoantibodies have pharmacological activity in vitro, which suggests that they may be involved in the pathogenesis of malignant hypertension.

Abnormal immune function in malignant hypertension.

OBJECTIVE: To investigate the extent to which the immune system is influenced in patients with previous malignant hypertension. DESIGN: Twenty-three patients with malignant hypertension (fundus hypertonicus grades III or IV) in the Gothenburg area were studied over a 3-year period. After treatment had been instituted they were investigated to establish the function of the cellular immune system (number of T lymphocytes and the proliferative response to T-cell mitogens), human leucocyte antigens A, B and C and frequency of autoantibodies. METHODS: The numbers of T lymphocytes were quantified as erythrocyte rosettes. Lymphocyte-stimulation tests were carried out using the T-cell mitogens phytohaemagglutinin and concanavalin-A. Autoantibodies were determined with immunoassay techniques and leucocyte A, B and C antigens with a lymphocytotoxicity test. RESULTS: The frequency of T lymphocytes and their baseline thymidine incorporation were significantly depressed in patients with previously malignant hypertension compared with control subjects. The group with malignant hypertension also had a decreased proliferative response to concanavalin-A but not to phytohaemagglutinin, and they had an increased frequency of antinuclear antibodies. Human leucocyte antigen B15 tended to occur more frequently in patients with malignant and non-malignant hypertension than in control subjects, especially if a family history of hypertension was taken into consideration. CONCLUSION: The results from the present study indicate that immune mechanisms are involved in malignant hypertension, either secondary to the vascular damage or as a primary abnormality.

Increased secretion of immunoglobulins in malignant hypertension.

Recent evidence suggests that immunogenic factors may be of importance for development and maintenance of severe hypertension. Twenty-three patients with a previously malignant phase of hypertension (MH) were investigated with respect to serum levels as well as actual production of immunoglobulins (lgs) and compared with a group of 22 patients with non-malignant hypertension (NMH) and 45 matched normotensive control subjects (C). Patients with MH had a significantly elevated secretion of IgG and IgA as compared with C. Total serum concentration of lgs did not differ between the groups, but a raised level of the subclass IgG3 was found in MH. There was a significant positive correlation between systolic blood pressure (SBP) and secretion of IgA and IgG when all hypertensive patients were studied. Six patients were subjected to repeated investigations during the first year after malignant phase. If examined in an early phase of MH (within 4 months) the secretion of IgG, IgA and IgM was enhanced compared with later stages (after 5-12 months). The results suggest that an immunological process is involved in MH. This could either be a primary immunological disturbance or more plausibly secondary effects due to the vascular damage caused by the very high blood pressure.

Hipertensión arterial maligna y antígeno HLA: estudio preliminar en 59 pacientes con insuficiencia renal crónica terminal / Malignant arterial hypertension and HLA antigens: preliminary study in 59 patients with terminal chronic renal insufficiency

Se estudiaron 59 pacientes que presentaban hipertensión arterial maligna e insuficiencia renal crónica en espera de un trasplante renal, y un grupo control constituido por 276 sujetos sanos

[Clinico-immunological assessment of the effectiveness of plasmapheresis in the combined therapy of patients with high arterial hypertension]. / Kliniko-immunologicheskaia otsenka éffektivnosti plazmafereza v kompleksnoi terapii bol'nykh s vysokoi arterial'noi gipertoniei.

After several plasmapheresis procedures 25 out of 28 patients with high arterial hypertension revealed stable BP lowering, accompanied by elimination of their refractoriness to medical therapy. Enhanced sensitivity of lymphocytes to antihypertensive drugs has been established by lymphocyte rosette-formation with allogenic erythrocytes loaded with these preparations. Plasmapheresis was followed by moderate reduction in IgA, IgM and IgG levels with their subsequent recovery to baseline values within 3-7 days. In a number of patients with drug hypersensitivity plasmapheresis contributed to a considerable attenuation of drug-induced allergy and caused a decrease in the initially elevated IgE level. Possible mechanisms of eliminating refractoriness to medical therapy by plasmapheresis are discussed.

Malignant hypertension and HLA antigens.

Thirty-two patients with malignant hypertension and terminal uremia and a group of 1263 healthy blood donors were studied regarding the incidence of different HLA antigens. HLA-Bw35; Cw4 antigens were found to be significantly more frequent in the group of patients with malignant hypertension than in the group of healthy individuals. The frequency of HLA-Bw35 in a group of 60 non-uremic patients with biopsy-proven glomerulonephritis and without malignant hypertension was also studied and found equal to the group of healthy blood donors. There was no overrepresentation of IgA nephritis among the HLA-Bw35 positive patients with glomerulonephritis, but advanced vascular lesions were more common among these than among patients with other HLA antigens.

Immunological changes in patients with previous malignant essential hypertension.

Increased T-lymphocyte reactivity against human arterial antigen was significantly more common in a group of 20 patients with previously malignant essential hypertension than in matched control subjects. Serum-levels of IgG and IgM and the prevalence of autoantibodies were also significantly higher in the patients. It is suggested that these changes, whether primary or secondary, may contribute to or aggravate the vascular damage in this condition and are therefore of pathogenetic importance.

Human leucocyte antigens in patients with previous essential malignant hypertension.

1. Human leucocyte ABC antigens were determined by means of a lymphocytotoxicity test in 27 patients with previous essential malignant hypertension and in 500 blood donors. 2. In 18 patients with grade IV retinopathy human leucocyte antigen B15 (HLA B15) was found in 44%, as compared with 23% in the control subjects (P = 0.888). 3. All patients with HLA B15 had a positive family history for hypertension. 4. In 18 patients with grade IV retinopathy HLA B15 was found in eight whereas none of the nine patients with grade III retinopathy had this antigen (P = 0.039). 5. Of the 27 patients, 19 had a positive family history of hypertension and of these eight had HLA B15, whereas none of the eight patients with a negative family history had this antigen (P = 0.068). 6. The findings do not rule out that HLA B15 may be associated with the development of the malignant phase in patients with essential hypertension, but a statistically significant relationship could not be established.