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.

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. OBJECTIVES: We sought to investigate the profile of expression of activation markers on basophils of patients with CIU and to explore the effect of interleukin (IL)-3 priming upon anti-IgE cross-linking stimuli through expression of activation markers and basophil histamine releasability. METHODS: Evaluation of the surface expression of FcepsilonRIalpha, CD63, CD203c and CD123 on whole blood basophils of patients with CIU undergoing autologous serum skin test (ASST) was performed by flow cytometry. The effect of pretreatment with IL-3 in the anti-IgE response was analysed by the expression of basophil activation markers and histamine release using enzyme-linked immunosorbent assay. RESULTS: Blood basophils of patients with CIU were reduced in number and displayed increased surface expression of FcepsilonRIalpha, which was positively correlated with the IgE serum levels. Upregulation of expression of both surface markers CD203c and CD63 was verified on basophils of patients with CIU, regardless of ASST response. High expression of IL-3 receptor on basophils was detected only in ASST+ patients with CIU. Pretreatment with IL-3 upregulated CD203c expression concomitantly with the excreting function of blood basophils and induced a quick hyper-responsiveness to anti-IgE cross-linking on basophils of patients with CIU compared with healthy controls. CONCLUSIONS: Basophils of patients with CIU showed an activated profile, possibly due to an in vivo priming. Functionally, basophils have high responsiveness to IL-3 stimulation, thereby suggesting that defects in the signal transduction pathway after IgE cross-linking stimuli are recoverable in subjects with chronic urticaria.

Clinical and serological follow-up studies of endemic pemphigus foliaceus (fogo selvagem) in Western Parana, Brazil (2001-2002).

BACKGROUND: Fogo selvagem (FS) has been described in several regions of Brazil, including the Western regions of the state of Parana. In 1990, Empinotti et al. reported case studies of 213 patients with FS that were collected from 1976 to 1988. The same author (J.C.E.) has observed that the frequency of cases in these regions of Parana has decreased. OBJECTIVES: The purpose of this study was to clinically and serologically evaluate a small group of the patients originally reported in 1990 and compare data with a group of control individuals. These patients were treated at the onset of the disease with systemic steroids. PATIENTS AND METHODS: Patients with FS, their unaffected relatives (n = 80) and genetically unrelated controls (n = 15) were identified during a field study from 1 May 2001 to 30 June 2002. Sera from nine patients with FS and six normal controls that were collected in the 1976-1988 evaluation were available for this study. The sera were tested by indirect immunofluorescence, enzyme-linked immunosorbent assay (ELISA) and immunoprecipitation using recombinant human desmoglein 1 (Dsg1). RESULTS: Only 16 of the originally identified 213 patients with FS were found during the field studies. Thirteen of the 16 patients were in clinical and serological remission; 20% of normal controls (19 of 95) were positive in the Dsg1 ELISA. The majority of these subjects (17 of 19) were genetically related to FS patients. Six normal controls that were positive in the Dsg1 ELISA in the original survey were found to be negative or weakly positive in this evaluation. CONCLUSION: The reduced frequency of positive serological markers of disease in patients and normal controls from Western Parana, as well as the absence of recurrent disease in previously identified patients, suggest that environmental antigenic stimulation of the population at risk may have decreased in recent years.

'Decubital candidosis': a study of 26 cases.

BACKGROUND: Candidoses are infections caused by yeasts of the genus Candida. 'Decubital candidosis' is a particular form of cutaneous candidosis that occurs on the dorsal skin of chronically bedridden patients; there are very few studies about this presentation in the medical literature. OBJECTIVE: To study the clinical, mycological and histopathological features of 26 cases of 'decubital candidosis' along with factors that may predispose to it. METHODS: Twenty-six patients were included and their general characteristics and clinical lesions were carefully studied. The presence of candidosis in other organs and the occurrence of predisposing factors were searched by reviewing the medical records. Mycological studies were performed and cutaneous biopsies were taken. RESULTS: Median age of patients was 46 years, 11 were male and 15 were female, 25 were caucasian, one was Asian and no one was Afro-Carribean. This finding suggests a greater resistance of Afro-Carribean skin to this form of candidosis. The median time of hospitalization until rash occurrence was 24.8 days. Clinical lesions consisted of erythema, erosions, pustules, papules and desquamation. The most significant predisposing factors for this eruption were prolonged bedrest and broad-spectrum antibiotics. Candidosis on other body sites was diagnosed in 10 cases and additional specific predisposing factors were observed in all 10. Potassium hydroxide examination was a reliable test for diagnosing this disease. Candida albicans was the agent in all 26 cases. Spongiform pustules were the most significant histopathological findings and yeasts were restricted to the horny layer in all biopsied cases. CONCLUSION: 'Decubital candidosis' is probably induced by prolonged bedrest and facilitated by long-term use of antibiotics. This cutaneous infection does not seem to predispose to systemic candidosis.

The role of subclass switching in the pathogenesis of endemic pemphigus foliaceus.

Endemic pemphigus foliaceus, like the sporadic form seen in the developed world, is mediated by IgG antibodies to desmoglein-1. We studied an endemic focus in Limao Verde, Brazil, where disease prevalence is 3.4%. We previously detected IgG antibodies to desmoglein-1 in 97% of patients, but also in 55% of normal subjects in the endemic focus, with progressively lower levels in normal subjects in surrounding areas. An environmental trigger is hypothesized to explain these and other findings. In this study we sought to determine if patients and enzyme-linked-immunosorbent-assay-positive normal subjects in Limao Verde differ in IgG subclass response to desmoglein-1. We developed a sensitive and specific subclass enzyme-linked immunosorbent assay using recombinant desmoglein-1 and standardized the assay to enable comparability between the four subclasses. We found that normal subjects have an IgG1 and IgG4 response, whereas patients have similar levels of IgG1 but a mean 19.3-fold higher IgG4 response. Patients in remission have a weak IgG4 response, and a 74.3-fold higher IgG4 response is associated with active disease. Finally, in five patients in whom we had blood samples from both before and after the onset of clinical disease, a mean 103.08-fold rise in IgG4 was associated with onset of clinical disease, but only a mean 3.45-fold rise in IgG1. These results suggest that the early antibody response in normal subjects living in the endemic area and in patients before the onset of clinical disease is mainly IgG1. Acquisition of an IgG4 response is a key step in the development of clinical disease.

The prevalence of antibodies against desmoglein 1 in endemic pemphigus foliaceus in Brazil. Cooperative Group on Fogo Selvagem Research.

BACKGROUND: Pemphigus foliaceus is an autoimmune skin disease mediated by autoantibodies against desmoglein 1. The endemic form is thought to have an environmental cause. The Terena reservation of Limão Verde in Mato Grosso do Sul, Brazil, is a recently identified focus of the disease, with a prevalence of 3.4 percent in the population. We tested the hypothesis that normal subjects living in an endemic area have antibodies against desmoglein 1. METHODS: We used an enzyme-linked immunosorbent assay to detect antibodies against desmoglein 1 in serum samples from 60 patients with endemic pemphigus foliaceus (fogo selvagem) who lived in Limão Verde or elsewhere in Brazil, 372 normal subjects (without pemphigus foliaceus) from Limão Verde and surrounding locations, and 126 normal subjects from the United States and Japan. RESULTS: Antibodies against desmoglein 1 were detected in 59 of the 60 patients with fogo selvagem (98 percent) but in only 3 of the 126 normal subjects from the United States and Japan (2 percent). Antibodies were also detected in 51 of the 93 normal subjects from Limão Verde (55 percent) and in 54 of the 279 normal subjects from surrounding areas (19 percent). Serum samples obtained one to four years before the onset of disease were available for five patients; all five had antibodies in the initial serum samples, and the onset of disease was associated with a marked increase in antibody values. CONCLUSIONS: The prevalence of antibodies against desmoglein 1 is high among normal subjects living in an area among where fogo selvagem is endemic, and the onset of the disease is preceded by a sustained antibody response. These findings support the concept that the production of antibodies against desmoglein 1 is initiated by exposure to an unknown environmental agent.

Desmoglein-1-specific T lymphocytes from patients with endemic pemphigus foliaceus (fogo selvagem).

Fogo selvagem (FS), the endemic form of pemphigus foliaceus, is a cutaneous autoimmune disease characterized by subcorneal blistering of the epidermis and the production of autoantibodies against the desmosomal antigen desmoglein-1 (Dsg1). Previously, we showed that mice injected with autoantibodies from FS patients develop a skin disease that reproduces the clinical, histological, and immunological features of FS, indicating that autoantibodies play an essential role in the development of this disease. The purpose of this study was to characterize the autoimmune T-cell response associated with FS. We provide here the first evidence, to our knowledge, that the great majority of FS patients have circulating T lymphocytes that specifically proliferate in response to the extracellular domain of Dsg1. Long-term T cells developed from these patients also responded to Dsg1, and this antigen-specific response was shown to be restricted to HLA-DR molecules. These Dsg1-reactive FS T cells exhibited a CD4-positive memory T-cell phenotype and produced a T helper 2-like cytokine profile. These findings represent the initial steps in defining the role of T cells in FS autoimmunity.

[Postinfectious Lucio phenomenon in diffuse leprosy. Report of 2 cases]. / Postinfektiöses Lucio-Phänomen bei diffuser Lepra. Bericht über zwei Fälle.

In the clinical classification of leprosy the diffuse nonnodular form belongs to the lepromatous subtype. In these patients only a diffuse cutaneous infiltration without nodules or plaques is seen. Although the cutaneous features can be difficult to identify, the reactional state in these cases may lead to a serious necrotizing vasculitis, known as Lucio's phenomenon. We describe two cases of Lucio's phenomenon triggered by erysipelas. The diagnosis of leprosy was established only after the immunologic reaction had occurred. Both patients were treated with steroids and thalidomide. In the second case, the bacterial infection led to sepsis and death. In at-risk patients with a necrotizing vasculitis, leprosy should be considered in the differential diagnosis.

Treatment of molluscum contagiosum with potassium hydroxide: a clinical approach in 35 children.

Potassium hydroxide (KOH) is a strong alkali that has long been known to digest proteins, lipids, and most other epithelial debris of skin scrapings to identify fungal infections. To our knowledge, KOH has never been used for the treatment of molluscum contagiosum (MC). We evaluated 35 children with MC for the clinical effectiveness of treatment with topical 10% KOH aqueous solution. The solution was applied by the parents of affected children, twice daily, on each MC lesion. The therapy was continued until all lesions underwent inflammation and superficial ulceration. Thirty-two of 35 patients achieved complete clinical cure after a mean treatment period of 30 days. Three children discontinued treatment: two reported severe stinging of the lesions and refused further applications; the other, with giant MC lesions, developed a secondary infection with prolonged treatment. Therapy with KOH was found to be effective and safe in the treatment of MC in children.

Comparison of black fly species (Diptera: Simuliidae) on an Amerindian reservation with a high prevalence of fogo selvagem to neighboring disease-free sites in the State of Mato Grosso do Sul, Brazil. The Cooperative Group on Fogo Selvagem Research.

Fogo selvagem is an autoimmune blistering skin disease that principally occurs among rural Brazilians living in geographically clumped disease foci. Exposure to hematophagous black flies possibly is related to the cause of the disease. We compared the occurrence, proportions, and richness of simuliid species immatures and the biting activity of adult females within a recently discovered, high prevalence focus of fogo selvagem, the Limão Verde Terena Reservation, to that of neighboring regions with no reported cases of fogo selvagem. Nine black fly species were collected from 12 stream sites during 5 trips to the fogo selvagem focus. The species showed longitudinal (upstream-downstream) trends in occurrence, proportions, and richness, and the abundance of simuliid immatures was greater at downstream sites. The most prevalent species at the focus, Simulium nigrimanum (Macquart), dominated the stream sites with highly abundant simuliid assemblages, and was the most common black fly in human bait collections. This species was absent or in very low numbers in neighboring valleys and villages that did not have cases of fogo selvagem.

Lymphocyte subsets and Langerhans cells in sun-protected and sun-exposed skin of immunosuppressed renal allograft recipients.

BACKGROUND: Patients who have received renal allografts experience early aging of the skin, opportunistic infections, and an increased incidence of skin cancer. OBJECTIVE: We compared the density of lymphocyte subsets and Langerhans cells in normal-appearing skin of renal allograft recipients without skin cancer at 5 to 6 years (group 1) and 14 years after transplant (group 2) with a matched normal control group. METHODS: Biopsy specimens of sun-protected and exposed areas from 18 white, kidney allograft recipients (10 in group 1 and 8 in group 2) with normal renal function and from 10 healthy volunteers were semiquantitatively analyzed for dermal lymphocyte subsets and Langerhans cells. RESULTS: There was a statistically significant decrease in all dermal cell elements in the sun-protected skin of both groups of patients who had received grafts. The sun-exposed skin of group 2 also showed a significant decrease of dermal CD4+ and CD8+ lymphocytes, and group 1 had a significant decrease in dermal CD8+ lymphocytes. The dermal CD1a+ cell population in the sun-exposed skin from both grafted groups did not differ from the control group. CONCLUSION: Kidney transplant recipients showed dermal depletion of cells related to immune surveillance against tumors even before skin cancer occurred, and this depletion seemed to become more marked with the duration of immunosuppression.

Histoplasmin reaction. Comparison of a polysaccharide antigen to the filtrate antigen.

This work was planned by taking into account all the knowledge accumulated from the immunological study of paracoccidioidomycosis. It aimed at comparing a polysaccharide antigen from Histoplasma capsulatum to a classic histoplasmin with the help of intradermal tests of delayed type of hypersensitivity. Tests were applied to 115 individuals in Santo Amaro, a town in the State of São Paulo. Positive results using classic histoplasmin were obtained in 46.0% cases whereas positive results using the polysaccharide antigen at its highest concentration were obtained in 51.30% cases. The major conclusion in this investigation is that it is possible to use the polysaccharide antigen as histoplasmin instead of the filtrate antigen.

An active focus of high prevalence of fogo selvagem on an Amerindian reservation in Brazil. Cooperative Group on Fogo Selvagem Research.

Fogo Selvagem (FS) is an autoimmune disease characterized by subcorneal vesicles and antidesmoglein-1 autoantibodies. Previous epidemiologic data have linked the onset of FS to exposure to an environmental antigen(s). This investigation describes a unique human settlement with an extraordinarily high prevalence of FS. This community is made up of Amerindians belonging to the Terena tribe, which has settled on the Limao Verde reservation in the state of Mato Grosso do Sul in Brazil. Twenty-six well-characterized FS cases have been identified within a total population of 998, yielding a prevalence of 2.6%. Seventeen of the patients (65 %) were males, and over 50% were older than 30 y of age. The incidence of the disease shows temporal periodicity, i.e., years with several cases of FS alternating with years with no cases. Over one-half of the cases occurred in genetically related family members. Another Terena reservation, the Ipegue/Taunay, located 90 km west of the Limao Verde reservation, was also evaluated as a control group. This reservation, with a population of 2203, had no recorded cases of FS. Thus, the Limao Verde reservation represents a new focus of FS in which the disease exhibits temporal, geographic, and familial clustering. These results suggest that the environmental antigen or antigens precipitating FS are endemic to the Limao Verde reservation. This reservation appears to be an ideal population for carrying out sero-epidemiologic, genetic, and environmental studies aimed at disclosing the etiology of FS.

Pemphigus herpetiformis is a rare clinical expression of nonendemic pemphigus foliaceus, fogo selvagem, and pemphigus vulgaris. Cooperative Group on Fogo Selvagem Research.

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.