Robert B. Bressler

Resident Cardiac Mast Cells Degranulate and Release Preformed TNF-α, Initiating the Cytokine Cascade in Experimental Canine Myocardial Ischemia/Reperfusion

BACKGROUND Neutrophil-induced cardiomyocyte injury requires the expression of myocyte intercellular adhesion molecule (ICAM)-1 and ICAM-1-CD11b/CD18 adhesion. We have previously demonstrated interleukin (IL)-6 activity in postischemic cardiac lymph; IL-6 is the primary stimulus for myocyte ICAM- 1 induction. Furthermore, we found that induction of IL-6 mRNA occurred very early on reperfusion of the infarcted myocardium. We hypothesized that the release of a preformed upstream cytokine induced IL-6 in leukocytes infiltrating on reperfusion. METHODS AND RESULTS Constitutive expression of TNF-alpha and not IL-1beta was demonstrated in the normal canine myocardium and was localized predominantly in cardiac mast cells. Mast cell degranulation in the ischemic myocardium was documented by demonstration of a rapid release of histamine and TNF-alpha in the cardiac lymph after myocardial ischemia. Histochemical studies with FITC-labeled avidin demonstrated degranulating mast cells only in ischemic samples of canine myocardium. Immunohistochemistry suggested that degranulating mast cells were the primary source of TNF-alpha in the ischemic myocardium. In situ hybridization studies of reperfused myocardium localized IL-6 mRNA in infiltrating mononuclear cells and in mononuclear cells appearing in the postischemic cardiac lymph within the first 15 minutes of reperfusion. Furthermore, isolated canine mononuclear cells incubated with postischemic cardiac lymph demonstrated significant induction of IL-6 mRNA, which was partially blocked with a neutralizing antibody to TNF-alpha. CONCLUSIONS Cardiac mast cells degranulate after myocardial ischemia, releasing preformed mediators, such as histamine and TNF-alpha. We suggest that mast cell-derived TNF-alpha may be a crucial factor in upregulating IL-6 in infiltrating leukocytes and initiating the cytokine cascade responsible for myocyte ICAM-1 induction and subsequent neutrophil-induced injury.

Prevention of Mast-Cell Degranulation by Ketotifen in Patients with Physical Urticarias

The capacity for ketotifen to prevent mast-cell degranulation in vivo was studied in patients with physical urticarias. Patients were exposed to the appropriate stimulus to elicit their physical urticaria before and during ketotifen therapy. Histamine concentrations in plasma samples, obtained before and serially after the physical provocation, were determined by radioenzymatic thin-layer chromatography. Ketotifen therapy was associated with marked reductions in plasma histamine levels after stimulation and in clinical evidence of urticaria in each patient. A direct correlation of ketotifen therapy and a reduction in histamine release was confirmed in a patient with a cold-induced urticaria who was studied again after discontinuation and again after reinstitution of therapy. Although the mechanism of action is unknown, this report shows that ketotifen is capable of inhibiting cutaneous mast-cell degranulation and its accompanying symptoms. These findings suggest important therapeutic alternatives for patients with mast-cell-mediated diseases.

Production of IL-5 and granulocyte-macrophage colony-stimulating factor by naive human mast cells activated by high-affinity IgE receptor ligation

BACKGROUND The late-phase allergic reaction is an eosinophilic inflammatory response that begins several hours after allergen exposure, may persist for 24 hours, and is an important pathogenic mechanism in allergic disease. OBJECTIVE Cultured naive human mast cells were used to investigate whether mast cells are a direct source of the eosinophil-promoting cytokines IL-5, IL-3, and granulocyte-macrophage colony-stimulating factor (GM-CSF). METHODS Naive human mast cells were derived from bone marrow mononuclear cells cultured in the presence of stem-cell factor. Cytokine message and protein production in response to high-affinity IgE receptor ligation of cultured mast cells were measured by semiquantitative polymerase chain reaction and ELISA, respectively. RESULTS IL-5, IL-3, and GM-CSF messenger RNA increased within 2 hours of mast cell activation, with IL-5 and GM-CSF message remaining elevated for 24 hours, whereas IL-3 mRNA rapidly declined. IL-5 and GM-CSF protein were measurable 4 to 6 hours after stimulation and peaked by 24 and 12 hours, respectively. IL-3 protein was not detectable. CONCLUSION These findings demonstrate that naive mast cells do not constitutively produce IL-5 or GM-CSF protein but are a major source of these eosinophilotropic cytokines on high-affinity IgE receptor ligation.

Urticaria and angioedema

Urticaria and angioedema are usually the clinical consequence of vasoactive mediators derived from mast cells in the skin or mucosal tissues. Efforts to classify mast cell-mediated causes of urticaria and angioedema have generally been frustrated by their diverse pathogenesis and clinical course. The term acute is typically used to describe fleeting lesions whose recurrence does not extend beyond 6 weeks. Chronic is the term used to describe lesions that persist for more than a few hours but usually less than a day, and recurrences extend for more than 6 weeks. These definitions do not take histology into account. Skin biopsies of fleeting lesions demonstrate a paucity of inflammatory cells, whereas more persistent lesions display a spectrum of perivascular cuffing by predominantly T cells and monocytes. The presence of leukocytoclastic vasculitis in persistent lesions indicates an underlying immune complex disease. Many of the physical urticarias have fleeting lesions that can be induced with the appropriate stimulus for years. This review article has emphasized the clinical course and histology of urticaria and angioedema lesions in an effort to provide a more complete understanding of the pathogenesis and appropriate treatment. Clearly, avoidance of an identifiable inciting stimulus is optimum management, although most patients have no etiology defined or the cause is not realistically avoidable. At present, treatment options for these patients rely on antihistamines to control the immediate consequence of mast cell degranulation. Corticosteroids are reserved for the treatment of patients whose urticaria or angioedema lesions persist, reflecting the increasing involvement of mononuclear cells in the disease process. For leukocytoclastic vasculitis, corticosteroids are indicated, and cytotoxic drugs may be required for adequate treatment. Future treatments of urticaria and angioedema will evolve based on elucidation of the relevant cells and soluble mediators and will include counterregulatory or antagonistic peptides and drugs. C1 esterase inhibitor deficiency is a relatively uncommon cause of angioedema but is important to understand because of its ability to clinically mimic mast cell-mediated angioedemas and its unique pathogenesis and treatment. HAE can be divided into two serologic subtypes that simply reflect the location of the defect in one of the codominantly expressed C1-INH genes on chromosome 11. AAE can be divided into two serologic subtypes. AAE type I is due to massive consumption of C1-INH, presumably by tumor-related immune complexes. AAE type II is due to an anti-C1-INH autoantibody.(ABSTRACT TRUNCATED AT 400 WORDS)

Therapy of chronic idiopathic urticaria with nifedipine: Demonstration of beneficial effect in a double-blinded, placebo-controlled, crossover trial

The efficacy of nifedipine, a calcium channel antagonist, in the treatment of chronic idiopathic urticaria, was evaluated in a double-blinded, placebo-controlled, crossover trial. Ten patients with chronic urticaria refractory to maximally tolerated doses of H1 and H2 antihistamines and in whom extensive evaluation failed to identify a cause for their urticaria were entered into the study. Patients continued with their prestudy antihistamine regimens. A study drug dosage was titrated in each patient and maintained throughout the trial. Patients were treated with placebo or nifedipine for 4 weeks and then crossed over to the other medication for 4 weeks. One patient withdrew because of unrelated medical illness, two patients withdrew after crossover to placebo because of intolerable urticaria, and seven patients completed the study. A beneficial effect of nifedipine was clearly demonstrated. Hive count, hive index, and itch index were all significantly improved at the end of 4 weeks of nifedipine treatment (p = 0.023, 0.003, and 0.003, respectively) but not placebo treatment (p = 0.194, 0.664, and 0.944, respectively). Additionally, end point hive index and itch index scores with nifedipine compared to corresponding placebo scores were significantly improved (p = 0.010 and 0.008, respectively). Nifedipine was well tolerated. Thus, when nifedipine is used as an adjunct to antihistamines, it appears to be a safe, efficacious drug for the treatment of chronic idiopathic urticaria.

Behcet's-like Syndrome Associated with Idiopathic CD4+ T-Lymphocytopenia, Opportunistic Infections, and a Large Population of TCRɑβ+ CD4-CD8-T Cells

Abstract Herein we report a patient with Behfet’slike syndrome, idiopathic CD4+ T- lymphocytopenia, opportunistic infections, and a large polyclonal population of TCRaj8+ CD4“ CD8- T cells. Microfluorimetric analysis of peripheral blood mononuclear cells revealed CD4+ T-cell counts of 10 ± 5/mm3. The CD3+ T cells were 99% TCRa/T, of which 74 ± 5% were CD4- CD8-. No clonal populations were detected by southern analysis for T-cell receptor V(

Cumulative reduction in serum cholinesterase following repeated therapeutic plasma exchange

gene rearrangements. No evidence of human immunodeficiency virus infec-tion was present, although nocardia, Candida, pneumocystis, cytomegalovirus, and herpes in-fections were documented. The concomitant presence of opportunistic infections and a large population of TCRafi+ CD4~ CD8“ T cells suggests a pathogenic association and an intense immune response to microbial lipid or lipoglycan antigens presented in the context of CD1 molecules. This case demonstrates the potential for idiopathic CD4+ T-lymphocyto- penia to occur in Beh^et’s-like syndrome with lethal

Oxygen Therapy in Chronic Obstructive Lung Disease

STUDY OBJECTIVE To investigate the magnitude of serum cholinesterase reduction following repeated therapeutic plasma exchange in patients with neuromuscular disease. DESIGN Serum cholinesterase activity was measured immediately before and after each plasma exchange in open-label fashion and then analyzed using an analysis of variance model. SETTING Inpatient neurology and allergy and immunology clinics at a university-affiliated hospital. PATIENTS 50 consecutive patients with neuromuscular disease. INTERVENTIONS All patients underwent repeated therapeutic plasma exchange, with each subject receiving up to a maximum of six plasma exchanges. MEASUREMENTS AND MAIN RESULTS Serum cholinesterase activity was determined spectrophotometrically. Analysis of variance revealed a significant reduction in serum cholinesterase following each therapeutic plasma exchange (p < 0.0001), a significant and consistent reduction across the six treatments (p < 0.0001), and a significant interaction between (before versus after exchange) and treatment number (p < 0.0001). Mean serum cholinesterase before repeated therapeutic plasma exchange was 4817 U/L, but it decreased to a mean of 929 U/L following six plasma exchanges. CONCLUSIONS There is a significant reduction in serum cholinesterase following repeated therapeutic plasma exchange. It is suggested that drugs metabolized by serum cholinesterase (e.g., succinylcholine, mivacurium) be used with caution in the period immediately following repeated therapeutic plasma exchange.

Water Intoxication Following Moderate-Dose Intravenous Cyclophosphamide

Excerpt To the editor, The information obtained from the Nocturnal Oxygen Therapy Trial (1) does indeed seem to indicate that continuous oxygen therapy is associated with a lower mortality than noc...