Erythema Nodosum Leprosum Neutrophil Subset Expressing IL-10R1 Transmigrates into Skin Lesions and Responds to IL-10.

Erythema nodosum leprosum (ENL) is an inflammatory complication in leprosy. Yet, the involvement of ENL neutrophils in the inflammatory response against Mycobacterium leprae remains poorly explored. Our primary aim was to investigate the utility of the surface expression of neutrophil IL-10R1 as an ENL biomarker and, secondarily, to evaluate whether leprosy or healthy M. leprae-stimulated neutrophils produce cytokines and are able to respond to IL-10. We, in this study, describe a subpopulation of circulating neutrophils of ENL patients that exclusively expressed IL-10R1, providing evidence that IL-10R1+ neutrophils are present in ENL lesions. It was also found that ENL neutrophils, but not those of nonreactional leprosy controls, were able to secret detectable levels of TNF ex vivo and the addition of IL-10 blocked TNF release. It was likewise observed that M. leprae-stimulated, healthy neutrophils expressed IL-10R1 in vitro, and ENL-linked cytokines were released by M. leprae-cultured neutrophils in vitro. Moreover, consistent with the presence of a fully functional IL-10R, the addition of IL-10 prevented the release of M. leprae-induced cytokines. Most importantly, dead M. leprae revealed its superior capacity to induce CCL4 and IL-8 in primary neutrophils over live Mycobacterium, suggesting that M. leprae may hamper the inflammatory machinery as an immune escape mechanism.

Neutrophils in Leprosy.

Leprosy is an infectious disease caused by the intracellular bacillus Mycobacterium leprae that mainly affects the skin and peripheral nerves. One of the most intriguing aspects of leprosy is the diversity of its clinical forms. Paucibacillary patients are characterized as having less than five skin lesions and rare bacilli while the lesions in multibacillary patients are disseminated with voluminous bacilli. The chronic course of leprosy is often interrupted by acute episodes of an inflammatory immunological response classified as either reversal reaction or erythema nodosum leprosum (ENL). Although ENL is considered a neutrophilic immune-complex mediated condition, little is known about the direct role of neutrophils in ENL and leprosy disease overall. Recent studies have shown a renewed interest in neutrophilic biology. One of the most interesting recent discoveries was that the neutrophilic population is not homogeneous. Neutrophilic polarization leads to divergent phenotypes (e.g., a pro- and antitumor profile) that are dynamic subpopulations with distinct phenotypical and functional abilities. Moreover, there is emerging evidence indicating that neutrophils expressing CD64 favor systemic inflammation during ENL. In the present review, neutrophilic involvement in leprosy is discussed with a particular focus on ENL and the potential of neutrophils as clinical biomarkers and therapeutic targets.

Impact of a Reference Center on Leprosy Control under a Decentralized Public Health Care Policy in Brazil.

OBJECTIVE: We evaluated the profile of patients referred to the Fiocruz Outpatient Clinic, a reference center for the diagnosis and treatment of leprosy in Rio de Janeiro, RJ, and analyzed the origins and outcomes of these referrals. METHODS: This is an observational retrospective study based on information collected from the Leprosy Laboratory database at Fiocruz, Rio de Janeiro, RJ, Brazil. A total of 1,845 suspected leprosy cases examined at the reference center between 2010 and 2014 were included. The originating health service referrals and diagnostic outcomes were analyzed as well as the clinical and epidemiological data of patients diagnosed with leprosy. RESULT: Our data show that the profile of the patients treated at the Clinic has changed in recent years. There was an increase in both the proportion of patients with other skin diseases and those who had visited only one health service prior to our Clinic. Among the total 1,845 cases analyzed, the outcomes of 1,380 were linked to other diseases and, in 74% of these cases, a biopsy was not necessary to reach a diagnostic conclusion. A decrease in new leprosy case detection among our patients was also observed. Yet, among the leprosy patients, 40% had some degree of disability at diagnosis. CONCLUSION: The results of the present study demonstrated the importance of referral centers in support of basic health services within the decentralization strategy. But, the success of the program depends on the advent of new developmental tools to augment diagnostic accuracy for leprosy. However, it should be emphasized that for new diagnostic methods to be developed, a greater commitment on the part of the health care system regarding research is urgently needed.

Expression of CD64 on Circulating Neutrophils Favoring Systemic Inflammatory Status in Erythema Nodosum Leprosum.

Erythema Nodosum Leprosum (ENL) is an immune reaction in leprosy that aggravates the patient´s clinical condition. ENL presents systemic symptoms of an acute infectious syndrome with high leukocytosis and intense malaise clinically similar to sepsis. The treatment of ENL patients requires immunosuppression and thus needs to be early and efficient to prevent both disabilities and permanent nerve damage. Some patients experience multiple episodes of ENL and prolonged use of immunosuppressive drugs may lead to serious adverse effects. Thalidomide treatment is extremely effective at ameliorating ENL symptoms. Several mechanisms have been proposed to explain the efficacy of thalidomide in ENL, including the inhibition of TNF production. Given its teratogenicity, thalidomide is prohibitive for women of childbearing age. A rational search for molecular targets during ENL episodes is essential to better understand the disease mechanisms involved, which may also lead to the discovery of new drugs and diagnostic tests. Previous studies have demonstrated that IFN-γ and GM-CSF, involved in the induction of CD64 expression, increase during ENL. The aim of the present study was to investigate CD64 expression during ENL and whether thalidomide treatment modulated its expression. Leprosy patients were allocated to one of five groups: (1) Lepromatous leprosy, (2) Borderline leprosy, (3) Reversal reaction, (4) ENL, and (5) ENL 7 days after thalidomide treatment. The present study demonstrated that CD64 mRNA and protein were expressed in ENL lesions and that thalidomide treatment reduced CD64 expression and neutrophil infiltrates-a hallmark of ENL. We also showed that ENL blood neutrophils exclusively expressed CD64 on the cell surface and that thalidomide diminished overall expression. Patient classification based on clinical symptoms found that severe ENL presented high levels of neutrophil CD64. Collectively, these data revealed that ENL neutrophils express CD64, presumably contributing to the immunopathogenesis of the disease.

Histoid leprosy: a rare exuberant case.

Leprosy is a neglected disease. We point up the need of recognizing the unusual clinical presentations of the disease in order to make early diagnosis and proper treatment possible, and break the transmission chain. The authors report a rare type of multibacillary leprosy: histoid leprosy and present images of numerous well-circumscribed indurated papules and nodules distributed throughout the entire body.

Diagnostic challenges of single plaque-like lesion paucibacillary leprosy.

The diagnosis of single-lesion paucibacillary leprosy remains a challenge. Reviews by expert dermatopathologists and quantitative polymerase chain reaction (qPCR) results obtained from 66 single-plaque biopsy samples were compared. Histological findings were graded as high (HP), medium (MP) or low (LP) probability of leprosy or other dermatopathy (OD). Mycobacterium leprae-specific genes were detected using qPCR. The biopsies of 47 out of 57 clinically diagnosed patients who received multidrug therapy were classified as HP/MP, eight of which were qPCR negative. In the LP/OD (n = 19), two out of eight untreated patients showed positive qPCR results. In the absence of typical histopathological features, qPCR may be utilised to aid in final patient diagnosis, thus reducing overtreatment and delay in diagnosis.

Diagnostic challenges of single plaque-like lesion paucibacillary leprosy

The diagnosis of single-lesion paucibacillary leprosy remains a challenge. Reviews by expert dermatopathologists and quantitative polymerase chain reaction (qPCR) results obtained from 66 single-plaque biopsy samples were compared. Histological findings were graded as high (HP), medium (MP) or low (LP) probability of leprosy or other dermatopathy (OD). Mycobacterium leprae-specific genes were detected using qPCR. The biopsies of 47 out of 57 clinically diagnosed patients who received multidrug therapy were classified as HP/MP, eight of which were qPCR negative. In the LP/OD (n = 19), two out of eight untreated patients showed positive qPCR results. In the absence of typical histopathological features, qPCR may be utilised to aid in final patient diagnosis, thus reducing overtreatment and delay in diagnosis.

Hybrid Clinical and Histopathological Pattern in Annular Lesions: An Overlap between Annular Elastolytic Giant Cell Granuloma and Granuloma Annulare?

Annular elastolytic giant cell granuloma (AEGCG) is a rare granulomatous skin disease of unclear pathogenesis which belongs to the group of disorders in the skin and elastic fibers with similar clinical features of granuloma annulare (GA). This case report is intended to describe a rare hybrid pattern in histopathology demonstrating coexistence of AEGCG and GA. An endocrine disease, such as diabetes mellitus (DM), could contribute to the coexistence of both lesions, and this possibility must be included in the medical investigation.

Eritema multiforme na hanseníase: uma reação tipo II. Estudo histo-morfométrico da vasculopatia do quadro reacional / ?

Lesões cutâneas tipo Eritema Multiforme (EM) são incomuns no curso da hanseníase e podem trazer dificuldades no diagnóstico, contribuindo para a demora do tratamento do episódio reacional e para complicações debilitantes devidas à neuropatia periférica. Com o objetivo de caracterizar clinica e morfologicamente essas lesões, 27 biópsias cutâneas de pacientes clinicamente diagnosticados com EM, foram analisados por técnicas histológicas de rotina, por método imunohistoquímico e por estudo morfométrico da microvasculatura e comparadas com dados obtidos das biópsias de lesões não reacionais dos mesmos pacientes colhidas antes do tratamento. Nossos resultados mostraram que o acometimento cutâneo no EM é superficial, com espessamento epidérmico, raras bolhas subepidérmicas, edema intenso da derme superior, infiltração inflamatória perivascular, contendo invariavelmente neutrófilos. Os vasos dérmicos sofrem alterações funcionais com edema e infiltração da parede, dissociação das fibras elásticas, dilatação e congestão, sem necrose fibrinóide, nem leucocitoclasia. O exame imuno-histoquímico revelou, durante a reação, expressão de HLA-DR e ICAM-1 pelos quaratinócitos e aumento do número de células CD1+. Na derme, além do predomínio de linfócitos CD4+ sobre os linfócitos CD8+, foram numerosas as élulas TNF-alfa+. O estudo morfométrico revelou, durante a reação, aumento significativo do número de vasos sangüineos dérmicos e da área total ocupada pelos vasos, quando comparados com vasos da biopsia pré-reacional dos mesmos pacientes. Esses achados sugerem que a análise morfológica e o estudo dos parâmetros teciduais da resposta imune avaliados por imuno-histoquímica e resposta vascular em biópsias cutâneas contribuem para o entendimento da imunopatogenia das vasculites imunologicamente induzidas e corrobaram a hipótese do envolvimento de citocinas imuno-inflamatórias suscitando os estados reacionais da hanseníase. Além disso, a freqüência de EM como primeira manifestação da hanseníase justifica o exame baciloscópico da linfa coletada da lesão, em todos os pacientes, tendo em vista o grau de magnitude da endemia em nosso país.

Envolvimento ganglionar na hanseníase virchowiana: a propósito de um caso de reaçäo hansênica simulando linfogranuloma venéreo / Lymphnode involvement in lepromatous leprosy: considerations on a case of leprotic reaction simulating lymphogranuloma venereum

A apresentaçäo clínica da hanseníase e sua exteriorizaçäo reacional foge, muitas vezes, do padräo habitual, fazendo com que profissionais da área de saúde confundam o diagnóstico. Os autores apresentam um caso de hanseníase que se manifestou em seu período reacional com acometimento ganglionar extenso induzindo ao diagnóstico diferencial com o linfogranuloma venéreo. A análise histopatológica do gânglio inguinal demonstrou grande quantidade de bacilos álcool-ácido resistentes. Após a introduçäo da talidomida, na dose de 300mg/dia, houve regressäo rápida e significativa do quadro reacional ganglionar, corroborando o diagnóstico histopatólogico

Parametros morfologicos e imunohistoquimicos da resposta imune celular na hanseniase: -na forma borderlinhe lepromatosa -na reaçao tipo II ou eritema nodoso leprotico / ?

Foram estudados, ao microscopio otico, os aspectos morfologicos e imunohistoquimicos de 18 biopsias de lesões cutaneas de Hanseniase, sendo: 8 casos, não tratados, da forma "borderline" lepromatosa e 10 casos de quadros reacionais do tipo II ou Eritema Nodoso Leprotico. Ao contrario do que se observou, na form/ multibacilar, todos os casos de reação exibiam a epiderme espessada, ausencia de faixa Unna, edema intersticial dermico, presença de quantidade variavel de leucocitos polimorfonucleares e alterações vasculares proeminentes. Dentre estas, a mais frequente foi a permeação da parede por edema e celulas inflamatorias, com fragmentação da camada elastica nas arteriolas e arterias de pequeno calibre. A necrose fibrinoide da parede vascular não foi vista em nenhum caso. Ao exame imunohistoquimico, as alterações epidermicas foram representadas, principalmente, pelo aumento total de celulas de Langerhans e pela expressão de HLA-DR, pelos queratinocitos, em 50% dos casos. Na derme. o infiltrado inflamatorio exibia maior densidade de linfocitos T, com predominio de celulas CD4 positivas. Esses achados sugerem uma recuperação parcial e temporaria, durante o episodio reacional, da imunidade celular especifica para o M. leprae e abrem novas perspectivas para um possivel papel das citocinas na patogenese do Eritema Nodoso Leprotico.