Tamar Reshef

Soluble intercellular adhesion molecule-1 and long-term risk of acute coronary events in patients with chronic coronary heart disease. Data from the Bezafibrate Infarction Prevention (BIP) Study.

OBJECTIVES The goal of this study was to assess soluble intercellular adhesion molecule-1 (sICAM-1) level as a predictor of future acute coronary events in patients with chronic coronary heart disease (CHD). BACKGROUND Increased sICAM-1 concentration has been shown to be associated with the incidence of CHD in healthy persons. Its significance in patients with CHD has been scarcely investigated. METHODS We designed a prospective, nested case-control study. Sera were collected from patients with CHD enrolled in a secondary prevention trial that evaluated the efficacy of bezafibrate in reducing coronary events. We measured baseline sICAM-1 concentration in the sera of patients who developed subsequent cardiovascular events (cases: n = 136) during follow-up (mean: 6.2 years) and in age- and gender-matched controls (without events: n = 136). RESULTS Baseline serum concentrations of sICAM-1 were significantly higher in cases versus controls (375 vs. 350 ng/ml; p < 0.05). Each 100 ng/ml increase in sICAM-1 concentration was associated with 1.27 (95% confidence interval [CI]: 1.00 to 1.63) higher relative odds of coronary events. Soluble ICAM-1 concentration in the highest quartile (>394 ng/ml) was associated with significantly higher odds of coronary events (compared with the lowest quartile), even after multivariate adjustment (2.31, 95% CI: 1.02 to 5.50). After adding fibrinogen and total white blood cell count to the multivariate model, the relative odds were 2.12 (95% CI: 0.88 to 5.35) and 2.70 (95% CI: 1.10 to 7.05), respectively. CONCLUSIONS Elevated sICAM-1 concentration in CHD patients is associated with increased risk of future coronary events independent of other traditional risk factors.

Activated T lymphocytes induce degranulation and cytokine production by human mast cells following cell-to-cell contact.

Activated mast cells reside in close apposition to T cells in some inflammatory processes. In this study, we analyzed whether this close physical proximity affects human mast cell degranulation and cytokine release. Thus HMC‐1 human mast cells or primary bone marrow‐derived human mast cells were cocultured with activated and with resting T cells. Mast cells cocultured with activated T cells released histamine and β‐hexosaminidase and produced tumor necrosis factor α (TNF‐α), an effect that peaked at 20 h. Kinetics of histamine release paralleled the formation of heterotypic aggregates. Separation of the two cell populations with a porous membrane prevented mediator release and TNF‐α production. Addition of the PI3‐kinase inhibitor, wortmannin, inhibited the heterotypic adhesion‐associated degranulation but not TNF‐α production. These data thus indicate a novel pathway through which human mast cells are activated to both release granule‐associated mediators and to produce cytokines in association with heterotypic adhesion to activated human T cells. J. Leukoc. Biol. 63: 337–341; 1998.

Soluble Intercellular Adhesion Molecule-1 and Risk of Future Ischemic Stroke A Nested Case-Control Study From the Bezafibrate Infarction Prevention (BIP) Study Cohort

Background and Purpose— Inflammation is considered to be involved in the pathogenesis of ischemic stroke. Our purpose was to assess the role of soluble intercellular adhesion molecule-1 (sICAM-1) concentration, a marker of inflammation, in predicting future ischemic stroke among patients at risk because of chronic coronary heart disease. Methods— We obtained baseline serum samples from patients with chronic coronary heart disease enrolled in the Bezafibrate Infarction Prevention trial (n=3090), which assessed the efficacy of bezafibrate in secondary prevention. Using a prospective nested case-control design, we measured baseline sICAM-1 concentration in sera of patients who developed ischemic stroke during a mean follow-up of 8.2 years (cases, n=134) and in age- and sex-matched controls without any subsequent cardiovascular events (n=134). Results— Baseline serum concentrations of sICAM-1 were significantly higher in cases compared with controls (379 versus 350 ng/mL, P <0.05). sICAM-1 concentration at the highest quartile (>394 ng/mL) was associated with significantly higher relative odds of ischemic stroke compared with the lower concentrations after adjustment for potential confounding variables (relative odds, 2.1; 95% CI, 1.1 to 4.3). After fibrinogen and total white blood cell count were added to the multivariable model, the relative odds were 2.1 (95% CI, 1.1 to 4.2) and 2.2 (95% CI, 1.1 to 4.8), respectively. The risk associated with raised concentrations of sICAM-1 seemed to be highest for large disabling strokes of cardioembolic origin. Conclusions— Elevated concentrations of sICAM-1, a marker of inflammation, are associated with increased risk of ischemic stroke, independent of other traditional cerebrovascular risk factors and of plasma fibrinogen, among patients at increased risk because of manifest coronary heart disease.

T Cell-Induced Mast Cell Activation: A Role for Microparticles Released from Activated T Cells

Close physical proximity between mast cells and T cells has been demonstrated in several T cell-mediated inflammatory processes. However, the way by which mast cells are activated in these T cell-mediated immune responses has not been fully elucidated. We previously identified and characterized a novel mast cell activation pathway initiated by physical contact with activated T cells and showed that this pathway is associated with degranulation and cytokine release. In this study, we provide evidence that mast cells may also be activated by microparticles released from activated T cells that are considered miniature versions of a cell. Microparticles were isolated from supernatants of activated T cells by Centricon filtration or by high-speed centrifugation and identified by electron microscopy, flow cytometry (Annexin stain), and expression of the integrin LFA-1. Stimulated T cells were found to generate microparticles that induce degranulation and cytokine (IL-8 and oncostatin M) release from human mast cells. Mast cell activation by T cell microparticles involved the MAPK signaling pathway. The results were similar when mast cells were stimulated by activated fixed T cells or by whole membranes of the latter. This suggests that microparticles carry mast cell-activating factors similar to cells from which they originate. By releasing microparticles, T cells might convey surface molecules similar to those involved in the activation of mast cells by cellular contact. By extension, microparticles might affect the activity of mast cells, which are usually not in direct contact with T cells at the inflammatory site.

Inhibitory effects of low molecular weight heparin on mediator release by mast cells: preferential inhibition of cytokine production and mast cell-dependent cutaneous inflammation.

There has been substantial evidence that suggests that heparin may modulate various aspects of immune function and inflammation in addition to its well known anticoagulant activity. In this regard heparin was found to suppress cell‐mediated immune responses or asthmatic reactions to allergen challenge. In the present study we analyse the effects of low molecular weight heparin (LMWH) on mast cell degranulation and cytokine production in vitro and on the elicitation of IgE‐mediated mast cell‐dependent late cutaneous allergic inflammation in vivo. We have established that LMWH preferentially inhibited tumour necrosis factor‐alpha (TNF‐α) and IL‐4 production without having any significant effect on mast cell degranulation. These effects have been observed in mast cells derived from three different origins that were activated by either immunological or non‐immunological stimuli. We have shown that there is inhibition of TNF‐α production (and not neutralization of activity), as elimination of the drug after a short preincubation and addition of LMWH to rTNF‐α had no effect on TNF‐α‐mediated cytotoxic activity. These results were also confirmed by ELISA. In vivo, s.c. injection of the LMWH inhibited the leucocyte infiltration associated with the late cutaneous response which followed passive cutaneous anaphylaxis (PCA) reaction, without affecting mast cell numbers or degranulation. These data suggest that LMWH may have an inhibitory role in mast cell‐mediated allergic inflammation, and thus might be considered as a possible therapeutic modality.

Prevalence and Evaluation of B12 Deficiency in Patients with Autoimmune Thyroid Disease

Background:Patients with autoimmune thyroid disease (AITD) have a higher prevalence of pernicious anemia compared with the general population. Clinical signs of B12 deficiency may be subtle and missed, particularly in patients with known autoimmune disease. We assessed the prevalence of vitamin B12 deficiency in patients with AITD and whether their evaluation may be simplified by measuring fasting gastrin levels. Methods:Serum B12 levels was measured in 115 patients with AITD (7 men and 108 women), with a mean age of 47 ± 15 years. In patients with low serum B12 levels (≤133 pmol/L), fasting serum gastrin and parietal cell antibodies (PCA) were measured. Results:Thirty-two patients (28%) with AITD had low B12 levels. Fasting serum gastrin was measured in 26 and was higher than normal in 8 patients. PCA were also measured in 27 patients with B12 deficiency and were positive in 8 patients. Five patients with high gastrin levels underwent gastroscopy with biopsy, and atrophic gastritis was diagnosed in all. The prevalence of pernicious anemia as assessed by high serum gastrin levels in patients with low B12 was 31%. Conclusions:Patients with AITD have a high prevalence of B12 deficiency and particularly of pernicious anemia. The evaluation of B12 deficiency can be simplified by measuring fasting serum gastrin and, if elevated, referring the patient for gastroscopy.

Secretion of stem cell factor by alveolar fibroblasts in interstitial lung diseases

Sarcoidosis (SA) and diffuse interstitial fibrosis (DIF) are characterized by alveolitis, mast cell hyperplasia and increased fibroblast proliferation. Stem cell factor (SCF) stimulates proliferation of hematopoietic progenitor cells involved in mast and stromal cell interaction. We assessed the role of SCF secreted by alveolar fibroblasts (AFb) in the development of fibrosis of DIF and SA in six patients with SA and six patients with DIF. Bronchoalveolar lavage (BAL) was performed by conventional methods. A total of 500 cells were differentially counted from Giemsa-stained cytopreps. AFb and supernatants were recovered from long-term cultures of BAL cells and from 24 h cultures of confluent AFb. Levels of SCF were measured by ELISA. Alpha actin content of AFb was characterized by immunohistochemistry. The expression of AFb mRNA for IL1-alpha and beta, TGF-beta, IFN-gamma, IL-2, IL-4, IL-5 and IL-6 was determined by RT-PCR. There was a lymphocytic predominance in the SA patients and an increase in neutrophils and eosinophils in DIF. SCF secreted by AFb from DIF was significantly higher than in SA. TNF + IL-1 significantly decreased the secretion of SCF by AFb. There was a positive correlation between SCF levels and the percentage eosinophils but not for metachromatic cells. Alpha-actin expression of AFb in DIF was significantly higher than in SA. Cytokine mRNA was extracted from AFb of two SA and two DIF patients. The profile showed that only in stimulated AFb isolated from the DIF patients can IL-5 transcripts be visualized. In conclusion, AFb can contribute to the onset of fibrosis by secreting SCF and IL-5 which, in turn, may recruit eosinophils.

Prospective Study of Chlamydia pneumoniae IgG and IgA Seropositivity and Risk of Incident Ischemic Stroke

Background and Purpose:Chlamydia pneumoniae infection or exposure to C. pneumoniae was implicated as a risk factor for ischemic stroke. Our aim was to evaluate prospectively the association between the presence of antibodies to C. pneumoniae (IgG and IgA) and the risk of incident ischemic stroke among patients with pre-existing vascular disease. Methods: Sera were collected from 3,090 coronary heart disease patients enrolled in a secondary prevention trial. We measured baseline antibodies (IgG and IgA) in the sera of patients who developed subsequent ischemic strokes (cases, n = 134) during follow-up (mean 8.2 years), and in 134 age- and gender-matched pairs without subsequent stroke or myocardial infarction. Results: The crude relative odds (95%CI) of incident ischemic strokes in seropositive patients at baseline (>1.1 relative value units) were 1.29 (95%CI, 0.69–2.47) for IgG and 1.31 (95% CI, 0.69–2.55) for IgA by matched-pair analyses, and 1.42 (95%CI, 0.69–2.98) for IgG and 1.57 (95%CI, 0.76–3.35) for IgA after adjustments for conventional risk factors and the inflammatory marker, soluble intercellular adhesion molecule-1. We explored the possibility that the risk of ischemic stroke may increase in parallel to increasing antibody titers, but did not demonstrate any significant association. Conclusions: Serological evidence for prior infection with C. pneumoniae did not emerge as an independent risk factor for incident ischemic stroke among patients at high risk due to pre-existing vascular disease.

Immunodeficiency and other clinical immunology: Nedocromil sodium inhibits T-cell function in vitro and in vivo

Abstract Nedocromil sodium, a topical antiinflammatory agent recommended as a prophylactic regimen for asthma, is known to inhibit both allergic and nonallergic inflammatory processes in which an essential role for T cells has been implicated. Therefore the direct effects of this drug on several aspects of T-cell activity were analyzed in the present study. By using murine lymphocytes we found that NS at concentrations of 10 −8 to 10 −6 mollL inhibited the mitogen- or antigen-induced proliferative responses of these cells. It is interesting to note that higher concentratrions were ineffective. Preincubation of immune lymph node cells from contact sensitized mice with the drug abrogated their ability to transfer contact sensitivity to naive recipients, an effect that was found to be specific for the treated cells. Nedocromil sodium also interfered with the mitogen-induced interleukin-2 and tumor necrosis factor production by T cells and with their ability to adhere to the bound protein components of the extracellular matrix laminin and fibronectin. All these effects may be attributed to the inhibition of the increase of cytosolic calcium, which accompanies the early phase of T-cell activation and which is an essential step in inducing the aforementioned phenomena.

Chlamydia pneumoniae and future risk in patients with coronary heart disease

AIM To evaluate the association between previous exposure to Chlamydia pneumoniae and future coronary risk in patients with coronary heart disease. METHODS A prospective, nested, case-control design was used. The patient sample was derived from a trial study of bezafibrate for the treatment of coronary heart disease. Anti-Chlamydia pneumoniae antibodies (IgG and IgA) in the baseline sera of 136 patients who had coronary events during follow-up (mean 6.2 years) were compared with those in 136 age- and gender-matched patients from the same trial without subsequent coronary events. RESULTS Mean titers of IgG and IgA antibodies were similar in cases and controls. The relative odds of future coronary events in patients who were seropositive at baseline were 1.0 (95% CI, 0.54-1.84) for IgG and 0.74 (95% CI, 0.41-1.31) for IgA. The relative odds did not change after adjustment for multiple confounding variables. The risk of future coronary events did not increase with increasing anti-Chlamydia pneumoniae antibody titers. CONCLUSIONS Prior exposure to Chlamydia pneumoniae in patients with chronic coronary heart disease is not associated with increased risk of recurrent coronary events.