Ingvild Nordøy

Cytokine network in congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy

Inflammatory cytokines may play a pathogenic role in the development of congestive heart failure (CHF). Elevated circulating levels of inflammatory cytokines have been reported in CHF, but most studies have focused on only a few cytokine parameters. However, the activity of these cytokines are modulated by soluble cytokine receptors and cytokines with anti-inflammatory activities, and in the present study several of these interacting factors were examined simultaneously in 38 CHF patients with various degrees of heart failure and in 21 healthy controls. Patients with CHF had increased plasma concentrations of tumor necrosis factor (TNF)alpha, interleukin-6, soluble TNF receptors and the soluble interleukin-6 receptor, glycoprotein (gp)130. They also had elevated ratios of TNFalpha/soluble TNF receptors and interleukin-6/soluble gp130 as well as enhanced interleukin-6 bioactivity in serum, suggesting inflammatory net effects. In addition to raised circulating levels of inflammatory cytokines, CHF patients with severe heart failure also had abnormalities in the levels of anti-inflammatory cytokines, with decreased levels of transforming growth factor beta1 and inadequately raised interleukin-10 in relation to the elevated TNFalpha concentrations. This dysbalance between inflammatory and anti-inflammatory cytokines was also found in monocyte supernatants from CHF patients. The abnormalities in the cytokine network were most pronounced in patients with the most severe heart failure, and several of the immunologic parameters, in particular soluble gp130, were correlated with variables reflecting deranged hemodynamic status. The present study analyzing the complexity of the cytokine network in CHF, demonstrates profound disturbances in the levels of both inflammatory and anti-inflammatory mediators with a marked dysbalance favoring inflammatory effects.

Elevated Circulating Levels of C-C Chemokines in Patients With Congestive Heart Failure

BACKGROUND Immunologic and inflammatory responses appear to play a pathogenic role in the development of congestive heart failure (CHF). Activation and migration of leukocytes to areas of inflammation are important factors in these immunologic responses. Because the C-C chemokines are potent chemoattractants of monocytes and lymphocytes and can modulate other functions of these cells (eg, generation of reactive oxygen species), we measured circulating levels of three C-C chemokines in CHF. METHODS AND RESULTS Levels of macrophage chemoattractant protein-1 (MCP-1), macrophage inflammatory protein- 1alpha (MIP-1alpha), and RANTES (regulated on activation normally T-cell expressed and secreted) were measured by enzyme immunoassays in 44 patients with CHF and 21 healthy control subjects. CHF patients had significantly elevated levels of all chemokines with the highest levels in New York Heart Association class IV, and MCP-1 and MIP-1alpha levels were significantly inversely correlated with left ventricular ejection fraction. Elevated C-C chemokine levels were found independent of the cause of the heart failure, but MCP-1 levels were particularly raised in patients with coronary artery disease. Studies on cells isolated from peripheral blood suggested that platelets, CD3+ lymphocytes, and in particular, monocytes, might contribute to the elevated C-C chemokine levels in CHF. The increased MCP-1 levels in CHF were correlated with increased monocyte activity reflected in an enhancing effect of serum from CHF patients on O2-generation in monocytes, which was inhibited by neutralizing antibodies against MCP-1. CONCLUSIONS This first demonstration of increased circulating levels of C-C chemokines in CHF with particularly high levels in patients with severe disease may represent previously unrecognized pathogenic factors in CHF.

Tumor Necrosis Factor (TNF) System Levels in Human Immunodeficiency Virus—Infected Patients during Highly Active Antiretroviral Therapy: Persistent TNF Activation Is Associated with Virologic and Immunologic Treatment Failure

Because persistent tumor necrosis factor (TNF)-alpha activation may play a pathogenic role in human immunodeficiency virus infection, TNF component levels were assessed over 78 weeks in plasma and peripheral blood mononuclear cells (PBMC) during highly active antiretroviral therapy (HAART) in 40 HIV-infected patients. HAART induced a significant decline in plasma levels of TNF-alpha and soluble TNF receptors and was associated with a fall in the abnormally increased unstimulated and a rise in the abnormally low Mycobacterium avium complex-purified-protein derivative-stimulated TNF-alpha released from PBMC. However, concentrations of these TNF components were not normalized. Patients with virologic and immunologic treatment failure after 52 weeks had higher levels of several TNF components than other patients early after initiation of therapy, also during periods with adequate virologic response. Although TNF components significantly decreased during HAART, these results support data indicating that full immunologic normalization is not achieved during such therapy. The persistent activation of the TNF system in a subgroup of persons may be involved in treatment failure.

Levels of Circulating Adhesion Molecules in Congestive Heart Failure and After Heart Transplantation

Recent reports suggest a role for immunologic and inflammatory processes in the pathogenesis of congestive heart failure (CHF) and accelerated coronary artery disease (CAD) after heart transplantation (HT). The interaction between endothelial cells, leukocytes, and platelets involving various adhesion molecules may be of particular importance. We therefore measured serum levels of soluble(s) vascular cell adhesion molecule-1 (VCAM-1), sP-selectin, and sE-selectin in 34 patients with severe CHF (23 with CAD and 11 with idiopathic dilated cardiomyopathy) and in 20 healthy controls. Twenty of the patients were followed with serial measurements of these circulating adhesion molecules (CAMs) for up to 2 years after HT. Levels of all 3 CAMs were significantly elevated in patients with CHF compared with controls irrespective of the etiology of heart failure, with particularly high concentrations of sVCAM-1. After HT, different patterns in CAMs were found over time. Whereas there was a normalization of sE-selectin levels after HT, concentrations of sVCAM-1 also declined, but without normalization. In contrast, sP-selectin levels were persistently elevated, with the highest concentrations at the end of the study period. The persistent elevation of sP-selectin and the lack of normalization of sVCAM-1 levels were associated with persistently raised serum levels of tumor necrosis factor-alpha, and these findings were not related to either acute episodes of allograft rejection or intercurrent infections. These results support the notion that immunologic and inflammatory processes are important features of CHF. Furthermore, the persistently elevated levels of CAMs and tumor necrosis factor-alpha found up to 2 years after HT may reflect a state of persistent immune activation in these patients, possibly involved in the development of CAD after HT.

Virological and immunological effects of antioxidant treatment in patients with HIV infection

Intracellular oxidative stress in CD4+ lymphocytes due to disturbed glutathione homeostasis may lead to impaired lymphocyte functions and enhanced HIV replication in patients with HIV infection, especially in those with advanced immunodeficiency. The aim of the present study was to assess whether short‐term, high‐dose antioxidant treatment might have effects on immunological and virological parameters in patients with HIV infection.

The Role of the Tumor Necrosis Factor System and Interleukin-10 during Cytomegalovirus Infection in Renal Transplant Recipients

The effects of cytomegalovirus (CMV) infection on monocyte and T cell activation and the role of the tumor necrosis factor (TNF) system and interleukin (IL)-10 were studied in a prospective study of 25 renal transplant recipients. Ten patients developed CMV disease (group A), 5 developed asymptomatic infection (group B), and 10 did not have CMV infection (group C). During CMV disease (group A), there was evidence of both monocyte and T cell activation. All patients with CMV infection (groups A and B) showed increased activation of the TNF system, concomitant with an increase in plasma levels of IL-10. Patients with CMV disease (group A) had more marked manifestations of TNF activation and more moderate IL-10 increase than patients with asymptomatic CMV infection (group B), reflected in a higher plasma IL-10/TNF-alpha ratio in asymptomatic patients. Thus, the balance between TNF-alpha and IL-10 may be important in the development of CMV infection and CMV-related disease.

Administration of intravenous immunoglobulin (IVIG) in vivo—down‐regulatory effects on the IL‐1 system

Modulation of the cytokine network may be of importance for the beneficial effects of therapy with IVIG seen in a wide range of immune‐mediated disorders. In the present study we investigate the effect of IVIG administration in vivo on the IL‐1 system in 12 patients with primary hypogammaglobulinaemia. Before IVIG infusion these patients had significantly elevated levels of IL‐1α and IL‐1β both in plasma and in supernatants from peripheral blood mononuclear cells (PBMC) compared with healthy controls. After one bolus infusion with IVIG (0.4 g/kg) we found a significant change in the profile of the components of the IL‐1 system: a marked increase in levels of IL‐1 receptor antagonist (IL‐1Ra) and neutralizing antibodies against IL‐1α, a moderate decrease in levels of IL‐1α, IL‐1β and soluble (s) IL‐1 receptor type I and a significant increase in sIL‐1 receptor type II levels. These changes were found both in plasma and in PBMC isolated after IVIG administration. Furthermore, pooled serum obtained after IVIG infusion suppressed lipopolysaccharide‐ and staphylococcal enterotoxin B‐stimulated, but not phorbol myristate acetate‐stimulated, release of IL‐1α and IL‐1β from PBMC isolated from healthy controls. Finally, these changes in circulating levels of various IL‐1 modulators after IVIG infusion appeared to cause a significantly impaired ability of IL‐1 to stimulate PBMC for tumour necrosis factor‐alpha release. Our findings suggest that IVIG administration may not only down‐regulate the activity in the IL‐1 system, but also hamper IL‐1 stimulation of PBMC.

CXC-chemokines in coronary artery disease: possible pathogenic role of interactions between oxidized low-density lipoprotein, platelets and peripheral blood mononuclear cells

Summary.  CXC‐chemokines may be involved in atherogenesis. Herein we examined the possible role of CXC‐chemokines in the inflammatory interactions between oxidized (ox‐) low‐density lipoprotein (LDL), platelets and peripheral blood mononuclear cells (PBMC) in 15 patients with coronary artery disease (CAD) without ‘traditional’ risk factors and 15 carefully matched controls. Our main findings were: (a) ox‐LDL stimulated the release of the CXC‐chemokines interleukin (IL)‐8, ENA‐78 and GRO‐α from PBMC, particularly in CAD. (b) In platelets, ox‐LDL induced release of ENA‐78 and, when combined with SFLLRN, also of GRO‐α, with significantly higher response in CAD. (c) Platelet‐rich plasma, especially when costimulated with ox‐LDL, enhanced the release of IL‐8 from PBMC, particularly in CAD patients. (d) Freshly isolated PBMC showed markedly increased IL‐8 mRNA expression in CAD patients. Our findings suggest enhanced inflammatory interactions between ox‐LDL, platelets and PBMC in CAD patients involving CXC‐chemokine related mechanisms, possible contributing to atherogenesis in these and other CAD patients.

Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders

Background: Primary immunodeficiency diseases (PIDDs) are clinically and genetically heterogeneous disorders thus far associated with mutations in more than 300 genes. The clinical phenotypes derived from distinct genotypes can overlap. Genetic etiology can be a prognostic indicator of disease severity and can influence treatment decisions. Objective: We sought to investigate the ability of whole‐exome screening methods to detect disease‐causing variants in patients with PIDDs. Methods: Patients with PIDDs from 278 families from 22 countries were investigated by using whole‐exome sequencing. Computational copy number variant (CNV) prediction pipelines and an exome‐tiling chromosomal microarray were also applied to identify intragenic CNVs. Analytic approaches initially focused on 475 known or candidate PIDD genes but were nonexclusive and further tailored based on clinical data, family history, and immunophenotyping. Results: A likely molecular diagnosis was achieved in 110 (40%) unrelated probands. Clinical diagnosis was revised in about half (60/110) and management was directly altered in nearly a quarter (26/110) of families based on molecular findings. Twelve PIDD‐causing CNVs were detected, including 7 smaller than 30 Kb that would not have been detected with conventional diagnostic CNV arrays. Conclusion: This high‐throughput genomic approach enabled detection of disease‐related variants in unexpected genes; permitted detection of low‐grade constitutional, somatic, and revertant mosaicism; and provided evidence of a mutational burden in mixed PIDD immunophenotypes.

Chemokines and soluble adhesion molecules in renal transplant recipients with cytomegalovirus infection

Cytomegalovirus (CMV) infection is associated with leucocyte infiltration in various organs, which supports a role for chemokines and adhesion molecules in the pathogenesis of CMV infection. In a prospectively conducted study of renal transplant recipients, 10 patients with CMV disease, five patients with asymptomatic CMV infection and 10 patients who did not have any CMV infection were included. During CMV infection, and in particular during CMV disease, plasma levels of the chemokines IL‐8, macrophage inflammatory protein‐1α (MIP‐1α) and monocyte chemotactic protein‐1 (MCP‐1) and the soluble adhesion molecules vascular cell adhesion molecule‐1 (VCAM‐1), intercellular adhesion molecule‐1 (ICAM‐1) and l‐selectin increased and were positively correlated with the degree of CMV pp65 antigenaemia. Furthermore, a decrease in plasma levels of these chemokines and adhesion molecules was observed following ganciclovir therapy in the patients with CMV disease. This could suggest a role for these molecules in the pathogenesis of CMV infection.