Celina Wakisaka Maruta

Activated status of basophils in chronic urticaria leads to interleukin-3 hyper-responsiveness and enhancement of histamine release induced by anti-IgE stimulus

Background Basophils and mast cells are the main target cells in chronic idiopathic urticaria (CIU). Besides the basopenia, intrinsic defects of the anti‐IgE cross‐linking signalling pathway of basophils have been described in CIU.

Pemphigus herpetiformis is a rare clinical expression of nonendemic pemphigus foliaceus, fogo selvagem, and pemphigus vulgaris

BACKGROUND Pemphigus herpetiformis is a rare and atypical variant of pemphigus that resembles dermatitis herpetiformis. Most patients show antiepidermal autoantibodies that stain the epidermal intercellular spaces by immunofluorescence, similar to pemphigus autoantibodies, and lack the immunopathologic features of dermatitis herpetiformis. OBJECTIVE The study was aimed at characterizing the specificity of the antiepidermal autoantibodies in seven patients with pemphigus herpetiformis. METHODS The antiepidermal autoantibodies were characterized by immunofluorescence, immunoblotting, and immunoprecipitation studies in seven patients who fulfilled the clinical, histologic, and immunofluorescence diagnostic criteria for pemphigus herpetiformis. RESULTS Five patients with features of pemphigus herpetiformis either had classic pemphigus foliaceus, or their disease evolved into classic pemphigus foliaceus. One of these patients had fogo selvagem. Two of the seven patients showed features of or had disease that evolved into pemphigus vulgaris. The antiepidermal autoantibodies present in all seven patients recognized desmoglein 1. CONCLUSION Pemphigus herpetiformis is a rare clinical and histologic expression of nonendemic pemphigus foliaceus, fogo selvagem, and pemphigus vulgaris.

Increased circulating pro-inflammatory cytokines and imbalanced regulatory T-cell cytokines production in chronic idiopathic urticaria

The immunologic characterization of chronic idiopathic urticaria (CIU), mainly regarding cytokine profile needs more investigation. We examined circulating inflammatory cytokine levels, T-cell induced secretion, and cytokine mRNA expression in patients with CIU subjected to the intradermal autologous serum skin test (ASST). Increased levels of circulating pro-inflammatory cytokines, such as TNF-alpha, IL-1beta, IL-12p70, and IL-6 have been observed in most of patients with CIU, together with an enhancement of IL-2 secretion following T-cell stimulation. Highlighting the inflammatory profile in CIU found in ASST positive, is the enhanced B-cell proliferative responsiveness and increased IL-17 secretion levels. ASST-positive patients also exhibited impaired IL-4 secretion associated with increased IL-10 production. Altered cytokine expression in patients with ASST-negative, was the down-modulation of spontaneous IL-10 mRNA expression levels in peripheral blood mononuclear cells. Our findings support the concept of immunologic dysregulation in CIU, revealing a systemic inflammatory profile associated with disturbed cytokine production by T cells, mainly related to IL-17 and IL-10 production.

Histamina, receptores de histamina e anti-histamínicos: novos conceitos

Drugs with antihistamine action are the most commonly prescribed medication in daily dermatologic practice, both to adults and children. This article addresses new concepts of the role of histamine receptors (H1 receptors) and discusses the anti-inflammatory effects of these drugs. Second generation antihistamines differs from first generation because of their high specificity and affinity for peripheral H1-receptors. Second generation antihistamines are also less likely to produce sedation because they have less effect on the central nervous system. Although the efficacy of the various H1-antihistamines in the treatment of allergic patients is similar, even when comparing first- and second-generation drugs, these drugs are still very different in terms of their chemical structure, pharmacology and toxic properties. Consequently, knowledge of their pharmacokinetic and pharmacodynamic characteristics is essential for a better medical care, especially that offered to pregnant women, children, the elderly, and patients with comorbidities.

Pemphigoid gestationis: clinical and laboratory evaluation

INTRODUCTION Pemphigoid gestationis, also known as herpes gestationis, is a rare autoimmune blistering disease associated with pregnancy. It usually occurs during the second or third trimester, but it may be present at any stage of pregnancy or the puerperium. The clinical, histologic, and immunopathological features of pemphigoid gestationis are similar to those of the pemphigoid group of disorders. METHODS We hereby report seven patients who were diagnosed with pemphigoid gestationis and followed at the Autoimmune Blistering Disease Clinic in the Department of Dermatology of the University of Sao Paulo Medical School between 1996 and 2008. DISCUSSION Demographic and clinical findings, such as median age, sites of involvement, and gestational age of onset or C3 of our patients, coincide with those described in previous reports. The majority of patients (85%) exhibited complement C3 and immunoglobulin G (IgG) deposition along the basement membrane zone (BMZ) on immunofluorescence. Herpes gestationis factor (HG) factor was postitive in four out of six patients (67%), and three out of five patients recognized the bullous pemphigoid recombinant antigen (BP180) by ELISA. CONCLUSION This study revealed a good outcome of the newborns from pemphigoid gestationis affected mothers, based on the absence of pemphigoid gestationis cutaneous lesions, mean birth weight, and normal Apgar scores and gestational age at birth.

Endemic pemphigus foliaceus (fogo selvagem) and pemphigus vulgaris: immunoglobulin G heterogeneity detected by indirect immunofluorescence

UNLABELLED Pemphigus are autoimmune intraepidermal blistering diseases in which immunoglobulin G (IgG) autoantibodies are directed against desmosomal glycoproteins. The aim of this study was to determine the IgG subclass profile of endemic pemphigus foliaceus (fogo selvagem) and pemphigus vulgaris utilizing indirect immunofluorescence. PATIENTS AND METHODS Twenty-five patients with pemphigus vulgaris, 25 with endemic pemphigus foliaceus (fogo selvagem), and 25 healthy controls were analyzed by indirect immunofluorescence for circulating autoantibodies (total IgG and its subclasses). RESULTS Our data revealed a significant correlation (P <.05) of disease activity and autoantibody levels in both forms of pemphigus, i.e., negative titers related to clinical remission, whereas positive results related to active disease. Immunoglobulin G subclass analysis in fogo selvagem demonstrated that in patients in remission, 56% showed positive immunoglobulin G4; in active disease, immunoglobulin G4 was the predominant subclass (100% positive in all cases). The IgG subclass profile in pemphigus vulgaris showed that in patients in remission, only 10% were positive for immunoglobulin G4; in active disease, positivity for immunoglobulin G4 was present in 78% to 88% of the cases. CONCLUSION Subclass characterization of immunoglobulin G autoantibodies is a useful tool for pemphigus follow-up, since immunoglobulin G4 (IgG4) is the subclass that is closely related to recognition of pathogenic epitopes, and consequently with disease activity. Careful monitoring should be performed for fogo selvagem in clinical remission with a homogeneous IgG4 response, since this may indicate more frequent relapses.

Epidermolysis Bullosa Acquisita in Childhood

Epidermolysis bullosa acquisita (EBA) is a subepidermal autoimmune blistering disease that is rarely reported in childhood. We describe a nine‐month‐old mulatto boy presenting with multiple, annular, widespread, tense blisters and oral lesions. The diagnosis of EBA was confirmed by histopathology, immunofluorescence, and immunoblotting analysis. The patient was successfully treated with systemic steroids (prednisone) and dapsone. After 20 months of initial treatment, clinical remission was observed, and dapsone remains as the current treatment. This case report emphasizes the rarity of EBA in childhood and the difficulties in reaching the final diagnosis.

Evaluation of D-dimer serum levels among patients with chronic urticaria, psoriasis and urticarial vasculitis

BACKGROUND It has been demonstrated that neutrophils, eosinophils and monocytes, under appropriated stimulus, may express tissue factor and therefore, activate the extrinsic pathway of coagulation. We performed a transversal and case-control study of patients with chronic urticaria and patients with psoriasis, in our outpatient clinic to evaluate the production of D-dimer. OBJECTIVE To evaluate D-dimer serum levels in patients with chronic urticaria and its possible correlation with disease activity. PATIENTS AND METHODS The study was conducted from October 2010 until March 2011. We selected 37 consecutive patients from our Allergy Unit and Psoriasis Unit, and divided them into three groups for statistical analysis: (i) 12 patients with active chronic urticaria (CU); (ii) 10 patients with chronic urticaria under remission and (iii) 15 patients with psoriasis (a disease with skin inflammatory infiltrate constituted by neutrophils, lymphocytes and monocytes). Another five patients with urticarial vasculitis were allocated in our study, but not included in statistical analysis. The serum levels of D-dimer were measured by Enzyme Linked Fluorescent Assay (ELFA), and the result units were given in ng/ml FEU. RESULTS Patients with active chronic urticaria had the highest serum levels of D-dimer (p<0.01), when compared to patients with CU under remission and the control group (patients with psoriasis). CONCLUSIONS Patients with active chronic urticaria have higher serum levels of D-dimer, when compared to patients with chronic urticaria under remission and patients with psoriasis. We found elevated serum levels of D-dimer among patients with urticarial vasculitis.

Up-regulation of chemokine C–C ligand 2 (CCL2) and C-X-C chemokine 8 (CXCL8) expression by monocytes in chronic idiopathic urticaria

The disturbed cytokine–chemokine network could play an important role in the onset of diseases with inflammatory processes such as chronic idiopathic urticaria (CIU). Our main objectives were to evaluate the relation between proinflammatory chemokine serum levels from CIU patients and their response to autologous skin test (ASST) and basophil histamine release (BHR). We also aimed to assess the chemokine secretion by peripheral blood mononuclear cells (PBMC) upon polyclonal stimulus and to evaluate chemokine C–C ligand 2/C‐X‐C chemokine 8 (CCL2/CXCL8) and Toll‐like receptor‐4 (TLR‐4) expression in monocytes. We observed significantly higher serum levels of the CXCL8, CXCL9, CXCL10 and CCL2 in CIU patients compared to the healthy group, regardless of the BHR or ASST response. The basal secretion of CCL2 by PBMC or induced by Staphylococcus aureus enterotoxin A (SEA) was higher in CIU patients than in the control group, as well as for CXCL8 and CCL5 secretions upon phytohaemagglutinin stimulation. Also, up‐regulation of CCL2 and CXCL8 mRNA expression was found in monocytes of patients upon SEA stimulation. The findings showed a high responsiveness of monocytes through CCL2/CXCL8 expression, contributing to the creation of a proinflammatory environment in CIU.

Statin effects on regulatory and proinflammatory factors in chronic idiopathic urticaria

Immunological dysfunction has been described to occur in chronic idiopathic urticaria (CIU), most notably in association with an inflammatory process. Some pharmacological agents as statins – drugs used in hypercholesterolaemia – display a broad effect on the immune response and thus should be tested in vitro in CIU. Our main objectives were to evaluate the effects of statins on the innate and adaptive immune response in CIU. Simvastatin or lovastatin have markedly inhibited the peripheral blood mononuclear cells (PBMC) proliferative response induced by T and B cell mitogens, superantigen or recall antigen. Simvastatin arrested phytohaemaglutinin (PHA)‐induced T cells at the G0/G1 phase, inhibiting T helper type 1 (Th1), Th2, interleukin (IL)‐10 and IL‐17A cytokine secretion in both patients and healthy control groups. Up‐regulation of suppressor of cytokine signalling 3 (SOCS3) mRNA expression in PHA‐stimulated PBMCs from CIU patients was not modified by simvastatin, in contrast to the enhancing effect in the control group. Statin exhibited a less efficient inhibition effect on cytokine production [IL‐6 and macrophage inflammatory protein (MIP)‐1α] induced by Toll‐like receptor (TLR)‐4, to which a statin preincubation step was required. Furthermore, statin did not affect the tumour necrosis factor (TNF)‐α secretion by lipopolysaccharide (LPS)‐stimulated PBMC or CD14+ cells in CIU patients. In addition, LPS‐activated PBMC from CIU patients showed impaired indoleamine 2,3‐dioxygenase (IDO) mRNA expression compared to healthy control, which remained at decreased levels with statin treatment. Statins exhibited a marked down‐regulatory effect in T cell functions, but were not able to control TLR‐4 activation in CIU patients. The unbalanced regulatory SOCS3 and IDO expressions in CIU may contribute to the pathogenesis of the disease.