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Biomedical subjects

M W Greaves

Publications and source records attributed to M W Greaves.

At least 55 records · Page 3Linked to original sources
PubMed1997

The pathogenesis of chronic idiopathic urticaria.

Chronic idiopathic urticaria (CIU) can be extremely disabling and difficult to treat, with little response to antihistamine therapy. The pathogenic mechanisms of the disease are not well understood, but the primary effector cell is the mast cell. Release of mast cell mediators can cause inflammation and accumulation and activation of other cells, including eosinophils, neutrophils, and possibly basophils. Recent work has demonstrated that about one third of patients with CIU have circulating functional histamine-releasing autoantibodies that bind to the high-affinity IgE receptor (Fc epsilon RI) or, less commonly, to IgE; mast cell-specific histamine-releasing activity that has not yet been fully characterized; no identifiable circulating histamine-releasing activity. The mainstay of treatment of CIU consists of antithistamines, but immunotherapy using plasmapheresis, intravenous immunoglobulin, and cyclosporin may be valuable in severely affected patients with treatment-resistant disease. The response to immunomodulation and the recent finding of an association with HLA DR4 lend further support for an autoimmune basis to CIU in some patients.

Basophils↗
PubMed1996

Pathophysiology of itching.

Itching is the predominant symptom of skin disease but it is ill-understood and a challenge for future research. Even the major nerve pathways for itch, and its relationship to pain are debatable. In inflamed skin, histamine plays a major role and its mode of release from mast cells in, for example, chronic urticaria is now better appreciated. Tachykinins including substance P and cytokines including interleukin-2 are evidently important peripherally. Opioid mu-receptor-dependent processes activate inhibitory circuits in the central nervous system and regulate the extent of intensity and quality of perceived itch. It is proposed that stimulation of large areas of skin such as by scratching, generates inhibitory activity which suppresses itch excitation. Therapeutic intervention based upon understanding these regulatory processes is a real prospect.

Humans↗
PubMed1996

Approach to the patient with chronic urticaria.

Although most patients are overinvestigated, the history may offer clues to food-additive reactivity or urticarial vasculitis. In addition, the history may point to physical urticarias triggered, for instance, by pressure or heat. Recent evidence implicates histamine-releasing autoantibodies in at least 25% of patients with chronic idiopathic disease.

Adult↗
PubMed1996

Dermal mast cell activation by autoantibodies against the high affinity IgE receptor in chronic urticaria.

Previous studies identified autoantibodies against the IgE high affinity receptor alpha-chain, Fc epsilon RI alpha, in sera of selected patients with severe chronic idiopathic urticaria. We have now determined the incidence of anti-Fc epsilon RI alpha autoantibodies in a group of 163 patients. Intradermal injection of autologous serum caused skin reactions indicative of mast cell degranulation in 98 (60%) patients. Based on histamine release from IgE-sensitized and nonsensitized basophil leukocytes of healthy donors, we detected anti-Fc epsilon RI alpha autoantibodies in sera from 38 (23%) urticaria patients and evidence for anti-IgE antibodies in a further nine patients. The sera that released histamine from basophils induced histamine release (4-34%, n = 12) from mast cells in incubated skin slices. Protein-G affinity chromatography of sera demonstrated that mast cell histamine release was IgG-mediated. Preincubation of sera or the IgG fraction with a recombinant alpha-chain of Fc epsilon RI inhibited histamine release from mast cells and basophils. Further studies with the mouse anti-human Fc epsilon RI alpha antibody 29C6 showed that mast cells and basophils were similarly sensitive to IgG-mediated direct cross-linking of Fc epsilon RI, with 0.01-1.0 micrograms/ml 29C6 evoking histamine release in each case. These studies demonstrate that circulating levels of anti-Fc epsilon RI alpha autoantibodies mediate histamine release from skin mast cells in vitro and, taken together with in vivo evidence of mast cell degranulation following intradermal injection of autologous serum, support the concept that anti-Fc epsilon RI alpha autoantibodies are relevant to the pathogenesis of severe chronic urticaria in about 25% of patients.

Adolescent↗
PubMed1996

Histamine: the quintessential mediator.

Histamine is unique in being the only substance described to date which fulfils all of the criteria established by Dale for an inflammatory mediator. Thus, histamine is known to cause the "Triple Response" of Lewis and to act via H1 and H2 receptors to produce vasodilation and increased vascular permeability; elevated levels of histamine are found in inflamed tissue; histamine is produced and stored in mast cells and there are established mechanisms for histamine release via mast cell surface receptors; and antihistamines alleviate the clinical manifestations of histamine release. There have been several recent advances in our understanding of histamine pharmacology and of the pathomechanisms of chronic idiopathic urticaria (CIU), a disease in which histamine plays an important role. Two new histamine receptors have been identified, the inhibitory (H3) receptor and the intracellular (H(ic)) receptor involved in cell proliferation. There is now evidence that mast cell derived histamine release in patients with CIU is due to an autoimmune disease, mediated by autoantibodies to the alpha-subunit of the high affinity IgE receptor on mast cells and basophils. Removal of these autoantibodies by plasmapheresis, or treatment with intravenous immunoglobulins may cause clinical remission. Cyclosporin A has also been found to be of benefit to some patients with CIU probably due to a mast cell "stabilising" effect, leading to reduced release of histamine and other mediators. This article reviews our current knowledge on histamine, its role, receptors and mechanisms for release.

Chronic Disease↗
PubMed1995

The effects of topical corticosteroids on delayed pressure urticaria.

Six patients with delayed pressure urticaria (DPU) applied clobetasol propionate (0.05%) ointment or its base to predetermined test sites on the right and left thigh as part of a randomized, double-blind study. A pressure challenge was administered to each test site at the initial visit and repeated after 3 days and 6 weeks of treatment and at between 4 and 8 weeks after treatment. The areas of pressure-induced weals were measured 6 h after each challenge. At the 6-week visit, a 4-mm punch biopsy was taken from pressure-challenged skin on each test site. Sections were stained for mast cells and immunohistochemical labelling was used to demonstrate neutrophils (neutrophil elastase), eosinophils (eosinophil cationic protein), monocytes/macrophages (EBM 11), cells expressing the beta-2 integrins (CD11/18) and the vascular adhesion molecules, E selectin and intercellular adhesion molecule-1 (ICAM-1). In the steroid-treated sites, there was a significant decrease (P < 0.05, Wilcoxon's matched-pairs test) in the size of the pressure weals compared with baseline at 3 days, 6 weeks and at follow-up. Demonstrable mast cells were significantly decreased (P = 0.059) in the pressure-challenged areas in the steroid-treated sites compared with the base-treated sites. The histological response to pressure was minimal in both sites perhaps demonstrating an active pharmacological effect of the ointment base. In conclusion, the application of potent topical steroids significantly reduced the clinical response to pressure in patients with DPU, possibly through a reduction in mast cells.

Administration, Topical↗
PubMed1995

Aquagenic pruritus.

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Diagnosis, Differential↗
PubMed1995

Immunohistological comparison of granulated cell proteins in induced immediate urticarial dermographism and delayed pressure urticaria lesions.

Urticarial dermographism and delayed pressure urticaria are two forms of physical urticaria which are well defined clinically and histologically. Previous studies have shown eosinophil granule protein deposition in urticarial reactions, including chronic urticaria, solar urticaria and delayed pressure urticaria. To evaluate and compare the involvement of granulated inflammatory cells in urticarial dermographism and delayed pressure urticaria, we studied sequential biopsies of induced lesions of urticarial dermographism and delayed pressure urticaria by indirect immunofluorescence, to detect eosinophil granule major basic protein (MBP) and neutrophil granule elastase. Biopsies from dermographic lesions at time 0, 5 min, 15 min, 2 h and 24 h, showed few infiltrating eosinophils, with minimal extracellular MBP deposition, and a few infiltrating neutrophils, with minimal neutrophil elastase deposition, throughout the evolution of the lesions. Sequential biopsies of delayed pressure urticaria at time 0, 20 min, 6, 12 and 24 h, showed eosinophil infiltration with extensive MBP deposition beginning at 20 min, and neutrophil infiltration with variable elastase deposition beginning at 20 min. Control tissue specimens from normal volunteers showed neutrophil infiltration and slight degranulation, but no eosinophil infiltration or degranulation. Comparison of urticarial dermographism with delayed pressure urticaria showed marked differences in the patterns of infiltration. Delayed pressure urticaria, with eosinophil and neutrophil degranulation, was strikingly similar to the IgE-mediated late phase reaction. In contrast, eosinophil and neutrophil involvement in urticarial dermographism was minimal. Considering the extent of eosinophil granule protein deposition and the biological activities of the eosinophil granule proteins, the findings in delayed pressure urticaria point to an important pathophysiological role of eosinophils in the disease.

Blood Proteins↗
PubMed1995

Mast cells and T lymphocytes in chronic urticaria.

Mast cells are considered to be the primary effector cells in urticaria but it is possible that lymphocytes contribute to the formation of weals by secreting histamine releasing factors. The aim of this study was to examine the population of mast cells and to quantify the T cell subsets and their activation status in delayed pressure urticaria (DPU), chronic idiopathic urticaria and normal controls. Three biopsies were obtained from each of four patients with chronic idiopathic urticaria but not DPU. Three biopsies were taken from each of 13 patients with DPU, from a combination of unchallenged skin and at 0, 2, 6, 24, 48, and 120 h after weighted steel rods (diameter 1.5 cm) had been applied to the thighs. Three biopsies were similarly obtained from each of four normal controls before an identical pressure challenge and at 6, 24 and 48 h afterwards. The chloracetate esterase stain was used to demonstrate mast cells and an alkaline phosphatase anti-alkaline phosphatase immunohistochemical technique to assess the phenotypic and activation characteristics of the T cell infiltrate. The mast cell count did not differ significantly between unchallenged skin from DPU patients and normal controls. Following a pressure challenge to the DPU patients, the number of stainable mast cells decreased significantly to a level comparable with that in spontaneous weals of chronic idiopathic urticaria. Investigation of T cell subsets showed a preponderance of CD4+ cells over CD8+ cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Chronic urticaria.

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Autoimmune Diseases↗
PubMed1994

Electrospray mass spectrometric characterization of the components of protein mixtures and its application to members of the chemokine family of interleukins.

Electrospray mass spectrometry has been employed to detect and characterize the members of a closely related family of immunologically active proteins (chemokines) produced in cell culture by stimulated fibroblasts. The reliability of the method to produce precise data concerning the relative proportions of proteins present in mixtures was investigated in a model system and found to be satisfactory in a range of 10:1 in concentration.

Cells, Cultured↗
PubMed1994

Platelet activating factor (PAF) and lyso-PAF in psoriasis.

Previous studies have shown that scale from lesional psoriatic skin contains substantial amounts of platelet activating factor (PAF). In this study, PAF and its immediate precursor, lyso-PAF, were measured in exudates from abrasions on lesional and uninvolved psoriatic skin, and from skin of healthy subjects. The mean amounts of PAF recovered from lesional and uninvolved psoriatic skin (n = 13) and from healthy skin (n = 14) were not significantly different (range 0.05-2.14 pmol/sample). Mean recoveries of lyso-PAF from lesional psoriatic skin (n = 9) and skin of healthy subjects (n = 13) were also similar (9.5 +/- 1.9 and 11.0 +/- 1.9 pmol/sample, respectively), but significantly less lyso-PAF was found in exudates from the uninvolved psoriatic skin (n = 9; 3.1 +/- 0.4 pmol/sample; P < 0.01 relative to both lesional psoriasis and healthy skin). The finding of reduced lyso-PAF in uninvolved psoriatic skin was unexpected because increased phospholipase-A2 activity is associated with psoriasis. These results do not support the hypothesis that extracellular PAF contributes significantly to the inflammation associated with psoriasis.

Adolescent↗
PubMed1994

Adhesion molecule expression and the inflammatory cell infiltrate in delayed pressure urticaria.

We have investigated the kinetics of the leucocyte infiltrate in delayed pressure urticaria (DPU) in relation to the in vivo expression of the cytokine-regulated cell surface adhesion molecules, E-selectin (endothelial adhesion molecule-1, ELAM-1), intercellular adhesion molecule-1 (ICAM-1), and vascular adhesion molecule-1 (VCAM-1). Immunohistochemical analysis was performed on biopsies taken from unchallenged skin, and at 0, 2, 6, 24, 48 and 120 h after weighted rods had been applied to 13 patients with DPU. There was moderate to marked upregulation of E-selectin at 6 and 24 h after application of pressure. At 24 h, more patients showed expression of VCAM-1 on perivascular cells than before pressure. Moderate expression of ICAM-1 was present in some biopsies from both unchallenged and pressure-challenged skin, but there was no clear trend. In DPU, there was a significant increase in the neutrophil count at 2 h after a pressure challenge, with further increases at 6 and 24 h. The median cell counts per high-power field of eosinophils and monocyte/macrophages increased significantly at 24 h after pressure. Biopsies from four normal controls subjected to an identical pressure challenge showed no detectable changes in adhesion molecule expression or in the cell infiltrate. The findings in four patients with chronic idiopathic urticaria not associated with DPU were qualitatively similar to (but intermediate in severity between) the findings in DPU weals at 6 and 24 h. These results suggest that vascular endothelial activation is an early response to pressure challenge in DPU, and is also present in chronic idiopathic urticaria.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗