Being Eaten Alive: How Energy-Deprived Cells Are Disposed of, Mediated by C-Reactive Protein-Including a Treatment Option.

In medicine, C-reactive protein (CRP) has become established primarily as a biomarker, predicting patient prognosis in many indications. Recently, however, there has been mounting evidence that it causes inflammatory injury. As early as 1999, CRP was shown to induce cell death after acute myocardial infarction (AMI) in rats and this was found to be dependent on complement. The pathological effect of CRP was subsequently confirmed in further animal species such as rabbit, mouse and pig. A conceptual gap was recently closed when it was demonstrated that ischemia in AMI or ischemia/hypoxia in the severe course of COVID-19 causes a drastic lack of energy in involved cells, resulting in an apoptotic presentation because these cells cannot repair/flip-flop altered lipids. The deprivation of energy leads to extensive expression on the cell membranes of the CRP ligand lysophosphatidylcholine. Upon attachment of CRP to this ligand, the classical complement pathway is triggered leading to the swift elimination of viable cells with the appearance of an apoptotic cell by phagocytes. They are being eaten alive. This, consequently, results in substantial fibrotic remodeling within the involved tissue. Inhibiting this pathomechanism via CRP-targeting therapy has been shown to be beneficial in different indications.

Targeting of Glucose Transport and the NAD Pathway in Neuroendocrine Tumor (NET) Cells Reveals New Treatment Options.

(1) Background: the potency of drugs that interfere with glucose metabolism, i.e., glucose transporters (GLUT) and nicotinamide phosphoribosyltransferase (NAMPT) was analyzed in neuroendocrine tumor (NET, BON-1, and QPG-1 cells) and small cell lung cancer (SCLC, GLC-2, and GLC-36 cells) tumor cell lines. (2) Methods: the proliferation and survival rate of tumor cells was significantly affected by the GLUT-inhibitors fasentin and WZB1127, as well as by the NAMPT inhibitors GMX1778 and STF-31. (3) Results: none of the NET cell lines that were treated with NAMPT inhibitors could be rescued with nicotinic acid (usage of the Preiss-Handler salvage pathway), although NAPRT expression could be detected in two NET cell lines. We finally analyzed the specificity of GMX1778 and STF-31 in NET cells in glucose uptake experiments. As previously shown for STF-31 in a panel NET-excluding tumor cell lines, both drugs specifically inhibited glucose uptake at higher (50 µM), but not at lower (5 µM) concentrations. (4) Conclusions: our data suggest that GLUT and especially NAMPT inhibitors are potential candidates for the treatment of NET tumors.

Sustainability of C-Reactive Protein Apheresis in Acute Myocardial Infarction-Results from a Supplementary Data Analysis of the Exploratory C-Reactive Protein in Acute Myocardial Infarction-1 Study.

In the multicenter, non-randomized, exploratory C-reactive protein (CRP) Apheresis in Myocardial Infarction (CAMI-1) study, CRP apheresis after ST-Elevation Myocardial Infarction (STEMI) significantly decreased blood CRP concentrations in humans. Cardiac damage was assessed by Cardiac Magnetic Resonance (CMR1) 3−9 d after onset of STEMI symptoms and quantified by myocardial infarct size (IS; %), left ventricular ejection fraction (LVEF; %), circumferential strain (CS) and longitudinal strain (LS). Compared with the control group (n = 34), cardiac damage was significantly lower in the apheresis group (n = 32). These findings suggested improved wound healing due to CRP apheresis already within few days after the STEMI event. In the current supplementary data analysis of CAMI-1, we have tested by a follow-up CMR (CMR2) after an average of 88 (65−177) d whether the effect of CRP apheresis is clinically maintained. After this time period, wound healing in STEMI is considered complete. Whereas patients with low CRP production and a CRP gradient cut off of <0.6 mg/L/h in the hours after STEMI (9 of 32 patients in the CRP apheresis group) did not significantly benefit from CRP apheresis in CMR2, patients with high CRP production and a CRP gradient cut off of >0.6 mg/L/h (23 of 32 patients in the CRP apheresis group) showed significant treatment benefit. In the latter patients, CMR2 revealed a lower IS (−5.4%; p = 0.05), a better LVEF (+6.4%; p = 0.03), and an improved CS (−6.1%; p = 0.005). No significant improvement, however, was observed for LS (−2.9%; p = 0.1). These data suggest a sustained positive effect of CRP apheresis on heart physiology in STEMI patients with high CRP production well beyond the period of its application. The data demonstrate the sustainability of the CRP removal from plasma which is associated with less scar tissue.

C-Reactive Protein (CRP) Blocks the Desensitization of Agonistic Stimulated G Protein Coupled Receptors (GPCRs) in Neonatal Rat Cardiomyocytes.

Recently, C-reactive protein (CRP) was shown to affect intracellular calcium signaling and blood pressure in vitro and in vivo, respectively. The aim of the present study was to further investigate if a direct effect on G-protein coupled receptor (GPCR) signaling by CRP can be observed by using CRP in combination with different GPCR agonists on spontaneously beating cultured neonatal rat cardiomyocytes. All used agonists (isoprenaline, clenbuterol, phenylephrine, angiotensin II and endothelin 1) affected the beat rate of cardiomyocytes significantly and after washing them out and re-stimulation the cells developed a pronounced desensitization of the corresponding receptors. CRP did not affect the basal beating-rate nor the initial increase/decrease in beat-rate triggered by different agonists. However, CRP co-incubated cells did not exhibit desensitization of the respective GPCRs after the stimulation with the different agonists. This lack of desensitization was independent of the GPCR type, but it was dependent on the CRP concentration. Therefore, CRP interferes with the desensitization of GPCRs and has to be considered as a novel regulator of adrenergic, angiotensin-1 and endothelin receptors.

Inhibitory and Agonistic Autoantibodies Directed Against the ß2-Adrenergic Receptor in Pseudoexfoliation Syndrome and Glaucoma.

Pseudoexfoliation syndrome (PEXS) and glaucoma (PEXG) are assumed to be caused by a generalized elastosis leading to the accumulation of PEX material in ocular as well as in extraocular tissues. The exact pathophysiology of PEXS is still elusive. PEXG, the most common type of secondary open-angle glaucoma (OAG), is characterized by large peaks of intraocular pressure (IOP) with a progressive loss of the visual field. Agonistic autoantibodies (agAAbs) against the ß2-adrenergic receptor (AR) have been shown to be present in sera of patients with primary and secondary OAG and ocular hypertension and are seemingly linked to IOP. In the present study, we investigated the autoantibodies directed against the ß2-AR in sera of patients with PEXS and PEXG. We recruited 15, 10, and 15 patients with PEXG, PEXS, and primary OAG, respectively. Ten healthy individuals served as controls. All patients underwent standard ophthalmological examination with Octopus G1 perimetry. agAAbs prepared from serum samples were analyzed in a rat cardiomyocyte-based bioassay for the presence of agAAbs. We identified the interacting loop of the ß2-AR and the immunoglobulin G (IgG) subclasses using synthetic peptides corresponding to the extracellular loops of the receptors and enzyme-linked immunosorbent assay, respectively. None of the controls were ß2-agAAb-positive (0.2 ± 0.5 U). No ß2-agAAbs (0.2 ± 0.4 U), but inhibitory ß2-AAbs were observed in 80% of the patients that partially blocked the drug-induced ß2-adrenergic stimulation; 5.8 ± 1.7 U vs. 11.1 ± 0.9 U for clenbuterol in the absence and the presence of sera from patients with PEXS, respectively. Epitope analyses identified the third extracellular loop of the ß2-AR as the target of the inhibitory ß2-AAbs, being of IgG3 subtype in PEXS patients. In contrast, patients with PEXG showed ß2-agAAbs (5.6 ± 0.9 U), but no inhibitory ones. The ß2-agAAbs levels of patients with PEXG and primary OAG patients (3.9 ± 2.8 U; p > 0.05) were at a similar level. In two cases of PEXG, the ß2-agAAbs exert synergistic effects with clenbuterol. The activity increased from 11.5 ± 0.3 (clenbuterol only) to 16.3 ± 0.9 U. As autoimmune mechanisms were reportedly involved in the pathogenesis of glaucoma, agonistic and inhibitory ß2-AAbs seem to be a part of this multifactorial interplay.

Agonistic autoantibodies against ß2-adrenergic receptor influence retinal microcirculation in glaucoma suspects and patients.

PURPOSE: Agonistic ß2-adrenergic receptor autoantibodies (ß2-agAAb) have been observed in sera of patients with ocular hypertension and open-angle glaucoma (OAG). They target the ß2-receptors on trabecular meshwork, ciliary body and pericytes (Junemann et al. 2018; Hohberger et al. 2019). In addition to their influence on the intraocular pressure, an association to retinal microcirculation is discussed. This study aimed to investigate foveal avascular zone (FAZ) characteristics by en face OCT angiography (OCT-A) in glaucoma suspects and its relationship to ß2-agAAb status in patients with OAG. MATERIAL AND METHODS: Thirty-four patients (28 OAG, 6 glaucoma suspects) underwent standardized, clinical examination including sensory testing as white-on-white perimetry (Octopus G1, mean defect, MD) and structural measures as retinal nerve fibre layer (RNFL) thickness, neuroretinal rim width (BMO-MRW), retinal ganglion cell layer (RGCL) thickness, and inner nuclear layer (INL) thickness with high-resolution OCT. FAZ characteristics were measured by OCT-A scans of superficial vascular plexus (SVP), intermediate capillary plexus (ICP), and deep capillary plexus (DCP). FAZ-R was calculated (area FAZ (SVP)/area FAZ (ICP)). Using cardiomyocyte bioassays we analysed serum samples for the presence of ß2-agAAb. RESULTS: (I) Total mean FAZ area [mm2]: 0.34±0.16 (SVP), 0.24±0.12 (ICP), and 0.49±0.24 (DCP); mean FAZ-R 1.58±0.94. No correlation was seen for FAZ-R with MD, RNFL, BMO-MRW, RGCL thickness and INL thickness (p>0.05). (II) ß2-agAAb have been observed in 91% patients and showed no correlation with MD, RNFL, BMO-MRW, RGCL thickness and INL thickness (p>0.05). (III) FAZ-R correlated significantly with the ß2-agAAb-induced increase of the beat rate of cardiomyocyte (p = 0.028). CONCLUSION: FAZ characteristics did not correlate with any glaucoma associated functional and morphometric follow-up parameter in the present cohort. However, level of ß2-agAAb showed a significantly correlation with FAZ-ratio. We conclude that ß2-agAAb might be a novel biomarker in glaucoma pathogenesis showing association to FAZ-ratio with OCT-A.

Immunoadsorption for Treatment of Patients with Suspected Alzheimer Dementia and Agonistic Autoantibodies against Alpha1a-Adrenoceptor-Rationale and Design of the IMAD Pilot Study.

BACKGROUND: agonistic autoantibodies (agAABs) against G protein-coupled receptors (GPCR) have been linked to cardiovascular disease. In dementia patients, GPCR-agAABs against the α1- and ß2-adrenoceptors (α1AR- and ß2AR) were found at a prevalence of 50%. Elimination of agAABs by immunoadsorption (IA) was successfully applied in cardiovascular disease. The IMAD trial (Efficacy of immunoadsorption for treatment of persons with Alzheimer dementia and agonistic autoantibodies against alpha1A-adrenoceptor) investigates whether the removal of α1AR-AABs by a 5-day IA procedure has a positive effect (improvement or non-deterioration) on changes of hemodynamic, cognitive, vascular and metabolic parameters in patients with suspected Alzheimer's clinical syndrome within a one-year follow-up period. METHODS: the IMAD trial is designed as an exploratory monocentric interventional trial corresponding to a proof-of-concept phase-IIa study. If cognition capacity of eligible patients scores 19-26 in the Mini Mental State Examination (MMSE), patients are tested for the presence of agAABs by an enzyme-linked immunosorbent assay (ELISA)-based method, followed by a bioassay-based confirmation test, further screening and treatment with IA and intravenous immunoglobulin G (IgG) replacement. We aim to include 15 patients with IA/IgG and to complete follow-up data from at least 12 patients. The primary outcome parameter of the study is uncorrected mean cerebral perfusion measured in mL/min/100 gr of brain tissue determined by magnetic resonance imaging with arterial spin labeling after 12 months. CONCLUSION: IMAD is an important pilot study that will analyze whether the removal of α1AR-agAABs by immunoadsorption in α1AR-agAAB-positive patients with suspected Alzheimer's clinical syndrome may slow the progression of dementia and/or may improve vascular functional parameters.

Autoantibodies Activating the ß2-Adrenergic Receptor Characterize Patients With Primary and Secondary Glaucoma.

Recently, agonistic autoantibodies (agAAb) activating the ß2-adrenergic receptor were detected in primary open-angle glaucoma (POAG) or ocular hypertension (OHT) patients and were linked to intraocular pressure (IOP) (1). The aim of the present study was to quantify ß2-agAAb in the sera of glaucoma suspects and patients with primary and secondary glaucoma. Patients with OHT (n = 33), pre-perimetric POAG (pre-POAG; n = 11), POAG (n = 28), and 11 secondary OAG (SOAG) underwent ophthalmological examinations including examinations with Octopus G1 perimetry and morphometry. Twenty-five healthy individuals served as controls. Serum-derived IgG samples were analyzed for ß2-agAAb using a functional bioassay. The beat-rate-increase of spontaneously beating cultured neonatal rat cardiomyocytes was monitored with 1.6 beats/15 s as cut-off. None of the sera of normal subjects showed ß2-agAAb. In POAG or OHT patients increased beating rates of 4.1 ± 2.2 beats/15 s, and 3.7 ± 2.8 beats/15 s were detected (p > 0.05). Glaucoma patients with (POAG) and without perimetric (pre-POAG) defects did not differ (pre-POAG 4.4 ± 2.6 beats/15 s, POAG 4.1 ± 2.0 beats/15 s, p > 0.05). Patients with SOAG yielded mean beating rates of 4.7 ± 1.7 beats/15 s (p > 0.05). ß2-agAAb were seen in 73% of OHT, 82% of pre-POAG, 82% of POAG, and 91% SOAG patients (p < 0.001). Clinical data did not correlate with beating rate (p > 0.05). The robust ß2-agAAb seropositivity in patients with OHT, pre-POAG, POAG, and SOAG suggest a primary common role for ß2-agAAb starting early in glaucoma pathophysiology and turned out to be a novel marker identifying all patients with increased IOP independent of glaucoma stage and entity.

PentraSorb C-Reactive Protein: Characterization of the Selective C-Reactive Protein Adsorber Resin.

C-reactive protein (CRP) is well known as a general marker of inflammation. It furthermore represents a reliable risk factor for cardiac events and mediates tissue damage in acute myocardial infarction (AMI). It has been demonstrated that selective CRP depletion by extracorporeal apheresis in a porcine AMI model had beneficial effects on the infarcted area and the cardiac output. We therefore developed a novel adsorber for CRP apheresis from human plasma (PentraSorb CRP). It is intended for use in the clinic as therapy for patients suffering from AMI or other acute inflammatory diseases with elevated CRP plasma levels. The PentraSorb resin specifically bound CRP from human blood plasma and almost no other proteins as determined via Sodium dodecyl sulfate polyacrylamide gel electropheresis (SDS-PAGE). The resin further efficiently and selectively depleted CRP from plasma with low as well as high CRP concentrations (10-100 mg/L) at different flow rates, ranging from 17 to 40 mL/min. The resin was regenerable for up to 200 times without losing its CRP binding capacity or affecting biocompatibility. The depletion of CRP from plasma was comparable between the utilized small-scale column (0.5 mL resin) and the PentraSorb CRP adsorber (20 mL resin volume). The established features can therefore be applied to the clinical setting. In summary, PentraSorb CRP provides a novel, specific, and efficient CRP-binding resin that could be used in apheresis therapy for patients suffering from inflammatory diseases such as AMI, stroke, acute pancreatitis, and Crohn's disease.

Prevalence and Determinants of Agonistic Autoantibodies Against α1-Adrenergic Receptors in Patients Screened Positive for Dementia: Results from the Population-Based DelpHi-Study.

BACKGROUND: There is a need to assess promising biomarkers for diagnosis and treatment response in real-life settings. Despite the important role of vascular risk factors, cardiovascular biomarkers have played a minor role in dementia research. Agonistic autoantibodies (agAAB) directed against G-protein-coupled receptors (GPCR) are discussed as modulators of pathology and clinical manifestation. OBJECTIVE: 1) Describe prevalence of agAAB directed against GPCR, especially agABB against α1-adrenergic receptors (α1-AR-agAAB) and agABB directed against ß2-adrenergic receptors (ß2-AR-agAAB) and 2) identify factors associated with agAAB in people with dementia during routine care. METHODS: Blood samples and data from 95 subjects who screened positive for dementia from a primary care cohort, analyzed using an enzyme-linked immunosorbent assay (ELISA) for detecting agAAB. Sociodemographic and clinical data were assessed, and medical records checked. RESULTS: In 40 (42%) samples, agAAB was detected, with n = 29 (31%) representing α1-AR-agAAB and n = 21 (22%) ß2-AR-agAAB. There was no association between the presence of any antibody and a formal diagnosis of dementia. However, patients with coronary heart disease were more likely (OR = 4.23) to have α1-AR-agAAB than those without coronary heart disease. There were no associations between agAAB and age, sex, education, or cognitive impairment. DISCUSSION: For the first time, we show that autoantibodies have a significant prevalence in people with dementia in a routine care setting. Previous findings were restricted to highly selective samples. We replicated the association between α1-AR-agAAB in patients with coronary heart diseases but were not able to find other factors associated with the presence of agAAB.

Agonistic Autoantibodies to the ß2-Adrenergic Receptor Involved in the Pathogenesis of Open-Angle Glaucoma.

Glaucoma is a frequent ocular disease that may lead to blindness. Primary open-angle glaucoma (POAG) and ocular hypertension (OHT) are common diseases with increased intraocular pressure (IOP), which are mainly responsible for these disorders. Their pathogenesis is widely unknown. We screened the sera of patients with POAG and OHT for the prevalence of autoantibodies (AAb) against G protein-coupled receptors (GPCRs) in comparison to controls. Employing frequency modulation of spontaneously contracting neonatal rat cardiomyocytes in vitro, agonistic GPCR AAb were to be detected in roughly 75% of the patients with POAG and OHT, however, not in controls. Using inhibitory peptides the AAb' target was identified as ß2 adrenergic receptor (ß2AR). The AAb interact with the second extracellular loop of ß2AR. The peptides 181-187 and 186-192 were identified as binding sites of the AAb within the extracellular loop II. The binding of the AAb to ß2ARs was verified by surface-plasmon-resonance analysis. The isotype of the AAb was (immunoglobulin) IgG3. In an additional pilot principal-of-proof study, including four patients with POAG, the removal of the AAb against the ß2AR and other immunoglobulins G by immunoadsorption resulted in a transient reduction of IOP. These findings might indicate a possible role of agonistic AAb directed against ß2ARs in the dynamics of aqueous humor and might support a contribution of adaptive autoimmunity in the etiopathogenesis of POAG and OHT.

Autoantibodies Directed Against the Endothelin A Receptor in Patients With Benign Prostatic Hyperplasia.

BACKGROUND: Over-stimulation of G-protein coupled receptors (GPCRs) such as α1-adrenergic, muscarinic, endothelin, and AT1 receptors is considered to drive benign prostatic hyperplasia (BHP) which is often associated with lower urinary tract syndrome (LUTS). However, in addition to physiologic GPCR ligands, there is a new class of autoantibodies called functional autoantibodies that target the same GPCRs (GPCR-AABs) for over-stimulation, thus, presenting pathogenic potency. We hypothesize that patients with BPH/LUTS could carry GPCR-AABs representing potential targets for treatment. METHODS: GPCR-AABs were identified, quantified, and characterized in the serum from 20 patients (aged 55-82 years, median 71 years) with BPH using the bioassay of spontaneously beating cultured neonatal rat cardiomyocytes. RESULTS: A sum of 60% of the patients were positive for agonistic autoantibodies directed against the endothelin A receptor (ETA-AABs). ETA-AABs were associated with the IgG 1 subclass, targeted an epitope located on the second extracellular receptor loop and their agonistic activity could be neutralized by the aptamer BC007. CONCLUSIONS: Agonistic ETA-AABs could-via uncontrolled over-boarding endothelin A receptor stimulation-contribute to the pathogenesis of BPH/LUTS. The in vitro demonstrated ETA-AAB neutralization by the aptamer BC007 could open the door for a new treatment strategy in patients with BPH/LUTS. Prostate 77:458-465, 2017. © 2016 Wiley Periodicals, Inc.

Immunoadsorption of Agonistic Autoantibodies Against α1-Adrenergic Receptors in Patients With Mild to Moderate Dementia.

Dementia has been shown to be associated with agonistic autoantibodies. The deleterious action of autoantibodies on the α1-adrenergic receptor for brain vasculature has been demonstrated in animal studies. In the current study, 169 patients with dementia were screened for the presence of agonistic autoantibodies. 47% of patients suffering from mild to moderate Alzheimer's disease and/or vascular dementia carried these autoantibodies. Eight patients positive for autoantibodies underwent immunoadsorption. Patients treated on four consecutive days were subsequently negative for autoantibodies and displayed stabilization of cognitive and mental condition during 12-18 months' follow-up. In patients treated for 2-3 days, autoantibodies were reduced by only 78%. They suffered a rebound of autoantibodies during follow-up, benefited from immunoadsorption too, but their mental parameters worsened. We provide first data on the clinical relevance of agonistic autoantibodies in dementia and show that immunoadsorption is safe and efficient in removing autoantibodies with overall benefits for patients.

Selective apheresis of C-reactive protein: a new therapeutic option in myocardial infarction?

BACKGROUND: There is substantial evidence that C-reactive protein (CRP) mediates secondary damage of the myocardium after acute myocardial infarction (AMI). The aim of this animal trial in pigs was to specifically deplete CRP from porcine plasma after AMI and to study possible beneficial effects of the reduced CRP concentration on the infarcted area. METHODS: Ten pigs received balloon catheter-induced myocardial infarction. CRP was depleted from five animals utilizing a new specific CRP-adsorber, five animals served as controls. The area of infarction was analyzed by cardiovascular magnetic resonance imaging on day 1 and day 14 after AMI. Porcine CRP levels were determined by ELISA. RESULTS: CRP-apheresis resulted in a mean reduction of the CRP levels up to 48.3%. The area of infarction was significantly reduced by 30 ± 6% (P = 0.003) within 14 days in the treatment group, whereas it increased by 19 ± 11% (P = 0.260) in the controls. Fourteen days after infarction, the infarcted area revealed compact, transmural scars in the controls, whereas animals receiving CRP-apheresis showed spotted scar morphology. In the interventional group, a significantly higher left ventricular ejection fraction (LVEF) was observed after 14 days as compared to the controls (57.6 ± 2.4% vs. 46.4 ± 2.7%; P = 0.007). CONCLUSIONS: In a pig model for AMI, we observed that selective CRP-apheresis significantly reduces CRP levels and the volume of the infarction zone after AMI. Additionally, it changes the morphology of the scars and preserves cardiac output (LVEF).

Antibodies to the α1-adrenergic receptor cause vascular impairments in rat brain as demonstrated by magnetic resonance angiography.

BACKGROUND: Circulating agonistic autoantibodies acting at G protein-coupled receptors have been associated with numerous sever pathologies in humans. Antibodies directed predominantly against the α(1)-adrenergig receptor were detected in patients suffering from widespread diseases such as hypertension and type 2 diabetes. Their deleterious action has been demonstrated for peripheral organs. We postulate that antibodies to the α(1)-adrenergig receptor are relevant pathomolecules in diseases of the central nervous system associated with vascular impairments. METHODOLOGY/PRINCIPAL FINDINGS: Using a rat model we studied the long-term action of antibodies against the α(1)-adrenergig receptor either induced by immunization with a receptor peptide or applied by intravenous injection. The vasculature in the rat brains was investigated by time-of-flight magnetic resonance angiography using a 9.4 Tesla small animal MR imaging system. Visual examination of maximum-intensity-projections (MIPs) of brain angiographs revealed the development of vascular defects in antibody- exposed animals between three and eight months of treatment. Relative vascular areas were derived from representative MIP image sections by grayscale analysis and used to form an index of vascular circulation. Animals exposed to the action of α(1)-adrenergig receptor antibodies showed significantly reduced vascular areas (p<0.05). Calculated index values indicated attenuated blood flow in both antibody-treated cohorts compared to their respective controls reaching with (relative units ± standard error, n = 10) 0.839 ± 0.026 versus 0.919 ± 0.026 statistical significance (p<0.05) for peptide-immunized rats. CONCLUSION/SIGNIFICANCE: We present evidence that antibodies to the α(1)-adrenergig receptor cause cerebrovascular impairments in the rat. Our findings suggest the pathological significance of these antibodies in pathologies of the human central nervous system linked to impairments of brain vasculature such as stroke and dementia.

Specific removal of C-reactive protein by apheresis in a porcine cardiac infarction model.

BACKGROUND: C-reactive protein (CRP) is a possible causative factor of the destructive processes observed during the weeks after myocardial infarction. METHODS: We developed a clinically relevant animal model including the removal of CRP from blood plasma utilizing a specific CRP adsorber and the visualization of the infarct scar in the living animal by cardiovascular magnetic resonance imaging as a tool to investigate the impact of CRP after acute myocardial infarction. RESULTS: We describe the facets of this model system and kinetics of clinical blood parameters like CRP and troponin. In addition, we demonstrate the potency of CRP apheresis reducing CRP levels by ~70% in the established treatment system. CONCLUSION: We showed for the first time that it is possible to conduct apheresis at the following 2 days after acute myocardial infarction in a porcine infarction model and to analyze the infarct by cardiovascular magnetic resonance imaging at day 1 and 14.

Pathophysiological role of autoantibodies against G-protein-coupled receptors in the cardiovascular system.

After more than 15 years of intensive research in the field of functional autoantibodies (AAB) directed against G-protein-coupled receptors, there is growing evidence of a causal involvement of AAB in various cardiovascular diseases such as dilated cardiomyopathy, peripartum cardiomyopathy, malignant and essential hypertension, and preeclampsia. It has been indicated that AAB against beta-1 adrenergic receptor, alpha-1 adrenergic receptor, angiotensin-II receptor AT(1) and muscarinic M(2)-receptors undergo agonist-like actions on the corresponding receptor and induce a permanent stimulation of G-protein-coupled signal cascades, which may cause Ca(2+) overload and cardiomyocyte destruction.Furthermore, the present review describes how G-protein-coupled receptor AAB are able to activate transcription factor nuclear factor-kappa B, which may regulate the expression of genes involved in immune and inflammatory responses.

Peptide based adsorbers for therapeutic immunoadsorption.

Peptides as ligands for immunoadsorption exhibit several potential advantages over native proteins. Two newly developed adsorbers are based on peptides covalently coupled to sepharose CL-4B. Globaffin is capable of binding immunoglobulins independent from their antigen specificity and thus, applicable in transplant recipients and several antibody mediated autoimmune diseases. Among others, the most important disorders suitable for the treatment with Globaffin are rheumatoid arthritis, systemic lupus erythematosus, and acute renal transplant rejection. Coraffin is a specific adsorber using two linear peptide ligands mimicking epitopes of the beta1-adrenergic receptor, that bind corresponding autoantibodies from patients suffering from idiopathic dilated cardiomyopathy. Specific immunoadsorption has been shown to be beneficial for patients with dilated cardiomyopathy. Coraffin can be used as a new therapeutic option for these patients, who get only limited benefit from medical therapy. Both adsorbers may be combined with all approved apheresis control devices available.