scholarly journals Keratinocytes and Activation of TREM-1 Pathway in Cutaneous Leishmaniasis Lesions

2021 ◽  
Vol 12 (4) ◽  
pp. 765-778
Author(s):  
Sara Nunes ◽  
Mariana Rosa Ampuero ◽  
Ícaro Bonyek-Silva ◽  
Reinan Lima ◽  
Filipe Rocha Lima ◽  
...  
Keyword(s):  
Immune Response ◽  
Cutaneous Leishmaniasis ◽  
Tissue Damage ◽  
Inflammatory Diseases ◽  
Critical Role ◽  
Human Keratinocytes ◽  
Skin Lesions ◽  
Leishmania Braziliensis ◽  
Adapter Protein ◽  
Skin Cells

Triggering Receptor Expressed on Myeloid Cells 1 (TREM-1) amplifies the immune response, operating synergistically with Toll-Like Receptors (TLRs) in the production of inflammatory mediators. TREM-1 signaling depends on the adapter protein DAP12, which results in the activation of NFkB, the expression of inflammatory genes, and the release of antimicrobial peptides, such as Beta-defensin 2. We evaluated the activation of the TREM-1 signaling pathways in Cutaneous Leishmaniasis (CL) caused by Leishmania braziliensis and linage human keratinocytes exposed to these parasites since the host immune response against Leishmania plays a critical role in promoting parasite killing but also participates in inflammation and tissue damage. We analyzed publicly available transcriptome data from the lesions of CL patients. In the CL biopsies, we found increased expression of the molecules involved in the TREM-1 pathway. We then validated these findings with RT-qPCR and immunohistochemistry in newly obtained biopsies. Surprisingly, we found a strong labeling of TREM-1 in keratinocytes, prompting the hypothesis that increased TREM-1 activation may be the result of tissue damage. However, increased TREM-1 expression was only seen in human lineage keratinocytes following parasite stimulation. Moreover, no up-regulation of TREM-1 expression was observed in the skin lesions caused by other non-infectious inflammatory diseases. Together, these findings indicate that L. braziliensis (Lb) induces the expression of the TREM-1 receptor in tissue keratinocytes regardless of tissue damage, suggesting that non-immune skin cells may play a role in the inflammatory response of CL.

scholarly journals Blockade of TLR2 and TLR4 Attenuates Inflammatory Response and Parasite Load in Cutaneous Leishmaniasis

2021 ◽  
Vol 12 ◽  
Author(s):  
Pedro Paulo Carneiro ◽  
Andreza S. Dórea ◽  
Walker N. Oliveira ◽  
Luiz Henrique Guimarães ◽  
Claúdia Brodskyn ◽  
...  
Keyword(s):  
Immune Response ◽  
Inflammatory Response ◽  
Cutaneous Leishmaniasis ◽  
Parasite Load ◽  
Skin Lesions ◽  
Innate Immune ◽  
Leishmania Braziliensis ◽  
Infected Cells ◽  
Host Inflammatory Response ◽  
Human Cutaneous Leishmaniasis

Human cutaneous leishmaniasis (CL) caused by Leishmania braziliensis is characterized by a pronounced inflammatory response associated with ulcer development. Monocytes/macrophages, the main cells harboring parasites, are largely responsible for parasite control. Toll-like receptor (TLR) signaling leads to the transcription of inflammatory mediators, such as IL-1β and TNF during innate immune response. TLR antagonists have been used in the treatment of inflammatory disease. The neutralization of these receptors may attenuate an exacerbated inflammatory response. We evaluated the ability of TLR2 and TLR4 antagonists to modulate host immune response in L. braziliensis-infected monocytes and cells from CL patient skin lesions. Following TLR2 and TLR4 neutralization, decreased numbers of infected cells and internalized parasites were detected in CL patient monocytes. In addition, reductions in oxidative burst, IL-1β, TNF and CXCL9 production were observed. TNF production by cells from CL lesions also decreased after TLR2 and TLR4 neutralization. The attenuation of host inflammatory response after neutralizing these receptors suggests the potential of TLR antagonists as immunomodulators in association with antimonial therapy in human cutaneous leishmaniasis.

scholarly journals CD52 is a prognostic biomarker and correlated with immune features in breast cancer

2020 ◽  
Author(s):  
Jianxin Wang ◽  
Yang Liu ◽  
Zhuowen Yang ◽  
Yang Sui ◽  
Jie Tian ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Immune Response ◽  
Clinical Data ◽  
Inflammatory Diseases ◽  
Critical Role ◽  
Aggressive Cancer ◽  
Immunotherapy Target ◽  
Tcga Dataset ◽  
Prognostic Prediction ◽  
The Relationship

Abstract Background: Breast cancer (BRCA) is the most commonly diagnosed cancer of women, which is aggressive cancer and has a mortality rate. CD52 and its monoclonal antibody (Alemtuzumab) play a critical role in inflammatory diseases, but the relationship between CD52 and BRCA is not clear.Methods: We first used the random forest algorithm to find the most critical genes related to the prognosis of BRCA patients. Then, according to the analysis of RNA sequence and clinical data of the TCGA dataset, we explored the relationship between CD52 with immune response-related pathways and immune metagenes. The pan-cancer analysis shows the importance of CD52 in a variety of tumorsResults:CD52 was related to the prognosis of BRCA patients (p < 0.001). Subsequent analysis based on RNA-seq and clinical data from the TCGA dataset revealed that CD52 is positively correlated with immune response-related pathways and immune metagenes. TIMER analysis showed that CD52 expression was positively correlated with immune infiltrating levels of B, CD4+ T, and CD8+ T cells, macrophages, neutrophils, and dendritic cells (DCs) in BRCA (r = 0.466, r = 0.645, r = 0.483, r = 0.149, r= 0.542,r = 0.665, respectively; p < 0.001). CpG sites (cg16068833, cg19743891, cg19743891, cg16664472, cg19677267, cg22517705, and cg27430637) were negatively correlated with CD52 expression (r = -0.662, r = -0.629, r =- 0.598, r = -0.519, r= -0.492, r = -0.445, respectively; p < 0.001). Furthermore, the expression of CD52 was significantly correlated with the following pathological stages (T stage, N stage, and survival state; p=0.024, p=0.047, and p=0.007, respectively). The results of the pan-cancers study suggest that CD52 may play an important role in the occurrence, development, and prognosis of multiple tumors.Conclusions: These findings suggested that CD52 is a promising immunotherapy target and prognostic prediction value for BRCA.

scholarly journals Involvement of the Inflammasome and Th17 Cells in Skin Lesions of Human Cutaneous Leishmaniasis Caused by Leishmania (Viannia) panamensis

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
K. Gonzalez ◽  
J. E. Calzada ◽  
C. E. P. Corbett ◽  
A. Saldaña ◽  
M. D. Laurenti
Keyword(s):  
Immune Response ◽  
Cutaneous Leishmaniasis ◽  
Th17 Cells ◽  
Inverse Correlation ◽  
Skin Lesions ◽  
Leishmania Infection ◽  
Caspase 1 ◽  
Immunological Markers ◽  
Th2 Immune Response ◽  
Skin Biopsies

Localized cutaneous leishmaniasis (LCL) caused by Leishmania (Viannia) panamensis is an endemic disease in Panama. This condition causes ulcerated skin lesions characterized by a mixed Th1/Th2 immune response that is responsible for disease pathology. However, the maintenance of the in situ inflammatory process involves other elements, such as Th17 and inflammasome responses. Although these processes are associated with parasite elimination, their role in the increase in disease pathology cannot be discarded. Thus, the role in Leishmania infection is still unclear. In this sense, the present study aimed at characterizing the Th17 and inflammasome responses in the skin lesions of patients with LCL caused by L. (V.) panamensis to help elucidate the pathogenesis of this disease in Panama. Th17 and inflammasome responses were evaluated by immunohistochemistry (IHQ) in 46 skin biopsies from patients with LCL caused by L. (V.) panamensis. The Th17 immune response was assessed using CD3, CD4, RoRγt, IL-17, IL-6, IL-23, and TGF-β1 antibodies, and the inflammasome response was assessed by IL-1β, IL-18, and caspase-1 antibodies. The presence of the Th17 and inflammasome responses was evidenced by a positive reaction for all immunological markers in the skin lesions. An inverse correlation between the density of amastigotes and the density of RoRγt+, IL-17+, IL-1β+, and caspase-1+ cells was observed, but no correlation between Th17 and the inflammasome response with evolutionary disease pathology was reported. These data showed the participation of Th17 cells and the inflammasome in the inflammatory response of the skin lesions of LCL caused by L. (V.) panamensis infection. These results suggest a role in the control of tissue parasitism of IL-17 and the activation of the NLRP3 inflammasome dependent on IL-1β but cannot exclude their role in the development of disease pathology.

scholarly journals Importance of IL-10 Modulation by Probiotic Microorganisms in Gastrointestinal Inflammatory Diseases

2011 ◽  
Vol 2011 ◽  
pp. 1-11 ◽  
Author(s):  
Alejandra de Moreno de LeBlanc ◽  
Silvina del Carmen ◽  
Meritxell Zurita-Turk ◽  
Clarissa Santos Rocha ◽  
Maarten van de Guchte ◽  
...  
Keyword(s):  
Immune Response ◽  
Inflammatory Cytokine ◽  
Inflammatory Diseases ◽  
Critical Role ◽  
Genetically Engineered ◽  
Wide Range ◽  
Prevention And Treatment ◽  
Therapeutic Properties ◽  
Anti Inflammatory Cytokine

Lactic acid bacteria (LAB) represent a heterogeneous group of microorganisms that are naturally present in many foods and possess a wide range of therapeutic properties. The aim of this paper is to present an overview of the current expanding knowledge of one of the mechanisms by which LAB and other probiotic microorganisms participate in the prevention and treatment of gastrointestinal inflammatory disease through their immune-modulating properties. A special emphasis will be placed on the critical role of the anti-inflammatory cytokine IL-10, and a brief overview of the uses of genetically engineered LAB that produce this important immune response mediator will also be discussed. Thus, this paper will demonstrate the critical role that IL-10 plays in gastrointestinal inflammatory diseases and how probiotics could be used in their treatment.

scholarly journals Evaluation of Regulatory Immune Response in Skin Lesions of Patients Affected by Nonulcerated or Atypical Cutaneous Leishmaniasis in Honduras, Central America

2018 ◽  
Vol 2018 ◽  
pp. 1-7 ◽  
Author(s):  
Gabriela Venicia Araujo Flores ◽  
Carmen Maria Sandoval Pacheco ◽  
Thaise Yumie Tomokane ◽  
Wilfredo Sosa Ochoa ◽  
Concepción Zúniga Valeriano ◽  
...  
Keyword(s):  
Immune Response ◽  
Cutaneous Leishmaniasis ◽  
Central America ◽  
Normal Skin ◽  
Skin Lesions ◽  
Moderate Correlation ◽  
Inflammatory Infiltration ◽  
Histological Techniques ◽  
Cellular Immune

In Honduras, Leishmania (L.) infantum chagasi causes both visceral leishmaniasis (LV) and nonulcerated or atypical cutaneous leishmaniasis (NUCL). NUCL is characterized by mononuclear inflammatory infiltration of the dermis, composed mainly of lymphocytes followed by macrophages with discrete parasitism. Considering that little is known about the pathogenesis of NUCL, the aim of this study was to evaluate the regulatory response in situ in skin lesions of patients affected by NUCL. Biopsies (n=20) from human cutaneous nonulcerative lesions were collected and processed by usual histological techniques. The in situ regulatory immune response was evaluated by immunohistochemistry using antihuman CD4, FoxP3, IL-10, and TGF-β antibodies. CD4+, FoxP3+, TGF-β+, and IL-10+ cells were observed in the dermis with inflammatory infiltration in all studied cases and at higher densities compared to the normal skin controls. A positive and strong correlation was observed between CD4+ and FoxP3+ cells, and a positive and moderate correlation was observed between FoxP3+ and TGF-β+ but not with IL-10+ cells. The data suggest that T regulatory FoxP3+ cells and the regulatory cytokines, especially TGF-β, play an important role in the immunopathogenesis of NUCL, modulating a cellular immune response in the skin, avoiding tissue damage, and leading to low tissue parasitic persistence.

scholarly journals Spontaneous regional heading of extensive skin lesions in diffuse cutaneous leishmaniasis (DCL)

1995 ◽  
Vol 28 (1) ◽  
pp. 45-47 ◽  
Author(s):  
Jackson M.L. Costa ◽  
Ana Cristina R. Saldanha ◽  
Conceição de Maria P. e Silva ◽  
Maria dos Remédios F.C. Branco ◽  
Aldina Barrai ◽  
...  
Keyword(s):  
Immune Response ◽  
Cutaneous Leishmaniasis ◽  
Cellular Immune Response ◽  
Skin Lesions ◽  
In Situ Characterization ◽  
Spontaneous Healing ◽  
Specific Therapy ◽  
Mucosal Involvement ◽  
Cellular Immune

The authors report a case of diffuse cutaneous leishmaniasis, with longstanding evolution and presenting with diffuse infiltrated lesions rich in amastigotes in the absence of mucosal involvement. In situ characterization with monoclonal antibodies revealed Leishmania amazonensis. Large regional lesions have presented spontaneous healing without specific therapy. Considering that DCL presents with a defect in the cellular immune response, thisfact demonstrate that this patient may develop a regional cellular immune response enough to destroy the parasites and to produce clearing of some lesions.

Salvia plebeia Suppresses Atopic Dermatitis-Like Skin Lesions

2014 ◽  
Vol 42 (04) ◽  
pp. 967-985 ◽  
Author(s):  
Jin Kyeong Choi ◽  
Hyun-Mee Oh ◽  
Soyoung Lee ◽  
Taeg Kyu Kwon ◽  
Tae-Yong Shin ◽  
...  
Keyword(s):  
Atopic Dermatitis ◽  
Inflammatory Diseases ◽  
Human Keratinocytes ◽  
Nuclear Factor Κb ◽  
Skin Lesions ◽  
Mechanisms Of Action ◽  
Histopathological Analysis ◽  
Cytokines And Chemokines ◽  
Mitogen Activated Protein ◽  
Underlying Mechanisms

Salvia plebeia R. Br. (Lamiaceae) has been used for folk medicines in Asian countries, including Korea and China, to treat skin inflammatory diseases and asthma. In this study, we investigated the effects of S. plebeia extract (SPE) on atopic dermatitis (AD)-like skin lesions and defined underlying mechanisms of action. We established an AD model in BALB/c mice by repeated local exposure of house dust mite extract (Dermatophagoides farinae extract, DFE) and 2,4-dinitrochlorobenzene (DNCB) to the ears. Repeated alternative treatment of DFE/DNCB caused AD-like skin lesions. The oral administration of SPE decreased AD symptoms based on ear thickness and histopathological analysis, in addition to serum IgE and IgG2a levels. SPE suppressed mast cell infiltration into the ear and serum histamine level. SPE inhibited Th1/Th2/Th17 phenotype CD4+ T lymphocytes expansion in the lymph node and the expression of Th1/Th2/Th17 cytokines in the ear tissue. To define the underlying mechanisms of action, the tumor necrosis factor (TNF)-α and interferon (IFN)-γ activated human keratinocytes (HaCaT) model was used. SPE significantly suppressed the expression of cytokines and chemokines through the down-regulation of mitogen-activated protein kinases, nuclear factor-κB, and STAT1 in HaCaT cells. Taken together, our results suggest that SPE might be a candidate for the treatment of AD.

scholarly journals Transkriptomik Veri Yaklaşımı ile Kutanöz Leyşmanyazisteki Moleküler Sinyal Yolakların ve Regülatör Moleküllerin Tanımlanması

2021 ◽  
Vol 55 (1) ◽  
pp. 67-80
Author(s):  
Özlem Ulusan Bağcı ◽  
Ayşe Caner
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Cutaneous Leishmaniasis ◽  
Ingenuity Pathway Analysis ◽  
Pathway Analysis ◽  
Leishmania Major ◽  
Parasite Species ◽  
Host Immune Response ◽  
Leishmania Braziliensis ◽  
Leishmania Spp

Leishmaniasis is a disease caused by the genus Leishmania spp., which are intracellular parasites. Depending on parasite species and host immune response, there are three basic clinical forms of the disease: cutaneous, mucocutaneous, and visceral leishmaniasis. Cutaneous leishmaniasis is a chronic disease and characterized by the presence of ulcerated skin lesions. The type of skin pathology seen during disease is determined in part by the infecting Leishmania spp., but also by a combination of inflammatory and antiinflammatory host immune response factors resulting in diverse clinical outcomes. In this study, it was aimed to determine the genes, molecular signaling mechanisms and biological functions of the molecules that play a role in the pathogenesis of the disease and immune response and determine host-parasite interactions in mice that are naturally resistant and susceptible to Leishmania major and Leishmania braziliensis. For this, transcriptomic series GSE56029 was downloaded from “Gene Expression Omnibus” (GEO) data base, including expression profiling of twenty-four tissue samples that were recovered from both naive mice and mice (BALB/c, C57BL/6) infected with L.major and L.braziliensis. Then, “Differentially Expressed Genes” (DEGs) were identified by limma package in R script. FDR q< 0.05 and absolute log2FC> 2 as threshold values were accepted in the analysis. Subsequently, functional and pathway enrichment analyses were performed for the DEGs by “Ingenuity Pathway Analysis” (IPA). For each of DEGs, p< 0.01, FDR q< 0.01, and absolute log2FC> 1 were used and analyzed with the software program IPA 8.0. Ingenuity Pathway Analysis revealed the most enrichment pathways to be the inflammation, dendritic cell maturation and “Triggering Receptor Expressed on Myeloid Cells 1” (TREM-1) signal mechanisms and that the DEGs related to the regulation of immune system process were closely associated with the progress of cutaneous leishmaniasis. The upstream regulator analysis predicted that TNF-α, IFNy, IL-1 β, IL-10RA and “Signal Transducer and Activator of Transcription-1” (STAT-1) are the regulators that explained gene expression changes causing biological activities in the tissues. Chemical compounds that may have anti-leishmanial effects were also identified in the study. In this study, the mechanisms belonging to the parasite species and host that determine the resistance/susceptibility phenotype were attempted to elucidate. Assessment of gene expression patterns, cytokine/chemokines, and signaling pathways in BALB/c and C57BL/6 mice infected with L.major and L.braziliensis will provide a better understanding of the potential mechanisms underlying infection from a genetic perspective. These results may guide for the future studies in terms of developing potential biomarkers for the diagnosis and prognosis prediction of cutaneous leishmaniasis and providing information about new treatment targets.

scholarly journals American cutaneous leishmaniasis: presentation and problems of patient management

1988 ◽  
Vol 21 (4) ◽  
pp. 165-172 ◽  
Author(s):  
Jeffrey D. Chulay ◽  
Charles N. Oster ◽  
Patrick B. McGreevy ◽  
Larry D. Hendricks ◽  
Richard D. Kreutzer
Keyword(s):  
Cutaneous Leishmaniasis ◽  
Incubation Period ◽  
Patient Management ◽  
Leishmania Donovani ◽  
Skin Lesions ◽  
Medical Attention ◽  
Leishmania Braziliensis ◽  
Leishmania Mexicana ◽  
American Cutaneous Leishmaniasis ◽  
The Mean

We report our experience with the diagnosis and treatment of 60 patients with American cutaneous leishmaniasis. They were infected in Panama (55), Brazil (4) or Colombia (I). Among 35 patients with a 3 week exposure in Panama, the mean maximum incubation period was 33 days (range 4-81 days). Diagnosis was delayed an average of 93 days after onset of skin lesions, due to the patient's delay in seeking medical attention (31 days), medical personnel's delay in considering the diagnosis (45 days), and the laboratory's delay in confirming the diagnosis (17 days). Forty-four patients (73%) developed ulcers typical of cutaneous leishmaniasis. Sixteen additional patients (27%) had atypical macular, papular, squamous, verrucous or acneiform skin lesions that were diagnosed only because leishmanial cultures were obtained. Of the 59 patients treated with pentavalent antimonial drugs, only 34 (58%) were cured after the first course of treatment. Lesions which were at least 2 cm in diameter, ulcerated, or caused by Leishmania braziliensis were less likely to be cured after a single course of treatment than were lesions smaller than 2 cm, nonulcerated or caused by Leishmania mexicana or Leishmania donovani.

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