Hermênio Cavalcante Lima

TNF-α mediates the induction of nitric oxide synthase in macrophages but not in neutrophils in experimental cutaneous leishmaniasis

Leishmania major infection in C57BL/6 mice is controlled by the activation of a Th1 response and nitric oxide (NO) production by macrophages. TNF‐α is considered one of the most important cytokines involved in this response. In the present study, we investigated the expression of nitric oxide synthase (iNOS) in the inflammatory cells present in the lesion and draining lymph nodes, and the cytokine production by lymph node cells in animals treated with anti‐TNF‐α. Our results demonstrated that mice treated with anti‐TNF‐α presented an increase in the number of parasites and the size of lesion, but they were able to control the infection. The increase in the lesion size correlated to the reduction of iNOS activity in the draining lymph nodes. Furthermore, the anti‐TNF‐α treatment also reduced the expression of iNOS in the macrophages, but did not affect the iNOS expression in the neutrophils. The anti‐TNF‐α mAb did not reduce the iNOS expression in IFN‐γ‐stimulated L. major infected neutrophils in vitro. Anti‐TNF‐α mAb treatment caused an increase in the production of IFN‐γ and IL‐10 by the lymph node cells from infected mice. Consequently, these results suggest that neutrophils do not respond to anti‐TNF‐α treatment and might be a source of NO to control L. major infection under these experimental conditions.

Histologic characterization of experimental cutaneous leishmaniasis in mice infected with Leishmania braziliensis in the presence or absence of sand fly vector salivary gland lysate.

Leishmania braziliensis is the causative agent of human cutaneous leishmaniasis in parts of the New World. In the murine model of infection, L. braziliensis does not produce severe or lasting cutaneous lesions in either BALB/c or C3H mice. However, when the parasites are injected into BALB/c mice with salivary gland lysate of the sand fly vector for the parasite, infection is significantly enhanced, as measured by lesion size, parasite burden, and the outcome of infection. Histologic examination of these cutaneous lesions showed that initially, nodular and diffuse dermal infiltrates of neutrophils, eosinophils, and histiocytes occurred in all mice. Over time, the saliva-free lesions progressed to small organized granulomas of epithelioid macrophages that contained few parasites, with eventual resolution of inflammation and mild dermal fibrosis. The saliva-associated lesions progressed to extensive, poorly organized accumulations of heavily parasitized epithelioid macrophages, with persistent neutrophils and eosinophils, and minimal fibroplasia. These results indicate that sand fly salivary gland lysate markedly modifies the inflammatory response to infection with L. braziliensis.

Cytokine-based therapy in psoriasis.

Psoriasis and psoriatic arthritis are chronic inflammatory diseases of unknown etiology, affecting 2–3% of the world population. Initially, psoriasis was thought to be a hyper-proliferation disorder of keratinocytes only, but as time passed, the role of immune system became more evident and now both diseases are considered autoimmune disorders. In last few years, the discovery of interleukin (IL)-23/Th17 axis in pathophysiology of psoriatic diseases shifts the cytokine paradigm from Th1 to Th17 cytokines, focused mainly on IL-17 and IL-22. Therapeutic experiences strongly support the use of cytokine antagonists as an important modality in the treatment of psoriatic arthritis and plaque psoriasis. Studies examining these therapeutic agents which target different steps of the psoriatic inflammatory cascade have also shown significant efficacy. The relatively new IL-23/Th17 axis in psoriatic diseases got more importance with the success of ustekinumab, a new monoclonal antibody against IL-12 and IL-23. In IL-17 and IL-22 knock-out and transgenic mouse models, it has been found that recombinant IL-23 fails to produce epidermal hyperplasia which resembles psoriasis. Also, some success in animal models of psoriasis was found with anti IL-17A and anti IL-22. More studies are needed to validate the efficacy and safety of these cytokine antagonists in psoriatic diseases. Using a historical perspective and a chess game as an analogy, the main objective of this review is to summarize the central role of some of these cytokines in psoriasis pathophysiology and to develop a strategic approach to new therapeutic weapons within the armamentarium of psoriasis treatment.

Molecular diagnosis of leishmaniosis in the Paraná state of southern Brazil

Abstract:  The objective of the present study was to establish a polymerase chain reaction (PCR) technique for the diagnosis of cutaneous and mucocutaneous leishmaniosis from autochthonous cases in the state of Paraná in southern Brazil as well as imported cases. We sought to determine its utility and accuracy compared with smears and present culture methods. To standardize PCR samples, skin and mucosal punch biopsies from human lesions were performed on patients living in different regions of the Paraná state (76 cases) and other endemic areas of Brazil and Argentina (7 cases). For PCR standardization, two pairs of primers (MP1L/MP3H and B1/B2) were utilized for amplification of the conserved sequences in the minicircle of kinetoplast DNA (kDNA) for the Leishmania braziliensis complex. Two other primer pairs (b1/b2 and a1/a2) were species‐specific for L. (V.) braziliensis and L. (V.) amazonensis, respectively. After differential diagnosis, eight patients had clinical diagnosis of the cutaneous ulcer changed to others pathologies such as syphilis, baso‐cellular carcinoma, varicose ulcer, ecthyma and paracoccidioidomycosis. Of the 75 patients with cutaneous (CL) and mucocutaneous (MCL) lesions who provided samples, 47 (46 CL + 1 MCL) were diagnosed with leishmaniosis by smear and 57 (52 LC + 5 MCL) were diagnosed by culture methods. In contrast, our PCR technique presented higher accuracy when compared to the direct examination and culture of parasites. PCR is applicable both for CL where all 61 lesions were diagnosed, and MCL where 12 of 14 lesions were diagnosed. This molecular biology technique is also a faster and more specific diagnostic method compared with present parasitological procedures.

Comparative study of histopathological and immunohistochemical findings in skin biopsies from patients with psoriasis before and after treatment with acitretin

Background:  Acitretin has been shown to be effective for psoriasis treatment. Its mechanism of action is not completely understood, and there are few studies focusing on histological and immunohistochemical differences before and after treatment of psoriasis with acitretin.

Resolution of an Infection with Leishmania braziliensis Confers Complete Protection to a Subsequent Challenge with Leishmania major in BALB/c Mice

Both Leishmania major and L. braziliensis induce cutaneous leishmaniasis in BALB/c mice. Whereas BALB/c mice die of infection with L. major, they cure an infection with L. braziliensis. We report here that after curing an infection with L. braziliensis, BALB/c mice are resistant to challenge with L. major. When challenged with L. major, L. braziliensis pre-treated BALB/c mice mounted a delayed-type hypersensitivity response to L. major and produced high amounts of interferon-gamma (IFN-gamma) but low amounts of interleukin-4. The IFN-gamma produced by the L. braziliensis pre-infected mice was involved in the protection seen against L. major challenge since treating the mice with a neutralizing anti-IFN-gamma abrogated the protection. This suggests that cross-reactive antigen epitopes exist between L. braziliensis and L. major and that pre-infection with L. braziliensis primes BALB/c mice to epitopes on L. major that can elicit a protective Th1 response to the parasite.

Insights and advances in chronic urticaria: a Canadian perspective

In the past few years there have been significant advances which have changed the face of chronic urticaria. In this review, we aim to update physicians about clinically relevant advances in the classification, diagnosis and management of chronic urticaria that have occurred in recent years. These include clarification of the terminology used to describe and classify urticaria. We also detail the development and validation of instruments to assess urticaria and understand the impairment on quality-of-life and the morbidity caused by this disease. Additionally, the approach to management of chronic urticaria now focuses on evidence-based use of non-impairing, non-sedating H1-antihistamines given initially in standard doses and if this is not effective, in up to 4-fold doses. For urticaria refractory to H1-antihistamines, omalizumab treatment has emerged as an effective, safe option.

Beyond flat weals: validation of a three‐dimensional imaging technology that will improve skin allergy research

Skin‐prick tests (SPTs) are a standard way to test for sensitizations to allergens, but to date, techniques that allow for high‐quality measurements of the resulting weals for research purposes are lacking. In this study, we assessed a new three‐dimensional (3D) imaging technology for its accuracy and consistency. We found that this new technology showed very little intraoperator and interoperator variation for repeated measurements of a model of known area by each of two operators. We also found that repeated measurements of the same object over 4 months showed virtually no variation. Finally, 3D imaging was superior to traditional ruler measurements for assessing SPT reactions to histamine and allergen. For high‐quality measurements of SPT reactions, 3D imaging is accurate, consistent and reliable.

Objective evaluation of skin prick test reactions using digital photography

Background: The skin prick test has been used worldwide to determine IgE‐mediated hypersensitivity. However, the most current method to record this reaction has problems with accuracy and precision.

Papel das células T reguladoras no desenvolvimento de dermatoses

Celulas T, em particular as celulas T CD4+, tem sido associadas a muitos aspectos das doencas de pele. A evidencia atual sugere, porem, que o papel dos linfocitos T CD4+ no desenvolvimento de inflamacao cutânea excede o de ativador pro-inflamatorio das celulas T de acao que dirigem a resposta imune. Subtipos de celulas T com capacidade reguladora, tais como Tregs CD4+CD25+high, tem sido identificadas. Observacoes recentes sugerem que em algumas doencas da pele a funcao dessas celulas esta modificada. Portanto, o desenvolvimento e a funcao de Tregs na dermatologia sao atualmente um topico atraente devido a sua importância no controle da resposta do sistema imune contra tumores e doencas infecciosas, bem como inibindo o desenvolvimento de auto-imunidade e alergia. Assim, mecanismos reguladores defeituosos podem permitir a quebra da tolerância imune periferica seguida por inflamacao cronica e doenca. Detalham-se as anormalidades funcionais e a contribuicao de diferentes subtipos de celulas T reguladoras no desenvolvimento de doencas dermatologicas nesta revisao. Acentuam-se os possiveis alvos terapeuticos e as modificacoes dos T reguladores causados por imunomoduladores usados no campo da dermatologia.