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Chromoblastomycosis (CBM) is a chronic fungal infection that affects skin and subcutaneous tissue, and little is known about the immunological aspects of such lesions. We have previously described the high expression of IL-17 in this group. Understanding the innate immune response of patients with CBM would improve the knowledge of its immunopathogenesis and contribute to the most appropriate therapies. Nineteen biopsies of verrucous form were obtained from patients with clinical and histopathological diagnosis of CBM, without treatment. This was done with a double immunostaining with conventional immunohistochemistry and immunofluorescence technique as well as confocal microscopy to detect Langerin and IL-17 expression. All of the specimens that were analyzed showed expression of Langerin in the epidermis - the same as the control group. However, only the CBM group presented cells expressing CD207 in the dermis. Interestingly, the coexpression of IL-17 and Langerin was visualized along the epidermis and dermis in 100% of the lesion group. We demonstrated for the first time in situ coexpression of IL-17 and Langerin (CD207) in epidermal cells of patients with CBM and speculated on their role as IL-17-producing cells or whether they could be a new subpopulation of dendritic cells distinct from Langerhans cells.

Jorge Lobo’s disease (JLD) is a cutaneous chronic mycosis caused by Lacazia loboi. We studied Factor XIIIa + dermal dendrocytes (FXIIIa + DD), Langerhans cells (LC) through the expression of langerin and the expression of S100 protein. A total of 41 biopsies and 10 normal skins (control) were developed with a polymer-based immunohistochemical method. Lesions presented infiltrate comprising macrophages, some asteroid corpuscles, lymphocytes, multinucleated giant cells and a large number of fungi. LCs presented short dendrites and were scarcely distributed. Dermal langerin + cells were detected in nine JLD lesions. FXIIIa + DD were hypertrophic, visualized in the inflammatory infiltrate of JLD lesions. Cells S100+ were present in JLD and control group with a similar number of cells. A total of 14 specimens did not express FXIIIa, and this considerable number probably contributed to the statistical similarity with the control group. The results indicate that LCs are present in the immune response against Lacazia loboi. Some dermal langerin + cells could be another subset of dendritic cells. Our data indicate changes of LCs in JLD cutaneous lesions and present, for the first time, results that show langerin + cells in the dermis and corroborate previous observations on the participation of FXIIIa + DD in the in situ immune response in JLD.

Dengue infection is an important tropical disease worldwide. The host immune response has been studied in order to better understand lesion mechanisms. It was performed an immunohistochemical study in 14 specimens of liver from patients with dengue hemorrhagic fever (DHF) to characterize cytokines and some factors present in liver lesions and their possible role in the pathogenesis of hepatic injury. Portal tract and hepatic acinus presented high expression of TLR2, TLR3, IL6, and granzyme B. Hepatic acinus also presented iNOS, IL18, and TGF-beta. Cells expressing IL12, IL13, JAk1, STAT1, and NF-κB were rarely visualized. Treg cells foxp3+ were absent. TLR2 and TLR3 seem to participate in cellular activation and cytokine production. Cytotoxic response seems to play a role. Although TGF-beta promotes the activation of Foxp3+ regulatory T cells, IL6 can significantly suppresses their generation. The expression of Treg cells is diminished probably as a result of the high frequency of these cytokines. Both cytokines play a role in the increased vascular permeability and edema observed in dengue liver specimens, with consequent plasma leakage and severity of the disease. It was observed a regular expression of IL-18 in hepatocytes and lymphocytes of the inflammatory infiltrate in portal tract, which reflects the acute inflammatory response that occurs in the liver and contributes to hepatic injury. At least in part, the increased number of cells expressing IL-18 could play a role of "up" regulation of FasL and correlate to the phenomenon of apoptosis, a mechanism of destruction of hepatocytes in DHF.

Yellow fever is a viral hemorrhagic fever, which affects people living in Africa and South America and is caused by the yellow fever virus, the prototype species in the Flavivirus genus (Flaviviridae family). Yellow fever virus infection can produce a wide spectrum of symptoms, ranging from asymptomatic infection or oligosymptomatic illness to severe disease with a high fatality rate. In this review, we focus in the mechanisms associated with the physiopathology of yellow fever in humans and animal models. It has been demonstrated that several factors play a role in the pathological outcome of the severe form of the disease including direct viral cytopathic effect, necrosis and apoptosis of hepatocyte cells in the midzone, and a minimal inflammatory response as well as low-flow hypoxia and cytokine overproduction. New information has filled several gaps in the understanding of yellow fever pathogenesis and helped comprehend the course of illness. Finally, we discuss prospects for an immune therapy in the light of new immunologic, viral, and pathologic tools.

Langerhans cell histiocytosis (LCH) is a rare disease characterized by proliferation of Langerhans-type cells that express CD1a, Langerin (CD207) and S100 protein. Birbeck granules are a hallmark by ultrastructural examination. LCH presents with a wide clinical spectrum, ranging from solitary lesions of a single site (usually bone or skin) to multiple or disseminated multisystemic lesions, which can lead to severe organ dysfunction. Most cases occur in children. Gastrointestinal tract involvement is rare and has been associated with systemic illness and poor prognosis especially in children under the age of 2 years. Adult gastrointestinal LCH is very rare. We report a case of a previously healthy, nonsmoking 48-year-old male who was referred for routine screening colonoscopy. Two sessile, smooth, firm and yellowish LCH polyps measuring 0.2 cm and 0.3 cm were detected in the sigmoid colon. Fifteen months later a second colonoscopy found two histologically confirmed hyperplastic polyps at the sigmoid colon. No other LCH lesions were seen. A third colonoscopy after 28 months of follow-up found a submucosal 0.5 cm infiltrated and ulcerated LCH polyp in the cecum, close to the ostium of the appendix. The patient had been asymptomatic for all this period. Imaging investigation for systemic or multiorgan disease did not find any sign of extracolonic involvement. On histology all lesions showed typical LCH features and immunohistochemical analysis showed strong and diffuse staining for CD1a and CD207. This case illustrates two distinct clinicopathologic features not previously reported in this particular clinical setting: metachronous colonic involvement and positivity for CD207.

Purpose: to describe the clinicopathologic features and treatment of a rare case of systemic paracoccidioidomycosis with choroidal and retinal involvement. Design: retrospective interventional case report. Participant: A 36-year-old young man with visual impairment in left eye with anterior uveitis and presence of whitish perimacular choroidal nodule, multiple underlying whitish spots and mid-periphery exudative retinal detachment. A primary extensive work-up for systemic infectious, autoimmune, neoplasic or inflammatory conditions was performed and high-resolution computer tomography scan demonstrated asymmetric parietal thickening of the trachea and bilateral diffuse multiple lobular opacities. Pulmonary bronchoscopy/biopsy of larynx, trachea and bronchial tube were also performed. Histopathological evaluation showed characteristic of Paracoccidioidomycosis. Intervention: Patient was treated with oral sulphadiazine (1.5 g/day). Main Outcome Measures: Anterior uveitis, retinal examination, histopathological evaluation and primary clinical outcome were observed during systemic treatment. Results: After 3 months of irregular treatment, choroidal lesions decreased in size forming atrophic scars and fibrotic spots; however visual acuity did not show any improvement. Conclusion: We report a rare case of systemic paracoccidioidomycosis with choroidal and retinal involvement treated with oral sulphadiazine.

Although the esophagus is a common site of opportunistic infection in AIDS patients, little is known about the impact of HIV as well as opportunistic infection in the esophageal mucosa. Our aim is to analyze the esophageal immune profile in HIV+ patients with different immunological status with and without the opportunistic Candida infection.Immunohistochemistry to CD4Esophageal CD4In contrast to CD8

Aims Leprosy is an infectious-contagious disease whose clinical evolution depends on the interaction of the infectious agent with the immune response of the host, leading to a clinical spectrum that ranges from lepromatous leprosy (susceptibility, LL) to tuberculoid leprosy (resistance, TT). The immune response profile will depend on the pattern of cytokine production and on the activity of macrophages during infection. Classically, the clinical evolution of leprosy has been associated with Th1/Th2 cytokine profiles, but the role of new cytokine profiles such as T helper 9 (Th9) remains to be elucidated. Methods To evaluate the tissue expression profile of these cytokines, a cross-sectional study was conducted using a sample of 30 leprosy skin lesion biopsies obtained from patients with leprosy, 16 TT and 14 lepromatous LL. Results Immunohistochemical analysis revealed a significant difference in interleukin (IL)-9, IL-4 transforming growth factor (TGF)-β and IL-10 levels between the two groups. IL-9 was more expressed in TT lesions compared with LL lesions. Higher expression of IL-4, IL-10 and TGF-β was observed in LL compared with TT. IL-4, IL-10 and TGF-β tended to be negatively correlated with the expression of IL-9, indicating a possible antagonistic activity in tissue. Conclusions The results suggest that Th9 lymphocytes may be involved in the response to Mycobacterium leprae, positively or negatively regulating microbicidal activity of the local immune system in the disease.

Jorge Lobo's Disease (JLD) is a cutaneous chronic granulomatous disease caused by the pathogenic fungus Lacazia loboi. It is characterized by a granulomatous reaction with multinucleated giant cells and high number of fungal cells. In order to contribute to the comprehension of immune mechanisms in JLD human lesions, we studied the cytotoxic immune response, focusing on TCD8+ and NK cells, and granzyme B. Forty skin biopsies of lower limbs were selected and an immunohistochemistry protocol was developed to detect CD8+ T cells, NK cells and Granzyme B. In order to compare the cellular populations, we also performed a protocol to visualize TCD4+ cells. Immunolabeled cells were quantified in nine randomized fields in the dermis. Lesions were characterized by inflammatory infiltrate of macrophages, lymphocytes, epithelioid and multinucleated giant cells with intense number of fungal forms. There was a prevalence of CD8 over CD4 cells, followed by NK cells. Our results suggest that in JLD the cytotoxic immune response could represent another important mechanism to control Lacazia loboi infection. We may suggest that, although CD4+ T cells are essential for host defense in JLD, CD8+ T cells could play a role in the elimination of the fungus.

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.

T regulatory cells (Tregs) play an important role in the mechanism of host's failure to control pathogen dissemination in severe forms of different chronic granulomatous diseases, but their role in leprosy has not yet been elucidated; 28 newly diagnosed patients (16 patients with lepromatous leprosy and 12 patients with tuberculoid leprosy) and 6 healthy Mycobacterium leprae-exposed individuals (contacts) were studied. Tregs were quantified by flow cytometry (CD4+ CD25+ Foxp3+) in peripheral blood mononuclear cells stimulated in vitro with a M. leprae antigenic preparation and phytohemagglutinin as well as in skin lesions by immunohistochemistry. The lymphoproliferative (LPR), interleukin-10 (IL-10), and interferon-γ (IFN-γ) responses of the in vitro-stimulated peripheral blood mononuclear cells and the in situ expression of IL-10, transforming growth factor-β (TGF-β), and cytotoxic T-lymphocyte antigen 4 (CTLA-4) were also determined. We show that M. leprae antigens induced significantly lower LPR but significantly higher Treg numbers in lepromatous than tuberculoid patients and contacts. Mitogen-induced LPR and Treg frequencies were not significantly different among the three groups. Tregs were also more frequent in situ in lepromatous patients, and this finding was paralleled by increased expression of the antiinflammatory molecules IL-10 and CTLA-4 but not TGF-β. In lepromatous patients, Tregs were intermingled with vacuolized hystiocyte infiltrates all over the lesion, whereas in tuberculoid patients, Tregs were rare. Our results suggest that Tregs are present in increased numbers, and they may have a pathogenic role in leprosy patients harboring uncontrolled bacillary multiplication but not in those individuals capable of limiting M. leprae growth.

Langerhans cells are identified by the expression of langerin. We detected this molecule in cutaneous and mucosal lesions in paracoccidioidomycosis, an important infection in Latin America. Langerin+ cells were scarcely distributed, with short dendrites in epidermis and epithelium and were frequent in the dermis and corium, in the inflammatory infiltrate and granulomas. Mucosal lesions presented a higher expression of langerin in lesions with loose granulomas. For the first time we presented the expression of langerin in paracoccidioidomycosis. Positive cells in dermis and corium could represent migrating Langerhans cells or a new subset of langerin+ cells with a role in paracoccidioidomycosis.

Leprosy still is an important public health problem in several parts of the world including Brazil. Unlike the diseases caused by other mycobacteria, the incidence and clinical presentation of leprosy seems little affected in immunosuppressed patients. We report the first case, to our knowledge, of a liver transplant patient who developed multi-bacillary leprosy. The patient presented with papules and infiltrated plaques with loss of sensation suggestive of leprosy 3.5 years after living-related liver transplantation for autoimmune hepatitis. A skin biopsy showing non-caseating macrophagic granulomas, neuritis, and intact acid-fast bacilli on Fite-Faraco stain, confirmed the diagnosis of borderline lepromatous leprosy. The donor of the liver did not show any evidence of leprosy. During follow-up, the patient presented 2 episodes of upgrading leprosy type I reactions, 1 mild before leprosy treatment, and 1 moderate 3 months after receiving standard multi-drug treatment (rifampicin, clofazimine, and dapsone). These reactions were accompanied by increase in liver function tests, especially of canalicular enzymes. This reaction occurred despite the patient's triple immunosuppression regimen. The moderate reaction was successfully treated with further immunosuppression (prednisone, 0.5 mg/kg). Currently, the patient is asymptomatic, off leprosy medication, with routine liver transplant follow-up. The dilemmas in diagnosis and management of such a case are discussed and the literature on leprosy in transplant recipients is reviewed.

The objective of the present study was to investigate the correlation between macrophage activity and apoptosis in the polar forms of leprosy because the immunopathological phenomena involved in these forms are still poorly understood. For this purpose, 29 skin biopsy samples obtained from patients with the polar forms of leprosy were analyzed. Macrophage activity and apoptosis were evaluated by immunohistochemistry using lysozyme, CD68, iNOS and caspase 3 as markers. The nonparametric Mann-Whitney test and Spearman's linear correlation test were used for statistical analysis. The results suggest that the apoptosis rate is under the direct influence of macrophage activity in lesions of patients with the tuberculoid form. In contrast, in lepromatous lesions other factors seem to induce programmed cell death, possibly TGF-beta. Further studies are necessary to identify additional factors involved in the immunopathogenesis of leprosy.

Summary The Toll-like receptor (TLR) signalling pathway is the first system that defends against Leishmania. After recognising Leishmania as nonself, TLRs trigger NF-κB expression. NF-κB proceeds to the nucleus and promotes the transcription of pro-inflammatory cytokines. TLR9 is thus an important factor in the induction of an effective immune response against Leishmania. We examined the pattern of TLR9 expression in 12 patients with cutaneous leishmaniasis caused by Leishmania braziliensis detected by polymerase chain reaction. Normal skin was analysed as a negative control. TLR9 expression was examined in the dermis and epidermis by immunohistochemical analysis of paraffin-embedded biopsy tissue. TLR9 expression was primarily observed in the granuloma. The protein was detected in a few cells in the dermis. A lower expression level was detected in the epidermis of patients with leishmaniasis when compared with normal skin. The presence of TLR9 in the skin of patients with cutaneous leishmaniasis is associated with granuloma and expressed by macrophages.

Leptospirosis is a zoonotic infection associated with severe diseases such as leptospirosis pulmonary haemorrhage syndrome (LPHS). The cause of pulmonary haemorrhage is unclear. Understanding which mechanisms and processes are involved in LPHS will be important in treatment regimens under development for this life-threatening syndrome. In the present study, we evaluated 30 lung specimens from LPHS patients and seven controls using histology and immunohistochemistry (detection of IgM, IgG, IgA and C3) in order to describe the pathological features associated with this syndrome. Immunoglobulin deposits were detected on the alveolar surface in 18/30 LPHS patients. Three staining patterns were observed for the immunoglobulins and C3 in the lung tissues of LPHS patients: AS, delicate linear staining adjacent to the alveolar surface, which was indicative of a membrane covering the luminal surface of type I and II pneumocyte cells; S, heterogeneous staining which was sporadically distributed along the alveolar septum; and IA, weak, focal intra-alveolar granular staining. Human LPHS is associated with individual and unique histological patterns that differ from those of other causes of pulmonary haemorrhage. In the present study, it was found that the linear deposition of immunoglobulins (IgA, IgG and IgM) and complement on the alveolar surface may play a role in the pathogenesis of pulmonary haemorrhage in human leptospirosis.

Background: CD8+ T cells and natural killer (NK) cells are involved in the immune response against some pathogens. For this purpose, we investigated the in situ paracoccidioidomycosis (PCM) immune response addressing the participation of NK cells, CD8+ T cells, perforin and granzyme B expression. Methods: Sixty biopsies of PCM skin and mucosa were classified according to the presence of compact granulomas (G1), poorly organized granulomas (G2) and both kinds in the same lesion (G3). CD8+ T cells, NK cells, perforin and granzyme B were showed by immunohistochemistry. Results: CD8+ T cells were increased over NK cells in cutaneous G1 and G2 lesions. There was no difference regarding such cells in G3 lesions, although they were abundant in such lesions. In mucosa, CD8+ T cells were increased in number over NK cells in all groups. Granzyme B in skin increased in G2 and G3. The number of granzyme did not differ in mucosal lesions in the three groups. Conclusions: CD8+ T cells and NK cells play a role in PCM cutaneous and mucosal lesions. The predominance of CD8+ T cells over NK cells may represent an effective response against the fungi. Moreover, the high number of granzyme B expressing cells corroborates this possibility. Pagliari C, Pereira NV, Kanashiro L, Stegun FW, Croda J, Seixas Duarte MI, Sotto MN. Characterization of cytotoxic immune response in skin and mucosal lesions of paracoccidioidomycosis.

Dendritic cells belong to a family of antigen-presenting cells that are localized at the entry sites, such as skin and mucosa. Dendritic cells are related to immune surveillance function. The role of Langerhans cells in the pathogenesis of skin infectious diseases is well studied; however, there are few articles addressing involvement of factor XIIIa-positive dermal dendrocytes (FXIIIa+ DD) in such processes. FXIIIa+ DDs are bone marrow-monocytic lineage-derived cells and members of the skin immune system. Due to their immune phenotype and functional characteristics, they are considered complementary cells to Langerhans cells in the process of antigen presentation and inducing immune response. To verify the interaction between FXIIIa+ DD and Leishmania amastigotes, 22 biopsies of American tegumentary leishmaniasis (ATL) skin lesions were subjected to double staining technique with anti-factor XIIIa and anti-Leishmania antibodies. FXIIIa+ DDs were hypertrophic and abundant in the cutaneous reaction of ATL. FXIIIa+ DDs harboring parasites were observed in 11 of 22 skin biopsies. The data obtained suggest that FXIIIa+ DD plays a role in the pathogenesis of ATL skin lesion as host cell, immune effector, and/or antigen-presenting cell.

The immunopathogenesis of chronic hepatitis C virus (HCV) infection is a matter of great controversy and has been suggested to involve a complex balance between cytokines with pro and anti-inflammatory activity. We investigated the expression of inflammatory cells and cytokines in the liver and serum of 51 chronically HCV infected patients and compared them to data from two sets of normal controls: 51 healthy blood donors and 33 liver biopsies of healthy liver donors. We also assessed the relationship between selected cytokines and cell populations in hepatic compartments and the disease stage. Compared with controls, hepatitis C patients had a greater expression of portal TNF-α, TGF-β and CD4+ and acinar IFN-γ, TNF-α, IL-1β and IL-4, as well as a higher serum concentration of IL-2, IL-10 and TGF-β. Significant positive correlations were found between portal CD4+ and TNF-α, portal CD8+ and TGF-β, portal CD45+RO and TNF-α, acinar CD45+RO and IFN-γ and acinar CD57+ and TGF-β. In conclusion, we have shown that (i) in this sample of predominantly mild disease, the immune response was associated with a pro-inflammatory response pattern, (ii) CD4+ T-lymphocytes played a major role in orchestrating the immune response and (iii) these events primarily took place in the portal space.

Objective To determine the frequency of cardiac alterations in necropsies of AIDS patients in pre-HAART era and better understand the pathogenesis of HIV-related cardiomyopathy. Design Retrospective study of 94 complete necropsies. Method Macroscopic, histopathologic (histochemical, immunohistochemical and in situ hybridization techniques) and ultra structural myocardial evaluation (23 cases). Results Cardiac alterations were observed in 94.4%; 74% showed variable degrees of cardiac dilation not related to known cardiovascular diseases. Eighty-two percent (81.8%) of patients with biventricular dilation showed diffuse-regressive alterations (thinning and waving cardiomyocytes with increase of lipofuscin pigment granules). Myocarditis was diagnosed in 27 cases (28.7%), 16 (59.3%) of known etiology. The ultra structural study has revealed cardiomyocytes alterations (mitochondriosis, loss of myofibrils, increase in the amount of perinuclear-lipofuscin pigment granules) associated to activation signals of capillary-endothelial cells (enhancement of pseudopodia and transcellular channels). Cardiomyocytes' apoptosis was demonstrated at structural level in 10 (43.5%) patients; tumor necrosis factor α (TNF α) was detected in 17/18 cases. Conclusions This pioneer study described the association of histopathological and ultra structural findings (thinning and waving cardiomyocytes with increase of lipofuscin pigment granules, mitochondriosis and loss of myofibrils) with different degrees of cardiac-chamber dilation probably representing a spectrum of alterations that would lead to myocardial dysfunction and development of HIV-related cardiomyopathy. Cardiomyocytes' apoptosis observed at ultra structural level and demonstration of TNF α associated to described alterations suggest that this cytokine plays an important role in both negative-inotropic effect and capacity to induce apoptosis through death receptor-controlled pathway.

The architectural and infiltrate pattern of liver human visceral leishmaniasis (HVL) have been systematically classified as typical, fibrogenic or nodular. Despite this histopathological classification, the immune response based on cytokines and cellular phenotypes have never been performed. The aim of this study was to determine the immunophenotypic pattern and cytokine profile of the nodular involvement of the liver in HVL. We evaluated nine cases of the nodular form of HVL. In situ immune response was studied through cytokine analysis and immunohistochemical study for phenotype markers: IL-1, IL-4, IL-10, TNF-alpha, IFN-gamma, CD4+ T cells, CD8+ T cells, CD20, CD68, CD57 and macrophage activation was determined by evaluation of iNOS activity. HVL seems to be related to a better immune response. Amastigotes were rarely found on liver sections. Leishmania antigen expression was also rare and located in the inflammatory nodules. The lower expression of IL-4 and IL-10, moderate expression of TNF-alpha and IFN-gamma demonstrate a panorama of Th1 phenotype. The increased expression of NK cells could help in sustaining this model of response. This pattern of immune response is probably responsible for improvement in the parasite's clearance from liver tissue and it is a prognostic marker of human visceral leishmaniasis.

Summary Background Kaposi sarcoma (KS) is associated with human herpesvirus 8 (HHV-8). The cutaneous immune response in this tumour is not well established and a better understanding is necessary. Objectives To evaluate the HHV-8 expression and immune response in cutaneous lesions of classic KS (CKS) and AIDS-associated KS (AIDS-KS). Methods We performed a quantitative immunohistochemical study of cells expressing HHV-8 latency-associated nuclear antigen (LANA), CD4, CD8 and interferon (IFN)-γ in skin lesions from patients with CKS and AIDS-KS (with or without highly active antiretroviral therapy, HAART). Results CKS showed higher LANA expression compared with AIDS-KS, regardless of HAART. We also found higher LANA expression in nodules compared with patch/plaque lesions. The tissue CD4+ cell proportion was lower in AIDS-KS patients without HAART than in patients with CKS. In CKS lesions, CD4+ and CD8+ cells expressed IFN-γ, as shown by double immunostaining. AIDS-KS presented low numbers of IFN-γ-expressing cells. CD8+ cell numbers were similar in all groups, which appeared unrelated to the clinical or epidemiological type of KS. Conclusions Our quantitative data on the pattern of KS lesions in selected groups of patients, as shown by in situ immune response, demonstrated a CD4+ T-cell involvement associated with IFN-γ, an environment of immune response-modified human immunodeficiency virus (HIV) infection. In our sample, the promotion of KS in patients without HIV appears to be related to higher HHV-8 load or virulence than in those with AIDS. This higher resistance may be explained by a sustained immune response against this herpesvirus, that is only partially restored but effective after HAART.

Measles, accounting for nearly 1 million deaths each year, presents intense involvement of lymphoid organs and the lungs. The immune response in situ in the lungs was determined in blocks recovered from 42 necropsies of children who died from measles determined by immune cell phenotype (CD4, CD8, CD20, CD45RO, CD68, natural killer [NK], and antigen S-100 B [S100]) and cytokine production (interferon, tumor necrosis factor, interleukin [IL]-1, IL-2, IL-4, IL-10, and IL-12). Compared with the lungs of age-paired controls, patients with measles presented severe depletion of CD4+, CD20+, CD68+, NK+, and S100+ cells in alveolus- and bronchus-associated lymphoid tissue without depletion of CD8+ cells. Most of these features were similar in both forms of measles lung involvement, Hecht giant cell, or interstitial pneumonia, but S100+ cells were depleted in bronchus-associated lymphoid tissue from patients with Hecht pneumonia, which also occurs more frequently in malnourished children. IL-10- and IL-12-producing cells were depleted in patients with measles, whereas IL-1-, interferon-, and IL-4-producing cells were more frequently seen in the alveolus of patients with measles compared with controls. Quantitative in situ immune cell phenotype and function in the lung in measles demonstrated severe immune dysfunction, with loss of key cells, such as dendritic, CD4+, and NK+ cells, and deficient cytokine production, which allows for a better comprehension of local reactions in this process.

Paracoccidioidomycosis (PCM) is a systemic disease caused by the fungus Paracoccidioides brasiliensis and Paracoccidioides lutzii. In PCM the skin and oral mucosa are often affected. Dendritic cells and keratinocytes of the integument play a role in innate and adaptive immune response against pathogens, due to their function as antigen presenting cells. Aiming to verify the interaction of P. brasiliensis with these cell populations, we studied 52 skin and 47 oral mucosa samples taken from patients with proven diagnosis of PCM. The biopsies were subjected to immunohistochemical and/or immunofluorescence staining with anti-factor XIIIa (marker of dermal dendrocytes), anti-CD207 (marker of mature Langerhans cells), anti-pan cytokeratins (AE1-AE3) and anti-P. brasiliensis antibodies. Analyses with confocal laser microscopy were also performed for better visualization of the interaction between keratinocytes and the fungi. In sum, 42% of oral mucosa samples displayed yeast forms in Factor XIIIa dermal dendrocytes cytoplasm. Langerhans cells in skin and oral mucosa samples did not show yeast cells in their cytoplasm. In sum, 54% of skin and 60% of mucosal samples displayed yeast cells in the cytoplasm of keratinocytes. The parasitism of keratinocytes may represent a possible mechanism of evasion of the fungus to local immune mechanisms. Factor XIIIa dendrocytes and keratinocytes may be acting as antigen-presenting cells to fulfill the probably impaired function of Langerhans cells in skin and oral mucosa of human PCM.

Acute kidney injury is an unusual complication during dengue infection. The objective of this study was to better identify the characteristics of glomerular changes focusing on in situ immune cells and cytokines. An immunohistochemical assay was performed on 20 kidney specimens from fatal human cases of dengue hemorrhagic fever (DHF). It was observed a lymphomononuclear infiltrate, neutrophils and nuclear fragmentation in the glomeruli, hydropic degeneration, nuclear retraction, eosinophilic tubules and intense acute congestion. Sickle erythrocytes were frequent in glomeruli and inflammatory infiltrate. The glomeruli presented endothelial swelling and mesangial proliferation. Lymphocytes CD4+ predominated over CD8+ T cells, B cells and natural killer cells. There were also an expressive number of macrophagic CD68+ cells. S100, Foxp3 and CD123 cells were not identified. Cells expressing IL17 and IL18+ cytokines predominated in the renal tissues, while IL4, IL6, IL10, IL13, TNF-alpha and IFN-gamma were rarely visualized. The high number of cells expressing IL17 and IL18+ could reflect the acute inflammatory response and possibly contribute to the local lesion. CD8+ T cells could play a role in the cytotoxic response. DHF is a multifactorial disease of capillary leakage associated with a "Tsunami of cytokines expression". The large numbers of cells expressing IL17 seems to play a role favoring the increased permeability.

Jorge Lobo's disease (JLD) is a chronic granulomatous mycosis described in various Latin American countries. The main objective of the present study was to investigate the possible role of Th17 and Foxp3+ Treg cells in the pathogenesis of Jorge Lobo's disease. Human skin biopsies were submitted to an immunohistochemistry protocol to detect Foxp3, interleukin (IL)-1beta, CD25, IL-6, IL-17, and IL-23. The epidermis presented acanthosis, hyperkeratosis, and frequent presence of fungi. The dermis presented inflammatory infiltrate comprising macrophages, lymphocytes, epithelioid and multinucleated cells, and an intense number of fungi. Foxp3+ Treg cells and IL-17+ cells were visualized in lymphocytes in the inflammatory infiltrate. IL-1, IL-2R (CD25), IL-6, and IL-23 were visualized in the dermis, intermingled with fungal cells, permeating or participating of the granuloma. Following IL-17, the most prominent cytokine was IL-6. IL-23 and cells expressing CD25 were present in fewer number. The comparative analysis between IL-17 and Foxp3 demonstrated a statistically significant increased number of IL-17+ cells. Th17 cells play a role in the immune response of JLD. IL-1beta and IL-6 added to the previously described increased number of TGF-beta would stimulate such pattern of response. Th17 cells could be present as an effort to modulate the local immune response; however, high levels of a Th17 profile could overcome the role of Treg cells. The unbalance between Treg/Th17 cells seems to corroborate with the less effective immune response against the fungus.

Recent works have demonstrated that mast cells may have an important role in immunologic reactions and inflammation once they synthesize and secrete many cytokines including IL4, IL5, IL6 and TNF-alpha. We have conducted research in order to verify if mast cells would participate in the local inflammatory immune response against Paracoccidioides brasiliensis in skin lesions characterized by a Th2 pattern of cytokines. Fifty-nine skin biopsies with previous histopathological diagnosis of paracoccidioidomycosis and immunohistochemical characterization of cytokines present in the inflammatory infiltrate were classified in three groups: group 1 (G1), with compact granuloma and a Th1 pattern of cytokines; group 2 (G2), with loose granuloma and a Th2 pattern of cytokines; group 3 (G3), both kind of granuloma in the same lesion, characterized by cytokines from Th1 and Th2 patterns. Ten biopsies from normal skin were used as control group. Mast cells were visualized and quantified by a toluidine blue/HCl staining and a double immunostaining was performed to detect a co-localization of mast cells and IL10. G2 presented an increased number of mast cells when compared to G1, G3 and control group and we frequently could find mast cells expressing IL10 in G2. The data obtained suggest that mast cells participate in the immune response against P. brasiliensis in skin lesions with loose granuloma and a Th2 pattern of cytokines. Considering these results, mast cells could constitute a source of IL10, contributing to a non-effective response against fungal antigens.

Yellow fever is an infectious, non-contagious disease caused by an RNA virus of the family Flaviviridae, which is transmitted to man by the bite of hematophagous mosquitoes. Infection with the yellow fever virus can progress with lesions in the heart, kidneys, central nervous system, and liver. In the liver, the histopathological picture is characterized by necrosis, steatosis and hepatocyte apoptosis, with a preferential midzone distribution. In the present study, liver samples from fatal patients with yellow fever were analyzed. The histopathological pattern was characterized by steatosis, lytic necrosis and hepatocyte apoptosis associated with a moderate mononuclear inflammatory infiltrate. The inflammatory component mainly consisted of CD4+ T lymphocytes, followed by CD8+ T lymphocytes, which showed a preferential portal and midzone distribution. Immunoreactivity to Fas ligand was mainly observed in hepatocytes of the midzone region. Based on these findings, we conclude that lymphocytes play an important role in the genesis of hepatic lesions in severe yellow fever, inducing hepatocyte apoptosis through the binding to Fas receptors. However, further studies are necessary to investigate the participation of other immune factors and to quantify the role of the cytotoxic cellular response in the lesion evolution during the course of disease in the liver.

The objective of the present study was to evaluate the duodenal mucosa of HIV-infected patients during antiretroviral therapy. This was an observational study conducted on HIV-positive patients and a control group. Group 1 comprised 22 HIV-negative individuals while 38 HIV-positive individuals were classified according to the CDC 1993 classification into group 2 (A1 or A2) or group 3 (B2, A3, B3, C2, C3). All subjects were submitted to upper gastrointestinal endoscopy with duodenal biopsies. Qualitative, semi-quantitative and quantitative histological analyses were performed. Results were considered significant when P < 0.05. A higher prevalence of inflammatory infiltrate and eosinophilia was observed in the HIV group, together with a reduction in mucosal CD4+ lymphocyte (L) counts [median (lower-upper quartiles), 12.82 (8.30-20.33), 6.36 (1.75-11.66) and 1.75 (0.87-3.14) in groups 1, 2 and 3, respectively] which was not correlated with disease stage. The extent of CD4+L count reduction was similar in blood and duodenal mucosa. Normal CD8+L and CD45RO+L counts, and normal numbers of macrophages and antigen-presenting cells were also found in the HIV patients. The cytokine pattern did not differ among groups. Tissue HIV, assessed by p24 antigen, correlated with a higher CD45RO+L count (77.0 (61-79.8) and 43.6 (31.7-62.8) in p24+ and p24-, respectively, P = 0.003), and IL-4 positivity (100 and 48.2% in p24+ and p24-, respectively, P = 0.005). The duodenal mucosa of HIV+ patients showed a relatively preserved histological architecture. This finding may be characteristic of a population without opportunistic infections and treated with potent antiretroviral therapy, with a better preservation of the immune status.

Pruritic Papular Eruption with Human Immunodeficiency Virus infection (PPE-HIV) is characterized by symmetrically distributed papules with pruritus in the skin of patients suffering advanced HIV infection. Although known since 1985, the etiology of this symptomatic dermatitis is unclear. We set out to characterize the phenotype of the infiltrating cells and the cytokine profile in the lesions, as an attempt to contribute to determining its etiopathogenesis. Clinical data and histological, immunohistochemical, and ultrastructural features of skin biopsies from 20 HIV patients with PPE were studied. The histopathological aspects, cell immunophenotypes, and cytokine expressions in the lesions where quantified and compared to perilesional skin, and to those in the clinically normal skin of HIV patients without PPE-HIV (n=11) and those in normal skin samples from HIV negative individuals (n=10). PPE-HIV occurred mainly in HIV patients with mean CD4+ counts of 124.6 +/- 104 lymphocytes/mm3. Furthermore, their eosinophil counts were significantly increased. The skin lesions were characterized by a predominantly perivascular dermal lymphohistiocytic inflammatory infiltrate. Langerhans cells were normally distributed in the epidermis and seen among the cellular components of dermal infiltrates. The density of CD8+ lymphocytes was elevated and the density of CD4+ cells was reduced in dermal infiltrates. Interleukin 5 was the predominant cytokine in the lesions. Electron microscopic analysis didn't disclose HIV or other infectious agents in the lesions. These results refute the hypothesis of an infectious etiology of PPE-HIV. CD8+ lymphocytes and Langerhans cells seem to have roles in the pathogenesis of PPE-HIV. The increased frequency of IL5 was associated with abundant eosinophils in the lesions, suggesting a type Th2 response in this dermatitis.

Background. A non-negligible percentage of patients with non-alcoholic fatty liver disease, a leading cause of hepatic progressive disorder related to insulin resistance, have no metabolic risk factors, and abnormal intestinal permeability has been suggested to be involved in the pathogenesis of the liver damage. Coeliac disease, a curable disorder characterised by inflammatory mucosal damage, may show hepatic histological features similar to steatohepatitis. Conflicting data have been reported on the prevalence of coeliac disease in non-alcoholic steatohepatitis. Aim. To search for coeliac disease in a series of patients with non-alcoholic fatty liver disease by screening with anti-tissue transglutaminase and anti-endomysium antibodies. Patients and methods. Fifty-nine consecutive patients with hypertransaminasemia and non-alcoholic fatty liver disease, 38 (64%) with steatohepatitis. Anti-endomysium antibodies were assayed by indirect immunofluorescence, IgA anti-tissue transglutaminase by ELISA. Patients who tested positive underwent HLA DQ typing and endoscopy. Results. Tissue transglutaminase antibodies were positive in six (10%) patients and anti-endomysium in two (3.4%); only two (3.4%), positive for both anti-endomysium positive and anti-transglutaminase, resulted to have coeliac disease based on histological findings. After 6 months of gluten-free diet, liver enzymes normalised. Conclusions. The prevalence of silent coeliac disease is 3.4% in patients with non-alcoholic fatty liver. The inclusion of anti-endomysium antibodies test in studying patients with non-alcoholic fatty liver and persistent biochemical abnormalities has to be taken into account, since positivity for tissue transglutaminase antibodies, in the absence of confirmatory anti-endomysium antibodies, is not sufficient to perform diagnostic endoscopy.

Background. A possible link between coeliac disease and dilated cardiomyopathy has recently been suggested. Aims. To assess the frequency of anti-endomysial antibodies, the marker for coeliac disease, in patients with different forms of heart failure, and to establish the clinical features of those endomysial antibody positive. Subjects and Methods. A total of 642 consecutive patients entering the waiting list for heart transplantation from 1995 through 1997 were studied. The prevalence of endomysial IgA antibodies, determined by indirect immunofluorescence, was compared to that observed in three surveys conducted in the Italian general population. Results. Of the 642 patients, 12 (1.9%; 95% confidence interval 0.97–3.2) resulted endomysial antibody positive, versus 349720 healthy controls (0.35%; 95% confidence interval, 0.23–0.47), accounting for a relative risk of 5.3 (95% confidence interval, 2.8–10.3). Anti-endomysial antibodies were found in 6275 patients with dilated cardiomyopathy and 6367 with other forms of heart failure (2.2% versus 1.6%; 95% confidence interval 0.8–4.7 and 0.6–3.5), with no statistical difference. The 12 endomysial antibody positive patients were leaner (body mass index, 22.0±1.9 vs 24.2±3.1, p

Chromoblastomycosis is a fungal infection caused by dematiaceous fungi inducing skin lesions of difficult treatment and of frequent recurrence. The objective of the present investigation was to characterize cell-mediated tissue reactions in the skin in cases of Chromoblastomycosis using histopathology and immunocytochemistry methods and to correlate them with different clinical forms of Chromoblastomycosis. Biopsies from 19 patients were stained with HE and Giemsa, and serial sections were immunohistochemically stained using CD45RO, CD20, CD4, CD8, CD68, CD1a, CD34, IL4, IL10, TNF-α and IFN-γ antibodies. A quantitative and semi quantitative analysis of the cell subsets and cytokines in the inflammatory infiltrates was performed by counting ten high-power fields (400×). The cutaneous lesion presented as verrucous plaque (n = 15) or erythematous atrophic plaque (n = 4). We observed two types of tissue reaction: A) a granulomatous reaction with a suppurative granuloma with several fungi cells in the cutaneous lesion presenting as verrucous plaque; B) a granulomatous reaction with a tuberculoid granuloma with few fungi cells in the cutaneous lesion presenting as atrophic plaque. The data obtained suggest that patients with lesion presented as verrucous plaque have a type Th2 immunological response, while patients with lesion presented as erythematous atrophic plaque have a type Th1 response.

We demonstrated and quantified by immunohistochemistry the factor XIIIa+ dermal dendrocytes (FXIIIa+ DD) in paracoccidioidomycosis skin lesions. Sixty-one biopsies were classified according to the tissue response in well-organized granulomas (group 1), poorly organized granulomas (group 2) and samples showing both kinds of granuloma (group 3). Ten biopsies from normal skin were used as controls. In order to verify the internalization of Paracoccidioides brasiliensis antigens by FXIIIa+ DD, we performed a double immunostaining technique. FXIIIa+ DD were hypertrophied with prominent dendrites and their number in the test groups was higher than in the control group, especially in the dermal papillae. P. brasiliensis yeasts were seen within the cytoplasm of FXIIIa+ DD in 40% of the immunostained biopsies. We could correlate these findings with the probable role of FXIIIa+ DD as antigen-presenting cells in the pathogenesis of skin lesions in paracoccidioidomycosis.

Background Chromoblastomycosis is a chronic fungal infection that affects skin and subcutaneous tissue. Lesions can be classified in tumorous, verrucous, cicatricial and plaque type. The cellular immune response in the severe form of the disease seems to correlate with a Th2 pattern of cytokines. The humoral immune response also seems to play a role. We intended to explore the populations of regulatory T cells and the Th17 pattern. Methodology Twenty-three biopsies of verrucous form were obtained from patients with clinical, culture and histopathological diagnostic of chromoblastomycosis, without treatment. It was performed an immunohistochemistry method to detect Foxp3, CD25, TGF-β, IL-6, IL-17 and IL-23. Principal findings IL-17 was the only cytokine with high expression in CBM when compared to normal skin. The expression of Treg cells, TGF- β, IL-6 and IL-23 were similar to normal skin. Conclusions/Significance The constitution of a local immune response with high expression of IL-17 and low expression of other cytokines could be at least in part, an attempt to help the immune system against fungal infection. On the other hand, high levels of local immune response mediated by Th17 profile could overcome the role of Treg cells. The inefficient immunomodulation as a consequence of the unbalance by Treg/Th17 cells seems to corroborate with the less effective immune response against fungi., Author Summary Chromoblastomycosis (CBM) is a chronic infection that affects skin and subcutaneous tissue, caused by some fungi which have a brownish color due to the presence of melanin pigments. The most frequent lesions are of verrucous type. Here we describe the participation of regulatory T cells and cells with the Th17 pattern of cytokines. High levels of Th17 cells participate in chronic inflammatory conditions, once at least in part they could improve the immune response and act in concomitance to the Th1 and Th2 patterns. Our results indicate a predominance of the Th17 pattern over Treg cells in verrucous lesions. We speculate that the local immune imbalance in CBM lesions characterized by exacerbated Th17 response, probably by suppressing the Treg response, is not effective for total fungal elimination. Even after long-period treatments, most patients has no absolute cure and often there is recurrence of the lesions. We believe that our study could contribute to the understanding of the immunopathogenesis of CBM and in such a way, presents some aspects to new possible therapies.

Background In this paper we study the distribution of leukocyte populations and of cytokine-producing cells in the spleen of a patient with visceral leishmaniasis resistant to clinical treatment. It is the first attempt to compare the distribution of leukocyte populations and cytokine-producing cells in the splenic compartments of a patient with visceral leishmaniasis with those observed in patients without the disease. Case presentation A 25-year-old male, farmer, was hospitalized on several occasions with diagnosis of visceral leishmaniasis and received all recommended treatments for the disease with only transient improvement followed by relapse. He was eventually subjected to splenectomy in order to control the effects of hypersplenism and to potentially overcome infection. After surgery and combined chemotherapy, the disease evolved to cure. In comparison with the spleens of the other two patients without visceral leishmaniasis, an increase was observed in the CD4/CD8 ratio and in the number of IL-10- and FoxP3-producing cells, while the number of IL-17-producing cells was lower in the spleen of the patient with visceral leishmaniasis. Conclusion This report confirms previous data on changes in the CD4/CD8 ratio in the spleens of patients with visceral leishmaniasis. Additionally the data presented herein suggests that splenic FoxP3- and IL-17-producing cells are involved in the chronicity of visceral leishmaniasis. Electronic supplementary material The online version of this article (doi:10.1186/1471-2334-14-491) contains supplementary material, which is available to authorized users.

Plasmacytoid dendritic cells (pDCs) are characterized by expression of CD123 and BDCA-2 (Blood Dendritic Cell Antigen 2) (CD303) molecules, which are important in innate and adaptive immunity. Chromoblastomycosis (CBM), lacaziosis or Jorge Lobo's disease (JLD), and paracoccidioidomycosis (PCM), are noteworthy in Latin America due to the large number of reported cases. The severity of lesions is mainly determined by the host's immune status and in situ responses. The dendritic cells studied in these fungal diseases are of myeloid origin, such as Langerhans cells and dermal dendrocytes; to our knowledge, there are no data for pDCs. Forty-three biopsies from patients with CBM, 42 from those with JLD and 46 diagnosed with PCM, were evaluated by immunohistochemistry. Plasmacytoid cells immunostained with anti-CD123 and anti-CD303 were detected in 16 cases of CBM; in those stained with anti-CD123, 24 specimens were obtained from PCM. We did not detect the presence of pDCs in any specimen using either antibody in JLD. We believe that, albeit a secondary immune response in PCM and CBM, pDCs could act as a secondary source of important cytokines. The BDCA-2 (CD303) is a c-type lectin receptor involved in cell adhesion, capture, and processing of antigens. Through the expression of the c-lectin receptor, there could be an interaction with fungi, similar to other receptors of this type, namely, CD207 in PCM and CD205 and CD209 in other fungal infections. In JLD, the absence of expression of CD123 and CD303 seems to indicate that pDCs are not involved in the immune response.

Sir, Human papillomaviruses (HPVs) are double-stranded DNA virus with over 100 different identified types. The virus mainly infects the cutaneous and mucosal squamous stratified epithelia of the anogenital region. HPV replication is linked to the differentiation and maturation of squamous cells, followed by terminal differentiation, with hyperplasia associated with the formation of local lesions (1–3). Some factors minimize or prevent the exposure of HPV to the immune system. The immune escape mechanisms are related to the absence of viral lyses in keratinocytes, or the absence of infection and replication of antigen-presenting cells (APC) in epithelium (1). Langerhans’ cells (LC) are dendritic cells that engulf and process antigen, and migrate through the dermis to draining lymph nodes (4). Factor XIIIa+ dermal dendrocytes (FXIIIa+ DD) constitute another skin dendritic cell population. They are able to differentiate and migrate to epidermis, indicating an interaction between dermis and epidermis in order to develop an immune response (5, 6). Although recent studies have shown FXIIIa+ DD involvement in other infectious process (7, 8), their interaction with HPV has been poorly explored (9). It has been demonstrated that in HPV infection of the lower genital tract, the virus has a direct effect on the local immune response, which may result in a malignant transformation. As shown previously, HPV alone decreases the number of cervical LC and induces changes in the pattern of cytokines released by these cells (10, 11). The role of LC in the immune response to HPV infection has been well studied in uterine cervix lesions. There are, however, other aspects to be clarified concerning the role of dendritic cell populations in HPV lesions. The aim of this study was to improve our knowledge of HPV infection of the vulva, focusing on the role of FXIIIa+ DD in such lesions.

O presente caso ilustra uma forma de eritema nodoso, cujo agente foi o Trypanosoma cruzi em paciente chagásica submetida a transplante cardíaco. O diagnóstico foi firmado através do exame histopatológico de biópsia da lesão cutânea e estudo imunohistoquímico. O tratamento com nifurtimox promoveu regressão total das lesões.

Dengue infection is an important tropical disease worldwide. The host immune response has been studied in order to better understand lesion mechanisms. It was performed an immunohistochemical study in 14 specimens of liver from patients with dengue hemorrhagic fever (DHF) to characterize cytokines and some factors present in liver lesions and their possible role in the pathogenesis of hepatic injury. Portal tract and hepatic acinus presented high expression of TLR2, TLR3, IL6, and granzyme B. Hepatic acinus also presented iNOS, IL18, and TGF-beta. Cells expressing IL12, IL13, JAk1, STAT1, and NF-κB were rarely visualized. Treg cells foxp3+ were absent. TLR2 and TLR3 seem to participate in cellular activation and cytokine production. Cytotoxic response seems to play a role. Although TGF-beta promotes the activation of Foxp3+ regulatory T cells, IL6 can significantly suppresses their generation. The expression of Treg cells is diminished probably as a result of the high frequency of these cytokines. Both cytokines play a role in the increased vascular permeability and edema observed in dengue liver specimens, with consequent plasma leakage and severity of the disease. It was observed a regular expression of IL-18 in hepatocytes and lymphocytes of the inflammatory infiltrate in portal tract, which reflects the acute inflammatory response that occurs in the liver and contributes to hepatic injury. At least in part, the increased number of cells expressing IL-18 could play a role of "up" regulation of FasL and correlate to the phenomenon of apoptosis, a mechanism of destruction of hepatocytes in DHF.

Few studies have addressed the ultrastructure of vascular permeability in urticaria.To describe the types of endothelial cell organelles involved in vascular permeability in drug-induced acute urticaria (DIAU).Seven patients with DIAU were enrolled in the study. Biopsies of urticarial lesions and apparently normal skin were performed. The 14 collected fragmentswere processed with immunogold electron microscopy using single stains for tryptase and factor XIIIa (FXIIIa) and double immunogold labeling for both tryptase and FXIIIa.Some sections demonstrated mast cells in the degranulation process, in both anaphylactic and piecemeal degranulation. After double immunogold staining, 10 nm (FXIIIa) and 15 nm (tryptase) gold particles wereboth present, covering the granules in the mast cells, indicating that both tryptase and FXIIIa were localized within the granules of these cells. Interestingly, we found strong evidence of the presence of caveolae and vesico-vacuolar organelles (VVOs) in the endothelial cells of the biopsies. In addition to these findings, we were able to demonstrate the presence of tryptase and FXIIIa in the endothelial celIs, in urticarial lesions and in apparently normal skin.VVOs are present in the endothelial cells of post-capillary venules in DIAU. This is the first report on the expression of FXIIIa and tryptase in the cytoplasm of endothelial cells in urticaria.

Summary The pathogenesis of lacaziosis continues to be obscure, and works have investigated the blood systemic immune response or the dermal immune response in restricted lesions in different body regions. Some authors describe that the inflammatory infiltrate in lacaziosis lesions showed a predominance of macrophages followed by CD45RO + , CD4 + , and CD8 + T cells; CD57 + natural killer cells; S-100 + cells; and CD20 + B lymphocytes. A 54-year-old man and living in the State of Para, Amazon region, Brazil, was seen with a lesion on the left lower limb, which had started as a small nodular area 18 years ago. The lesion showed progressive growth and disseminated to other parts of the body. Our findings showed that dermal immune response differs depending on the type of lesions and clinical presentation, with presence of CD1a + , FXIIIa + , CD45 + , CD4 + , CD8 + , and S-100 + cells and cytokine profile with expression of interleukin 1 β , tumor necrosis factor α , transforming growth factor β , IL-10, and interferon γ .

Paracoccidioidomycosis (PCM) is a systemic mycosis caused by the dimorphic fungus Paracoccidioides brasiliensis, with high incidence in Brazil and very significant in Latin America. The disease is clinically classified as acute, subacute or chronic where the primary lesion initiates in the lungs and can spread to other organs such as the skin and mucous membranes. The lesions are characterized by granulomatous formation, organized according to the type of pattern of host immune response. We demonstrated and quantified by immunohistochemistry the expression of Foxp3, CD25, TGF-beta and IL-10 in thirty cutaneous lesions with different presentation of granulomatous response. Cells expressing Foxp3 and CD25 were increased in lesions with compact granulomas. The expression of TGF-beta and IL-10 was similar in all PCM lesions. As previous studies, our data suggest the correlation of Treg cells with the chronicity of the disease and the participation in suppressing mechanism as a possible source of IL-10. TGF-β and IL-10, two important suppressor cytokines, are expressed in great amounts in the lesions but our results do not allow correlating with the differences in the granulomatous response.

Yellow fever is a viral hemorrhagic fever, which affects people living in Africa and South America and is caused by the yellow fever virus, the prototype species in the Flavivirus genus (Flaviviridae family). Yellow fever virus infection can produce a wide spectrum of symptoms, ranging from asymptomatic infection or oligosymptomatic illness to severe disease with a high fatality rate. In this review, we focus in the mechanisms associated with the physiopathology of yellow fever in humans and animal models. It has been demonstrated that several factors play a role in the pathological outcome of the severe form of the disease including direct viral cytopathic effect, necrosis and apoptosis of hepatocyte cells in the midzone, and a minimal inflammatory response as well as low-flow hypoxia and cytokine overproduction. New information has filled several gaps in the understanding of yellow fever pathogenesis and helped comprehend the course of illness. Finally, we discuss prospects for an immune therapy in the light of new immunologic, viral, and pathologic tools.

BACKGROUND: Few studies have evaluated the ultrastructure of the superficial skin nerves in urticaria. OBJECTIVE: The objective of this study was to describe findings in superficial skin nerves in cases of drug-induced acute urticaria. METHODS: Seven patients with drug-induced acute urticaria were included in the study. Skin biopsies were obtained from the urticarial lesion and from the apparently normal skin. The 14 fragments collected were processed for immunogold electron microscopy using single stains for antitryptase and anti-FXIIIa antibodies, as well as double immunogold labeling for both. RESULTS: Some sections showed mast cells in the process of degranulation. Following double immunogold staining, 10 nm (FXIIIa) and 15 nm (Tryptase) gold particles were found together throughout the granules in mast cells, indicating that tryptase and FXIIIa are located inside each one of the granules of these cells. Interestingly, we found strong evidence of the presence of tryptase and factor XIIIa in the superficial skin nerves of these patients, both in cases of urticarial lesions (wheals) and in the apparently normal skin. CONCLUSIONS: Tryptase and FXIIIa are present in the superficial nerves of the skin in drug-induced acute urticaria. This is the first report of tryptase and FXIIIa expression in the superficial skin nerves of patients with urticaria. Tryptase may be participating in neural activation in these patients, while FXIIIa may be present in the nerves to guarantee the functional integrity of structures. FUNDAMENTOS: Poucos autores têm estudado a ultraestrutura dos nervos superficiais na urticária. OBJETIVO: Descrever os achados nos nervos cutâneos superficiais em casos de urticária aguda induzida por medicamentos. MÉTODOS: Sete pacientes com urticária aguda induzida por medicamentos foram incluídos no estudo. Foram obtidas biopsias da pele da lesão urticariforme e da pele aparentemente normal. Os 14 fragmentos coletados foram processados usando imunomarcação com ouro para anticorpos anti-triptase e anti-FXIIIa separadamente, além da dupla imunomarcação com ambos anticorpos. A seguir as amostras foram submetidas à análise por microscopia imunoeletrônica. RESULTADOS: Alguns cortes demonstraram mastócitos em processo de degranulação. Após a imunomarcação dupla, partículas de ouro de 10 nm (FXIIIa) e partículas de ouro de 15 nm (Triptase) apresentavam-se juntas em grânulos de mastócitos indicando que a triptase e o FXIIIa se localizam dentro de cada um dos grânulos dessas células. Curiosamente, foi encontrada uma forte evidência da presença da triptase e do fator XIIIa nos nervos superficiais dos pacientes avaliados, tanto em lesões urticadas, como na pele aparentemente normal. CONCLUSÕES: A triptase e o FXIIIa estão presentes nos nervos superficiais da pele na urticária aguda medicamentosa. Este é o primeiro relato da expressão de triptase e de FXIIIa nos nervos superficiais na urticária. A triptase poderia estar participando da ativação neural nos pacientes estudados. O FXIIIa poderia estar presente nos nervos, com a finalidade de manter a integridade funcional dessas estruturas.

The course of leprosy depends of the host immune response which ranges from the lepromatous pole (LL) to the tuberculoid pole (TT). A comparative study was conducted in 60 patients with the LL and TT. The results showed a mean expression of TGF-β of 339 ± 99.4 cells/field for TT and of 519.2 ± 68.2 cells/field for LL. Frequency of apoptosis was 6.3 ± 1.8 in TT and 14.0 ± 6.1 in LL. A correlation (p = 0.0251) between TGF-β and caspase-3 in the LL was found. This finding indicates a role of TGF-β and apoptosis in the immune response in leprosy.

We report a patient with severe multi-bacillary leprosy complicated by recurrent episodes of erythema nodosum necrotisans that required thalidomide and/or corticosteroids during follow-up. Although the patient was from an area to which Chagas disease is endemic, this diagnosis was initially missed and was only investigated when heart failure developed in the patient. The difficulties of managing erythema nodosum necrotisans and heart failure concomitantly and those involved in excluding the diagnosis of acute myocarditis caused by reactivation of Chagas disease secondary to the immunosuppressive regimen are discussed. Other potential causes for the heart failure and possible interactions between the two diseases and their treatments are discussed. We also reviewed the literature for the association between leprosy and Chagas disease, both of which are highly endemic in Brazil. This case emphasizes the importance of searching for subclinical co-infections in leprosy patients because reactions frequently develop during specific treatment in these patients, and these reactions require prolonged therapy with immunosuppressive drugs.