Macrophage subsets in different types of urticaria

Summary Biopsy specimens from lesional and uninvolved skin of nine patients with delayed pressure urticaria, three patients with acute urticaria, six patients with chronic recurrent urticaria, and four patients with urticaria pigmentosa were analyzed by routine histology and by immunochemistry for their reactivity with monoclonal antibodies to three different subsets of macrophages. Skin from 12 healthy volunteers served as control. Uninvolved skin of patients did not differ from that of healthy volunteers. An antibody against activated macrophages (27E10) was reactive to a marked extent with macrophages in wheals of pressure urticaria, more variably in acute and chronic urticaria, and practically not at all in urticaria pigmentosa. Antibodies with specificities for macrophages in healing (RM3/1) and normal (25F9) tissue reacted more markedly in all but pressure urticaria lesions, compared with normal skin. These findings indicate an active involvement of inflammatory macrophages in whealing reactions while these cells play apparently no role in cutaneous mast cell proliferation (urticaria pigmentosa).     

Neue Therapieoptionen der Urtikaria und ihrer Subtypen

Urticaria is one of the most common skin diseases. It is divided into several categories including acute and chronic urticaria as well as physical urticaria and special subtypes such as cholinergic and autoimmune urticaria. The causes of urticaria are multiple. In more than 80%, urticaria is triggered by an inflammatory focus, a subclinical infection or autoimmune actions. In addition, non-specific pharmacological or toxin-mediated release of inflammatory mediators from basophils or mast cells can also trigger urticaria. These new aspects in the pathophysiology of urticaria suggest new and promising therapeutic strategies. The first line treatment of urticaria still consists of non-sedating H1-antihistamines. Since urticaria has a profound impact on quality of life, effective treatment is very important. We consider new therapeutic options based on our long-term experience in treating patients with urticaria.     

慢性荨麻疹患者血清组胺释放活性检测

目的 检测慢性荨麻疹患者血清组胺释放活性,探讨慢性荨麻疹的发病机制.方法 通过体外分离人皮肤肥大细胞,进行肥大细胞组胺释放试验,测定组胺释放率.结果 62例慢性荨麻疹患者中,自体血清皮肤试验阳性者24例占38.71%.混合细胞悬液中肥大细胞的组胺自发释放率<5%.血清活化皮肤肥大细胞引起的组胺释放率从3.1%～79.5%(16.44%±14.26%),明显高于正常人对照组(P<0.01),其中27例组胺释放率>15%(43.55%);自体血清皮肤试验(+)组的组胺释放率及阳性率均明显高于自体血清皮肤试验(-)组(P<0.01).结论 部分慢性荨麻疹患者血清中存在组胺释放活性,可直接活化肥大细胞,释放组胺等血管活性介质,引起荨麻疹.     

Aspirin sensitivity and urticaria

The relationship of aspirin sensitivity to urticaria is complex. Aspirin sensitivity can cause acute urticaria in some individuals, aggravate pre-existing chronic urticaria in others or, rarely, act as a cofactor with food or exercise to provoke anaphylaxis. Individuals who react with urticaria appear to come from a different population to those who react with asthma, although there is some overlap. Aspirin-sensitive chronic urticaria patients may also react adversely to some food additives. The pharmacological mechanisms of aspirin-sensitive urticaria are not fully understood but probably involve diversion of arachidonic acid metabolism from prostaglandin to cysteinyl leukotriene formation leading to direct effects on blood vessels and delayed mast cell degranulation with release of histamine. Cross-reactivity amongst all nonsteroidal drugs is common in aspirin-aggravated chronic urticaria but appears not to occur with selective cyclo-oxygenase 2 inhibitors.     

Chronic idiopathic urticaria and its management

ABSTRACT: Chronic urticaria is defined as the daily or almost daily occurrence of wheals for at least 6 weeks. This disorder affects 0.1% of the general population and is more common in females. Recently a subgroup of patients with chronic urticaria has been found to have circulating autoantibodies directed against the high-affinity IgE receptor (Fc∍RI) or against IgE antibodies. These "autoantibodies" are felt to play a role in mast cell histamine release. Urticaria patients with these circulating antibodies also have a higher prevalence of other autoimmune diseases. The management of patients with chronic urticaria is to identify and eliminate the underlying cause, however, an etiology for chronic urticaria is rarely identified. Thus the approach to treatment usually centers on the use of antihistamines initially with the addition of other immune modulating agents as necessary.     

Increased expression of endothelial cell adhesion molecules due to mediator release from human foreskin mast cells stimulated by autoantibodies in chronic urticaria sera

Histamine-releasing antibodies that act against the epitope of the alpha chain of Fc(epsilon)RI (anti-Fc(epsilon)RI(alpha) antibody) that may affect pathogenesis in serum of patients with chronic urticaria. We assessed the capability of anti-Fc(epsilon)RI(alpha) antibody in sera from patients with chronic urticaria to release histamine and cytokines, and to induce the expression of endothelial cell adhesion molecules. We also assessed the release of inflammatory mediators from cultured foreskin mast cells, and expression of endothelial cell adhesion molecules on human dermal microvascular endothelial cells. Cells were pretreated with mast cell-conditioned media: culture media of mast cells treated with sera from chronic urticaria patients containing anti-Fc(epsilon)RI(alpha) antibody. Histamine release from human foreskin mast cells challenged with sera, increased after both 20 min and 16 h intervals. Leukotriene D4 release also increased at both 20 min and 16 h. Tumor necrosis factor-alpha increased significantly in foreskin mast cell culture challenged with sera of chronic urticaria patients. After the stimulation of human dermal microvascular endothelial cells with the conditioned media, the expression of intercellular cell adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin increased significantly. Treatment of the conditioned media with anti-tumor necrosis factor-alpha monoclonal antibody partially inhibited the expression of intercellular cell adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin. The data suggest that sera from patients with chronic urticaria containing anti-Fc(epsilon)RI(alpha) antibody release mediators and tumor necrosis factor-alpha by activating human foreskin mast cells. This release can play a pathogenic role in chronic urticaria by activating endothelial cells, in part due to the actions of tumor necrosis factor-alpha from mast cells.     

Absence of MHC class II antigen on mast cells at sites of inflammation in human skin

Abstract Since the presence of major histocompatibility complex (MHC) antigens has recently been reported on murine and human mast cells under various conditions, we have investigated their expression on mast cells in different types of cutaneous inflammation. Cryostat sections from lesional biopsies of patients with psoriasis, atopic eczema, chronic urticaria, lichen planus, bullous pemphigoid and urticaria pigmentosa were immunohistochemically stained with monoclonal antibodies against MHC class I and class II antigens using a double staining APAAP/toluidine blue methodology. While strongly positive staining with the antibody directed against MHC class I antigens was found on nearly all mast cells in normal skin and in inflammatory dermatoses, reactivity for HLA-DR and HLA-DQ antigens on mast cells could not be detected, except for less than 2% of cells with doubtful staining. Human mast cells therefore probably play no significant rôle as antigen-presenting cells in the conditions studied.     

Acute phase inflammatory markers in patients with non‐steroidal anti‐inflammatory drugs (NSAIDs)‐induced acute urticaria/angioedema and after aspirin challenge

Background Active chronic urticaria, identified as a mast cell‐ and basophil‐dependent inflammatory disorder of the skin is able to elicit acute phase response (APR). However, systemic inflammatory response in different types of urticaria is poorly characterized. Aim To determine APR pattern in a clearly defined group of patients with acute urticaria and/or angioedema – induced by NSAIDs. Methods Plasma IL‐6 and serum C‐reactive protein (CRP) concentrations were studied in 17 patients with NSAIDs‐induced acute urticaria/angioedema (NSAIDsAU) and in 20 healthy controls. Eleven patients who used NSAIDs were presented at the emergency room with acute urticaria/angioedema while the remaining six manifested the symptoms during the aspirin challenge test. Patients were examined in a dynamic manner: during the acute phase, and next, after subsidence of the symptoms. Results CRP and IL‐6 concentrations increased significantly in patients with NSAIDsAU as compared with their asymptomatic period and the healthy subjects. In addition, NSAIDsAU patients showed elevated concentration of the biomarkers following aspirin provocation with the baseline values recovered in the asymptomatic period. Conclusion These results indicate that an acute systemic inflammatory response is activated in patients with NSAIDs‐induced urticaria and/or angioedema. The study supports the evidence proving that up‐regulation of CRP and IL‐6 in urticaria/angioedema does not necessarily reflect any concomitant infection or other inflammatory processes, but may be due to the disease itself.     

Sex hormones and urticaria

Chronic urticaria is characterized by mast cells/basophils activation which initiate the inflammatory response. Pathogenetically, the disease may in many cases represent an autoimmune phenomenon. Altered function of the neuro-endocrine-immune system due to stress and other factors has also been implicated its pathogenesis. Sex hormones modulate immune and inflammatory cell functions, including mast cell secretion, and are regarded as responsible for gender and menstrual cycle phase-associated differential susceptibility and severity of some autoimmune and inflammatory diseases. Chronic urticaria is approximately twice more frequent in women than in men. In addition, urticaria may be associated with some diseases and conditions characterized by hormonal changes, including endocrinopathy, menstrual cycle, pregnancy, menopause and hormonal contraceptives or hormone replacement therapy. Hypersensitivity reactions to endogenous or exogenous female sex hormones have been implicated in the pathogenesis of urticarial lesions associated with estrogen and autoimmune progesterone dermatitis. We observed lower serum dehydroepiandrosterone sulfate (DHEA-S) concentration in patients with chronic urticaria with positive and negative response to autologous serum skin test. Thus, the influence of fluctuations in the hormonal milieu and altered sex hormone expression on the triggering-off, maintenance or aggravation of urticaria should be taken into account. In addition, the possible impact of estrogen mimetics, in the environment and in food, on the development of disease associated with mast cell activation must be considered. This review endeavours to outline what is known about the possible influence of sex hormones in the expression of urticaria.     

Neutrophilic urticaria: clinical features, histological changes and possible mechanisms

Neutrophilic urticaria (NU) is a histologically defined entity, but its clinical and pathogenetic aspects are poorly understood. We investigated 22 NU patients whom we identified by examining 118 biopsies of weals. The patients comprised 11 of 20 with acute urticaria, nine of 49 with chronic urticaria, one of 10 with cold urticaria and one of 10 controls undergoing prick tests. Clinically, NU patients had a shorter mean duration of disease than other urticaria patients and significantly increased erythrocyte sedimentation rate and leucocytosis. Histologically, not only neutrophil counts, but to a lesser extent also eosinophil counts and mononuclear cell infiltrates were significantly increased in lesional skin of NU, and there was more marked vasodilatation and endothelial swelling. On immunohistochemistry, increased tumour necrosis factor α and interleukin (IL)-3 expression was noted, compared with other urticarias, whereas IL-8 expression was only minor. These data characterize NU as an acute phase urticarial reaction associated with an intense inflammatory infiltrate and marked upregulation of some mast cell-derived cytokines.     

The chloroacetate esterase reaction for mast cells in dermatopathology: a comparison with metachromatic staining methods

This paper compares standard metachromatic methods with Leder's chloroacetate esterase reaction on mast cells in paraffin wax-embedded tissue of urticaria pigmentosa and a variety of inflammatory and benign neoplastic cutaneous conditions. Our conclusions are that Leder's method allows easier identification of mast cells and can be a useful adjunct to conventional metachromatic methods. The technique could be conveniently adopted in routine dermatopathology for mast cell identification.     

CHRONIC AUTOIMMUNE URTICARIA: WHERE WE STAND?

It is well-recognized that 30-40% of chronic idiopathic urticaria is autoimmune in nature. Chronic autoimmune urticaria is caused by anti-FcεRI and less frequently, by anti-IgE autoantibodies that lead to mast cell and basophil activation, thereby giving rise to the release of histamine and other proinflammatory mediators. Activation of the classical complement pathway and formation of C5a are important in dermal mast cell activation. C5a is also a neutrophil and eosinophil chemoattractant. Chronic autoimmune urticaria has been found to be associated with autoimmune thyroid disease. The autologous serum skin test is used as a screening test for chronic autoimmune urticaria and has a sensitivity and specificity of about 70 and 80%, respectively. The current gold standard diagnostic test is the basophil histamine release assay. The treatment of chronic autoimmune urticaria, as in chronic idiopathic urticaria, is with H1 antihistamines. Oral corticosteroids may be used during acute flares. Refractory cases have been shown to respond to cyclosporine and other immunomodulators. The prevalence of chronic autoimmune urticaria in Singapore is similar to that reported in Western countries at about 42%. The presence of thyroid autoimmunity appears to be higher than reported, with 22.5% of patients with chronic idiopathic urticaria here, exhibiting presence of thyroid autoantibodies.     

Aktuelle Positionsbestimmung zur Bedeutung von Nahrungsmittelallergien und -unverträglichkeiten bei der Urtikaria

Foods are usually the first suspect as the cause of urticaria. However, a causal relationship is found only in special subtypes of urticaria. IgE-mediated food allergy should be clearly separated from non-allergic hypersensitivity (pseudoallergic reactions). The former may play a role in acute urticaria, particularly in patients with atopic dermatitis. The responsible food proteins vary with age. IgE-mediated sensitization can apply to food-dependent exercise-induced urticaria/anaphylaxis but more often the combination of food intake (irrespective of which type) plus exercise results in symptoms. In chronic urticaria, IgE-mediated sensitization to food is normally irrelevant while pseudoallergic reactions to food additives and perhaps also to biogenic amines may be involved. Another urticaria subtype that may be caused by food is contact urticaria which is mostly found in the context of occupational food handling. Very rarely anisakiasis and nickel may cause food-induced urticaria. Aspirin is able not only to exacerbate and aggravate urticaria but can also enhance food-dependent urticaria.     

Mast cells with bilobed or multilobed nuclei in a nodular lesion of a patient with urticaria pigmentosa

Mast cells with bilobed or multilobed nuclei have only rarely been observed in the bone marrow of patients with systemic mastocytosis and in a case of subdural mast cell sarcoma. To our knowledge, they have not been reported in cutaneous mast cell disease. We report a rare occurrence of mast cells with bilobed or multilobed nuclei (atypical mast cell type II) in a nodular lesion of a 24-year-old woman with urticaria pigmentosa. The typical and atypical mast cells were confirmed by Giemsa and Leder's naphthol-AS-D-chloroacetate esterase stains and by immunohistochemical staining for tryptase and KIT protein (CD117). Although the nodular lesion with atypical mast cells did not appear to be cytologically malignant, the occurrence of atypical mast cells in a nodular lesion but not in a papular lesion might denote progression of the disease as suggested by the emergence of cells positive for p53.     

Urticaria

Urticaria is often classified as acute, chronic, or physical based on duration of symptoms and the presence or absence of inducing stimuli. Urticarial vasculitis, contact urticaria, and special syndromes are also included under the broad heading of urticaria. Recent advances in our understanding of the pathogenesis of chronic urticaria include the finding of autoantibodies to mast cell receptors in nearly half of patients with chronic idiopathic urticaria. These patients may have more severe disease and require more aggressive therapies. Extensive laboratory evaluation for patients with chronic urticaria is typically unrevealing and there are no compelling data that associate urticaria with chronic infections or malignancy. Pharmacologic therapy consists primarily of the appropriate use of first- and second-generation histamine H1 receptor antihistamines. Additional therapy may include leukotriene receptor antagonists, corticosteroids, and immunomodulatory agents for severe, unremitting disease. Despite our greater understanding of the pathogenesis of urticaria, the condition remains a frustrating entity for many patients, particularly those with chronic urticaria.     

Urticaria and mast cells in adolescence]

Adolescent patients are often affected by dermographic, cholinergic, cold or solar urticaria brought about by distinct physical stimulation. These physical forms of urticaria as well as cutaneous and systemic mastocytosis are due to the release of inflammatory mediators from the mast cells. As these diseases usually show characteristic cutaneous symptoms, they can easily be distinguished from other subtypes of urticarial reaction. In order to make the reader familiar with physical urticaria and mastocytosis, we describe the clinical features, pathogenic factors, and therapeutic possibilities of these disorders in adolescence.     

Corticotropin-releasing hormone receptor-1 and histidine decarboxylase expression in chronic urticaria

Certain skin disorders, such as contact dermatitis and chronic urticaria, are characterized by inflammation involving mast cells and worsen by stress. The underlying mechanism of this effect, however, is not known. The skin appears to have the equivalent of a hypothalamic-pituitary-adrenal (HPA) axis, including local expression of corticotropin-releasing hormone (CRH) and its receptors (CRH-R). We have reported that acute stress and intradermal administration of CRH stimulate skin mast cells and increase vascular permeability through CRH-R1 activation. In this study, we investigated the expression of CRH-R1, the main CRH-R subtype in human skin, and the mast cell related gene histidine decarboxylase (HDC), which regulates the production of histamine, in normal and pathological skin biopsies. Quantitative real time PCR revealed that chronic urticaria expresses high levels of CRH-R1 and HDC as compared to normal foreskin, breast skin and cultured human keratinocytes. The lichen simplex samples had high expression of CRH-R1, but low HDC. These results implicate CRH-R in chronic urticaria, which is often exacerbated by stress.     

Dermal dendrocytes FXIIIA+ phagocytizing extruded mast cell granules in drug‐induced acute urticaria

Background Few authors have been attempting between mast cells and dermal dendrocytes interactions on urticaria. Objective To describe the extruded mast cell granules and dermal dendrocytes in drug‐induced acute urticaria. Methods Seven patients with drug‐induced acute urticaria were enrolled in the study. We token skin biopsies of urticaria lesion and perilesional skin. The 14 fragments collected were processed to immunogold electron microscopy using single stains to tryptase and FXIIIa, besides double immunogold labeling with both. Results Some sections demonstrated mast cells in degranulation process, both in anaphylactic and piecemeal degranulation types. After double immunogold staining, 10 nm (FXIIIa) and 15 nm (Tryptase) gold particles were present together over the granules in mast cells indicating that tryptase and FXIIIa are each localized within the granules of these cells. Interestingly, we found a strong evidence of than the exocytosed mast cell granules contents both FXIIIa and tryptase immunolabeled are phagocytized by dermal dendrocytes. Conclusions The current observations provide morphological evidence that the exocytosis‐phagocytosis mechanisms of mast cell granules represents one pathophysiological example of mast cells‐dermal dendrocytes interactions in urticaria.     

Giardia lamblia — Ursache von Urtikaria und Pruritus oder zufällige Assoziation?

Three patients with chronic urticaria or pruritus were found to suffer from an asymptomatic intestinal infection caused by the protozoan Giardia lamblia. Treatment with metronidazole per os or tinidazole per os was successful; the pruritic symptoms in one patient improved markedly. Giardia lamblia (Giardia intestinalis) are enteroparasites and produce gastrointestinal symptoms such as acute and chronic diarrhea. Cutaneous manifestations associated with giardiasis occur extremely rarely. Urticaria and itching may be explained as an infection-associated allergy. Hitherto, the following cutaneous signs have been described: urticaria, angioedema, mouth ulcers, pruritus, atopic dermatitis, and anal eczema. We considered that the cutaneous manifestations described here, i. e., urticaria and itching, were secondary to the associated gastrointestinal infection due to Giardia lamblia cysts and trophozoite forms, as they disappeared under specific treatment with metronidazole or tinidazole.     

The inflammatory response in drug-induced acute urticaria: ultrastructural study of the dermal microvascular unit

BACKGROUND: Drug exposure is one of the main aetiologies of urticaria and represents the second most common cause in acute urticarias. Studies involving the ultrastructural aspects of urticaria are relatively rare in the literature. Most of the articles published report on skin biopsies of experimentally induced urticaria, and acute urticaria has been studied even less from a morphological point of view. OBJECTIVES: The aims of this study were to observe ultrastructural cell characteristics in five patients with drug-induced acute urticaria and possible aspects of the inflammatory skin response. METHODS: Clinical manifestations, light microscopy and transmission electron microscopy were evaluated. RESULTS: With light microscopy, a mild perivascular lymphocyte-monocyte infiltrate was observed with few neutrophils and dermal oedema in skin biopsies of five patients. With electron microscopy, a mild vascular dilatation was observed, with platelets in the lumen and several lymphocytes and dendritic cells close to the superficial dermal vessels. Some mast cells appeared normal, whereas others were granule-depleted. In some areas, mast cells, lymphocytes and satellite dendritic cells were closely associated, as well as some macrophages. A significant number of plasma cells, eosinophils and polymorphonuclear neutrophils were not observed; however, the presence of lymphocytes and macrophages was significant. The epidermis and the dermal-epidermal junction were preserved, except for a discrete oedema in keratinocytes. CONCLUSIONS: The ultrastructural aspect of drug-induced acute urticaria is similar to that observed in urticaria caused by Urtica dioica, intradermal histamine and cold urticaria. The presence of the cellular triad with mast cells, dendritic (or satellite) cells and lymphocytes suggests a functional interaction of these cells. These findings support the possible existence of mechanisms in the dermis that may participate in protective and/or injurious vasocentric immune reactions.