Helen I. Joller-Jemelka

Glucose-induced β cell production of IL-1β contributes to glucotoxicity in human pancreatic islets

In type 2 diabetes, chronic hyperglycemia is suggested to be detrimental to pancreatic beta cells, causing impaired insulin secretion. IL-1beta is a proinflammatory cytokine acting during the autoimmune process of type 1 diabetes. IL-1beta inhibits beta cell function and promotes Fas-triggered apoptosis in part by activating the transcription factor NF-kappaB. Recently, we have shown that increased glucose concentrations also induce Fas expression and beta cell apoptosis in human islets. The aim of the present study was to test the hypothesis that IL-1beta may mediate the deleterious effects of high glucose on human beta cells. In vitro exposure of islets from nondiabetic organ donors to high glucose levels resulted in increased production and release of IL-1beta, followed by NF-kappaB activation, Fas upregulation, DNA fragmentation, and impaired beta cell function. The IL-1 receptor antagonist protected cultured human islets from these deleterious effects. beta cells themselves were identified as the islet cellular source of glucose-induced IL-1beta. In vivo, IL-1beta-producing beta cells were observed in pancreatic sections of type 2 diabetic patients but not in nondiabetic control subjects. Similarly, IL-1beta was induced in beta cells of the gerbil Psammomys obesus during development of diabetes. Treatment of the animals with phlorizin normalized plasma glucose and prevented beta cell expression of IL-1beta. These findings implicate an inflammatory process in the pathogenesis of glucotoxicity in type 2 diabetes and identify the IL-1beta/NF-kappaB pathway as a target to preserve beta cell mass and function in this condition.

Troponin as a risk factor for mortality in critically ill patients without acute coronary syndromes

OBJECTIVES We sought to assess the mechanism and prognostic value of elevated troponins in patients without acute coronary syndromes (ACS). BACKGROUND Cardiac troponins are used as specific markers for the diagnosis of ACS. Recent studies reported a considerable number of critically ill patients without ACS as being troponin-positive, especially patients with sepsis, pulmonary embolism, renal failure, and stroke. METHODS We analyzed 58 consecutive, critically ill patients admitted for reasons other than ACS, according to their troponin status. Thirty-day mortality, left ventricular ejection fraction (LVEF), and a panel of inflammatory cytokines were compared between troponin-positive and troponin-negative patients. Relevant coronary artery disease was excluded either by stress echocardiography or autopsy. RESULTS Of the 58 critically ill patients, 32 (55%) without evidence of ACS were troponin-positive. Positive troponin levels were associated with higher mortality (22.4% vs. 5.2%, p < 0.018) and a lower LVEF (p = 0.0006). Troponin-positive patients had significantly higher median levels of tumor necrosis factor (TNF)-alpha, its soluble receptor, and interleukin (IL)-6. A subgroup of 10 aplastic patients was troponin-negative at study entry. Three became troponin-positive during leukocyte recovery and subsequently died, whereas all the others stayed troponin-negative and survived. Flow-limiting coronary artery disease was not demonstrable at autopsy or stress echocardiography in 72% of troponin-positive patients. CONCLUSIONS Elevated troponin is a mortality risk factor for medical intensive care patients admitted for reasons other than ACS. It is associated with decreased left ventricular function and higher levels of TNF-alpha and IL-6.

Frequent chronic hepatitis B virus infection in HIV-infected patients positive for antibody to hepatitis B core antigen only

Persons with immune deficiency may present with atypical results in serological tests for hepatitis B virus (HBV). Frozen serum specimens that were sequentially obtained over time from a cohort of 57 HIV-infected patients, all of whom tested positive only for antibody to hepatitis B core antigen (anti-HBcAg), were therefore restested for HBV markers, including HBV DNA. The results were assessed for their time course and correlated with clinical data and alanine aminotransferase (ALT) values. Forty-eight patients were male; intravenous drug users constituted the principal risk group (n=30), followed by homosexual men (n=22). Thirty-three persons tested positive for antibody to hepatitis C virus (anti-HCV). During a median of 31 months from the first to the last serum, anti-HBcAg remained the sole marker of HBV infection in 98.2% of the patients. Polymerase chain reaction (PCR) to detect DNA for HBV core and HBV surface gene was positive in 126 (62.4%) and 121 (59.9%) of all 202 serum samples, respectively. Over time, HBV DNA was detected at least once in 51 (89.5%) patients. In contrast, decomplexed hepatitis B surface antigen (HBsAg) was detected at least once in 14 (24.6%) patients. Among patients positive for HBV DNA and negative for anti-HCV, eight (36.4%) of 22 had chronic hepatitis (ALT elevation ≥6 months) that was attributable only to persisting HBV infection. Similarly, 12 (41.4%) of 29 patients positive for both HBV DNA andanti-HCV had chronic viral hepatitis, but their ALT values were significantly higher. In HIV-infected patients, anti-HBcAg as the sole serological HBV marker detected must be considered indicative of chronic HBV infection and is in part associated with chronic hepatitis and ALT elevation.

Effects of work demands on immunoglobulin A and cortisol in air traffic controllers

The professional activity of air traffic controllers (ATC) is often considered to be rather stressful. Certain characteristics of this job are likely to produce stress; for example an ATC can not predict when a situation becomes critical and he is not able to regulate the workload. In order to assess psychophysiological stress reactions in this working situation, saliva samples were taken from 158 male air traffic controllers before and after each of two working sessions. In contrast to the expected immunosuppressive effects, the working sessions caused a marked increase in the concentration and secretion rate of salivary immunoglobulin A (sIgA), as well as in the concentration of salivary cortisol. The increase in sIgA, however, was not correlated with the salivary cortisol response or with the amount of actual or perceived workload, whereas the cortisol response was correlated with both workload measures. It is suggested that positive emotional engagement is responsible for the observed sIgA increase and that measuring this physiological response may be a valuable tool for differentiating between positive and negative stress effects or between successful and unsuccessful adaptation or coping with situational demands.

Change in circulating levels of the chemokines macrophage inflammatory proteins 1α and 1β, RANTES, monocyte chemotactic protein-1 and interleukin-16 following treatment of severely immunodeficient HIV-infected individuals with indinavir

Objective:To evaluate the in vivo relationship between HIV replication and circulating levels of the chemokines macrophage inflammatory protein (MIP)-1α, MIP-1β, RANTES (acronym for Regulated upon Activation, Normal T-cell Expressed and presumably Secreted), interleukin (IL)-16 and monocyte chemotactic protein (MCP)-1, which have recently been characterized as factors capable of regulating in vitro HIV replication. Design and methods:We have compared changes in plasma HIV-RNA levels and circulating levels of MIP-1α, MIP-1β, RANTES, IL-16 and MCP-1 in 20 severely immunodeficient HIV-infected individuals (CD4+ T cells = 14 ± 3 cells × 106/l; plasma HIV RNA = 4.45 ± 0.27 log10 copies/ml) undergoing treatment with the HIV protease inhibitor indinavir that was added to pre-existing nucleoside-based therapy. At weeks 0, 2, 6 and 12, viral load was quantified using a commercial reverse- transcription polymerase chain reaction assay, peripheral blood T-cell sub- populations assessed by flow cytometry, and chemokine levels quantified using commercial sandwich enzyme-linked immunosorbent assay kits. Results:Following initiation of indinavir-based therapy, significant decreases in plasma HIV-RNA levels (change = 2.0 ± 0.75 log10 copies/ml) were observed in conjunction with significant increases in absolute CD4+ (change = 83 ± 19 cells × 106/l) and CD8+ (change = 293 ± 96 cells × 106/l) T-cell numbers. Concomitantly, significant increases in MIP-1α (19% increase), MIP-1β (14% increase), RANTES (15% increase) and IL-16 (1213% increase) levels occurred. In contrast, MCP-1 levels decreased significantly (47% decrease). Conclusion:The in vivo demonstration of an association between diminishing plasma HIV-RNA levels and the emergence of a circulating chemokine profile capable of inhibiting HIV replication corroborates recent in vitro observations and provides evidence for the restoration of chemokine capacity by HIV protease inhibitor-based therapy.

Soluble CD14 but not interleukin-6 is a new marker for clinical activity in atopic dermatitis.

SummaryLevels of soluble IL-2 receptors, IL-6, soluble CD23, soluble CD14 and ECP (eosinophilic cationic protein) were measured as markers of T-cell, B-cell, monocyte and eosinophilic leucocyte activation in 26 patients with atopic dermatitis (AD) on admission to (A) and at discharge from (D) the Department of Dermatology in Zurich. The serum levels of sIL-2R, IL-6, sCD23, sCD14 and ECP were significantly elevated in AD patients in comparison with the normal values of healthy donors. A significant decrease in sIL-2R (p=0.0093) and in sCD14 (p=0.0134) levels was demonstrated between A and D, correlating with the improvement in the skin intensity score (SIS). In addition, a significant correlation of the sCD14 levels and the SIS at A was demonstrated (p=0.0415). These results also incriminate monocytes in the pathogenesis of AD, indicating that, besides sIL-2R and ECP, SCD14 could also be a possible marker for the disease activity.

Markers for Cell-Mediated Immune Response Are Elevated in Cerebrospinal Fluid and Serum After Severe Traumatic Brain Injury in Humans

The brain is believed to be an immunologically privileged organ, sheltered from the systemic immunological defense by the blood-brain barrier (BBB). However, there is increasing evidence for a marked inflammatory response in the brain after traumatic brain injury (TBI). Markers for cellular immune activation, neopterin, beta2-microglobulin (beta2M), and soluble interleukin-2 receptor (sIL-2R), were measured for up to 3 weeks in cerebrospinal fluid (CSF) and serum of 41 patients with severe TBI in order to elucidate the time course and the origin of the cellular immune response following TBI. Neopterin gradually increased during the first posttraumatic week in both CSF and serum. Concentrations in CSF were generally higher than in serum, suggesting intrathecal release of this marker. beta2M showed similar kinetics but with higher serum than CSF concentrations. Nonetheless, intrathecal release as assessed by the beta2M index could be postulated for most of the patients. The mean levels of sIL-2R in both CSF and serum were elevated during the whole study period, serum concentrations being up to 2 x 10(4) times higher than in CSF. No significant intrathecal production of sIL-2R could be detected. The present data shows that severe TBI leads to a marked cell-mediated immune response within the brain and in the systemic circulation. In the intrathecal compartment the activated cells appear to be predominantly of the macrophage/microglia lineage, while the immune activation in the systemic circulation seems to involve mainly T-lymphocytes.

Incidence and in-vivo relevance of anti-interferon antibodies during treatment of low-grade cutaneous T-cell lymphomas with interferon alpha-2a combined with acitretin or PUVA

Interferon-α combined with retinoid or PUVA is used for the treatment of cutaneous T-cell lymphoma. Anti-IFN-α antibodies (IFN ab) occur regularly during IFN-α treatment. We investigated the incidence of neutralizing and binding IFN ab and analysed their relationship with clinical and immunological parameters. A group of 17 CTCL patients were treated with IFN alpha-2a three times weekly subeutaneously at a dose of 3 Mill. I.U. combined either with retinoid (acitretin, Neotigason; 0.5 mg/kg body weight) daily or with 5-methoxypsoralen (1.2 mg/kg body-weight) plus UVA radiation three times weekly. Prior to and during treatment we monitored stage, skin involvement by a tumour burden index, serum levels of β2-microglobulin, neopterin, binding and neutralizing IFN ab, Interleukin-6 (IL-6), soluble IL-2 receptors (sIL-2r) and the CD4/CD8 ratio of peripheral blood mononuclear cells. We observed two complete, two partial and six minor responses, four patients with stable disease and three patients with progressive disease. Of the 17 patients, 7 developed binding IFN ab, but only 2 had neutralizing IFN ab which were associated with high titres of binding IFN ab. IFN ab formation was more frequent in patients with normal CD4/CD8 ratios and a high tumour burden index and showed a trend to be more frequent in PUVA-cotreated patients than in retinoid-cotreated patients. Responses were more frequently seen in IFN ab-negative patients. IFN ab developed in patients treated with PUVA or retinoid combined with IFN. Binding as well as neutralizing IFN ab may have an impact on the treatment success in CTCL patients.

Levels of soluble ICAM-1 in atopic dermatitis. A new marker for monitoring the clinical activity?

Levels of soluble intercellular adhesion molecule‐1 (sICAM‐1) were measured in sera from patients with an acute exacerbation of their atopic dermatitis (AD) (n= 16) on admission to and discharge from our department of dermatology. At admission, the sICAM‐1 levels in sera from patients with AD were slightly higher than those of the blood donors (n= 100) and dropped at discharge significantly (P= 0.014) after improvement of the skin conditions. Therefore, sICAM‐1 may be, together with soluble interleukin‐2 receptor (sIL‐2), eosinophilic cationic protein (ECP), and CD14, another marker for monitoring AD.

Altered intracellular expression of the chemokines MIP-1alpha, MIP-1beta and IL-8 by peripheral blood CD4+ and CD8+ T cells in mild allergic asthma.

Background: The ability of chemokines to regulate Th1 and Th2 responses suggests a role in the pathogenesis of atopic disorders such as allergic asthma where Th2 response dominance has been observed. Although the impact of allergic asthma on local chemokine production in the lung has been the subject of investigation, little is know about the influence of disease progression on peripheral chemokine production. We now report use of whole blood culture and flow cytometry to assess the influence of mild allergic asthma on peripheral T‐cell chemokine expression.