Immunoregulatory mechanisms and CD4−CD8− (double negative) T cell subpopulations in human cutaneous leishmaniasis: A balancing act between protection and pathology (2023)

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  • Cited by (41)
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International Immunopharmacology

Volume 8, Issue 10,

October 2008

, Pages 1338-1343

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Cellular immune responses directed against protozoan parasites are key for controlling pathogen replication and disease resolution. However, an uncontrolled, or improperly controlled, response can be deleterious to the host in terms of both allowing for the establishment of pathology, as well as less effective establishment of memory responses. Human cutaneous leishmaniasis is a disease caused by the infection with Leishmania spp. following a bite from the sandfly, the natural vector of this disease. Tens of millions worldwide are currently infected with Leishmania and no effective vaccines have been developed to date. In the face of the complexity presented by the interaction between a host (humans) with the parasite, Leishmania, and the fact that this parasite is inoculated by another complex, biologically active, vector, the sandfly, it is clearly important to study the immunoregulatory mechanisms that are induced in humans naturally infected by this parasite if we hope to develop effective vaccines and immunotherapeutic treatments in the future. Our laboratory has focused over the years on the study of the local and systemic T cell response during the first episode of cutaneous leishmaniasis suffered by individuals before they undergo antimony treatment. The goal of this review is to briefly outline our findings with hopes of putting our most recent studies concerning the dichotomy between alpha/beta TCR and gamma/delta TCR expressing, CD4−CD8− (double negative—DN) T cells in the context of a balanced immune response against Leishmania and to discuss the implications of these findings toward our understanding of human leishmaniasis.

Section snippets

Human leishmaniasis — a complex disease resulting from the host–parasite–vector interaction

Human leishmaniasis is caused by the infection with the obligate intracellular protozoan parasite, Leishmania, and is expressed as one or more of several possible clinical forms including principally the visceral and tegumentary diseases (localized cutaneous, mucosal or disseminated) [1]. Several factors influence the progression of an infected individual into these clinical forms of disease including, but not limited to, host genetics (protective and susceptibility factors), host environment

Protection vs. pathology vs. memory…a three-way balancing act

The study of the cellular immune response and determination of cytokine profiles in both murine models and in humans has been determined over the years through the application of a number of quantitative and semi-quantitative methodologies. These methods have ranged from single-cell cytoplasmic staining of cytokines within specific cell populations to ELISA from culture supernatants or body fluids, and quantitative PCR. In tissues investigators have used in situ detection of cytokines by

CD4−CD8− (double negative—DN) T cells in human cutaneous leishmaniasis: alpha/beta DN T cells likely have a role in protection and pathology, while gamma/delta DN T cells could play a more important role in negative regulation

In addition to classic CD4+ and CD8+ T cells, there is a minority subpopulation of T cells that express neither CD4 nor CD8, thus termed double negative (DN) T cells. Within this DN T cell population several subpopulations can be found. In the broad sense, they contain T cells expressing either the gamma/delta or alpha/beta TCR, and within each of these populations, several subpopulations can be defined. Amongst the alpha/beta TCR DN T cells in humans, studies have identified cells of both


We would like to thank the collaboration over the past ten years of Dr. Edgar Carvalho and his group at Hospital Edgard Santos, UFBA, in Salvador, Bahia, Brazil, without which the studies described in this overview of our work would not have been possible. We would also like to thank the following funding agencies for support of our work over the years: WHO/TDR, CNPq, FINEP, FAPEMIG, and NIH-NIAID.

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    • Host's immune response in unresponsive and responsive patients with anthroponotic cutaneous leishmaniasis treated by meglumine antimoniate: A case-control study of Th1 and Th2 pathways

      2019, International Immunopharmacology

      Citation Excerpt :

      Generally, the disease susceptibility in uncontrolled or non-healed infections has been related to Th2 proliferation and production of IL-4, IL-5 and IL-10. In contrast, healing responses and resistance to infection have been associated with expansion of IFN-γ-producing Th1 cells [18–21]. T-cell responses in individuals with mild infection involve a mixture of Th1 and Th2, whereas patients with exacerbating disease show an absence of Th1 response to specific Leishmania antigens.

      The objective of the present study was to compare the host's immune responses between unresponsive and responsive patients with anthroponotic cutaneous leishmaniasis (ACL) treated by meglumine antimoniate.

      A case-control study was carried out in an endemic focus in Iran. Blood samples were taken from patients and peripheral blood mononuclear cells (PBMCs) were isolated. Two wells were considered for each isolate of unresponsive and responsive patients; one was exposed to L. tropica (Lt-stimulated cells) and the other remained non-exposed (non-stimulated cells). After 24 h of incubation, whole RNA was extracted from each sample. Real-time quantitative PCR was carried out to confirm the differences in expression levels of IL-12 P40, IFN-γ, IL-1β, IL-4 and IL-10 among isolates. Data were analyzed and P < 0.05 was considered to be statistically significant.

      In our study, Lt-stimulated cells and non-stimulated cells in unresponsive groups demonstrated significantly lower expression levels of IL-1β, IL-12 P40 and IFN-γ genes and higher expression levels of IL-4 and IL-10 genes, compared to Lt-stimulated cells and non-stimulated cells in responsive groups. There was a negative correlation between IL-12 P40 with IL-10 and IL-1β with IL-10 in ACL Lt-stimulated cells in unresponsive group, while a positive correlation between IL-12 P40 with IL-1β and IL-12 P40 with IFN-γ in ACL Lt-stimulated cells in responsive group.

      Probably, different immune responses caused by various factors play a major role in the pathogenesis and development of unresponsiveness in ACL patients. The profile and timing of cytokine production correlated well with the treatment outcome of Leishmania infection.

    • Gene expression profile of cytokines produced in biopsies from patients with American cutaneous leishmaniasis

      2019, Acta Tropica

      American cutaneous leishmaniasis (ACL) causes a local inflammatory process, inducing expression of several cytokine genes. Particularly, IFN-γ can predict to disease susceptibility. Based in these data, this study was aimed to investigate the gene expression profile of IFN-γ, IL-10, IL-27, TNF-γ, TGF-β and IL-6 produced in biopsies from ACL patients; and whether the gene expression profile of IFN-γ could determine the disease evolution. Gene expression of 6 cytokines was investigated in 40 formalin-fixed paraffin embedded (FFPE) biopsies from patients with cutaneous leishmaniosis (CL); and 10 FFPE biopsies from patients with mucosal leishmaniasis (ML) (control). All 50 patients were infected with Leishmania (Viannia) braziliensis. Gene expression was determined by qPCR; and a normal control group was used for calculations (5 normal biopsies). Values were expressed as Relative Quantification (RQ). The 40 CL patients were classified into 2 groups. CLlowIFN-γ, 35 patients with RQ for IFN-γ below 100; and CLhighIFN-γ, 5 (12.5%) patients with RQ above 100. Significant increase of mRNA levels of IFN-γ, IL-10 and IL-27 was shown in CLhighIFN-γ group when compared with CLlowIFN-γ and ML groups. TNF-α levels in CLlowIFN-γ group were higher than CLhighIFN-γ and ML groups. TGF-β and IL-6 were similar in 3 groups. Comparison of cytokine expression/group showed that CLlowIFN-γ group had an equilibrium between the cytokines analyzed. In ML group, IFN-γ was over-expressed; but in CLhighIFN-γ group, besides IFN-γ, IL-27 was also over-expressed. The immune response to Leishmania induces to identification of some markers, which can be determined by analysis by gene expression of cytokines produced in biopsies.

    • Immunization with Leishmania donovani protein disulfide isomerase DNA construct induces Th1 and Th17 dependent immune response and protection against experimental visceral leishmaniasis in Balb/c mice

      2017, Molecular Immunology

      Citation Excerpt :

      Subsequently, patients develop various clinical conditions such as splenomegaly, pancytopenia, anemia, and disseminated hemorrhages (Murray et al., 2005). Two distinct lineages of T-cells, namely CD4 + Th1 andCD4 + Th17, are responsible for the controlled and programmed immune response mediated against Leishmania and supported by various cytokines (such as interleukin-2 [IL-2], interferon-γ[IFN-γ], IL-6, and the tumor necrosis factor [TNF]), and chemokine(such as CXCL8 [also known as IL-8], CXCL10 [also known as IP-10], CXCL1, and CXCL6; Bhattacharya and Ali, 2013; Sanjabi et al., 2009; Gollob et al., 2008). The Th1 group of CD4+ T cells counters Leishmania infection within macrophages in an infected spleen and liver through support from IL-12, IL-2, IFN-γ, etc.

      In the present study, the efficacy of Leishmania donovani protein disulfide isomerase (LdPDI) as a DNA vaccine was evaluated in BALB/C mice. Mice immunized with the LdPDI-DNA construct were found to be the most immuno-reactive, as the construct induced higher T-cell proliferation. The increased T-cell proliferation was associated with a substantial rise in Th1 and Th17+ CD4 cell response and triggered a higher proportion of CD8+ T cells for the release of interferon-gamma along with a reduced splenic parasite load on Days20 and 60 post challenge (PC). Furthermore, the vaccine construct triggered increased interferon (IFN)-γ, interleukin(IL)-17A, and IL-22 release accompanied by decreased extracellular signal-regulated kinases (ERK) 1/2 signaling and increased mitogen-activated protein kinase (MAPK) signaling coinciding with an increase in the amount of nitrite and reactive oxygen species (ROS)in vaccinating the splenocyts. We summarize from our data that the PDI-DNA construct of Leishmania donovani has the potential to elicit protective immunity through the pro-inflammatory cytokines of CD8+ and CD4+(Th1 and Th17) following an intervention in the downstream signaling event of ERK1/2 (probably through p38MAPK signaling). Therefore, the study suggests a new control against visceral leishmaniasis in the future.

    • American tegumentary leishmaniasis: mRNA expression for Th1 and Treg mediators are predominant in patients with recent active disease

      2016, Immunobiology

      Citation Excerpt :

      In humans, the spectrum of the disease may vary from subclinical infection to manifestations such as localized, disseminated or diffuse cutaneous lesions, or even the involvement of the nasal mucosa, pharynx and larynx. In all these possibilities, the expansion of T helper cells exerts a fundamental influence (Gollob et al., 2008). Classically, a Th1 profile is responsible for producing interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α), which activates the inducible nitric-oxide synthase (iNOS) to catalyze NO secretion by macrophages, eliminating the parasite.

      Besides the Th1×Th2 paradigm, Treg and Th17 cytokines may play a role in the response to American tegumentary leishmaniasis. Considering the sensitivity and accuracy of qPCR and the lack of studies using this approach, we evaluated mRNA expression for IFN-γ, TNF-α, IL-4, IL-10, IL-6, IL-17A, IL-22, TGF-β, Foxp3 and RORC in peripheral blood mononuclear cells (PBMC) from patients with active disease, after stimulation with L. (V.) braziliensis soluble or insoluble fractions. Our results show that the antigens promoted specific mRNA expression related to the immune response in patients with ATL, and the insoluble fraction seems to stimulate the immune response in a higher intensity. The pro-inflammatory response was also fueled by IFN-γ and TNF-α, probably due to the active disease. IL-4, in certain way, seems to regulate this response along with IL-10 that may be produced by Treg cells, which are supposedly present in the patients’ samples due the evidenced expression of Foxp3, in the presence of AgIns. In contrast, down-regulated RORC suggests that the significant levels of IL-6 expressed in response to AgSol were not able to induce an expressive Th17 profile along with TGF-β, which might have predominantly contributed to the development of a regulatory profile in the active disease.

    • Leishmania infection and neuroinflammation: Specific chemokine profile and absence of parasites in the brain of naturally-infected dogs

      2015, Journal of Neuroimmunology

      Citation Excerpt :

      Recently, different subsets of T lymphocytes gained focus on parasitic diseases, especially the double negative (DN) T cells, which express neither CD4 nor CD8, including αβ DN T cells, γδ DN T cells, NK T cells (D'Acquisto and Crompton, 2011). In cases of human cutaneous leishmaniasis, elevated numbers of circulating αβ DN T cells are described, associated with elevated production of IFN-γ and TNF-α and high levels of the activation markers CD69 and CD56 (Antonelli et al., 2006; Gollob et al., 2008). Further, the association between NK T cells and immune response during VL has already been studied in the liver of mice infected with L. donovani (Amprey et al., 2004).

      Visceral leishmaniasis is a chronic disease caused by Leishmania infantum. We aimed to detect the parasite in the brain of fifteen naturally-infected dogs using in situ hybridization and immunohistochemistry, and the gene expression of selected chemokines by RT-qPCR. We detected no parasite in the brain, but perivascular deposition of parasite DNA and IgG in the choroid plexus. We noticed up-regulation of CCL-3, CCL-4 and CCL-5, coherent with T lymphocyte accumulation, stating the brain as a pro-inflammatory environment. Indeed, not necessarily the parasite itself, but rather its DNA seems to act as a trigger to promote brain inflammation during visceral leishmaniasis.

    • Cytokines and NO in American tegumentary leishmaniasis patients: Profiles in active disease, after therapy and in self-healed individuals

      2013, Microbial Pathogenesis

      Citation Excerpt :

      According to the authors, susceptibility to the mucocutaneous form of disease may be directly associated with regulatory polymorphisms affecting TNF-α production. Besides the benefits of Th1 response, Gollob et al. [32] suggest that IL-10 production may be critical for the disease control. Thus, it is postulated that IL-10 levels presented by the patients in this study regulate the production of proinflammatory cytokines, consequently leading to the clinical resolution of the disease.

      Studies suggest the influence of immune response on the successful treatment of American tegumentary leishmaniasis (ATL), and indicate the existence of protective immunity in self-healed patients. Thus, the aim of this work was to quantify interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), interleukin (IL-) 10, IL-17, IL-22 and nitric oxide (NO) in culture supernatants of PBMC from patients with active disease (AD), after treatment (AT), and from self-healed (SH) and healthy subjects (CT), in response to Leishmania (Viannia) braziliensis insoluble antigen (AgIns). All groups of patients produced IFN-γ, indicating a predominant proinflammatory profile. AD and AT patients presented TNF-α levels, with a slight increase after therapy, whereas it was weakly quantified in SH. Interestingly, NO secretion was significant in these individuals, whereas IL-17 appeared in low levels and seems to be regulated by NO. Although IL-22 was detected in AD, its role is still questionable. The presence of IL-10 in all groups of patients suggests that the cytokine plays distinct roles in the disease. These results indicate that specific cellular immunity takes part against Leishmania, but with some similarities between the different clinical states herein described; these mediators seem to be necessary for the cure to occur.

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    What is the mechanism of immunity in leishmaniasis? ›

    Lymphocytes are involved in adaptive immune responses to Leishmania infection, primarily through the elaboration of cytokines that activate or dampen the antiparasitic activity of macrophages. It is well known that T cells play a major role in immunity to the various forms of Leishmania.

    What is the T cell response in leishmaniasis? ›

    Studies in the literature have shown the important role played by CD4 T cells in protection against human leishmaniasis by producing cytokines able to activate the macrophages that kill the parasites.

    Which immune response is host protective during Leishmania infection Th1 or Th2? ›

    The control of leishmanial infection is mediated by a Th1-type immune response, and experimental studies in murine models of CL have established a clear-cut dichotomy between Th1-mediated protection and Th2-mediated disease susceptibility (reviewed by Sacks & Noben-Trauth, 2002).

    Is it painful to have Leishmaniasis? ›

    The sores may start out as papules (bumps) or nodules (lumps) and may end up as ulcers (like a volcano, with a raised edge and central crater); skin ulcers may be covered by scab or crust. The sores usually are painless but can be painful.

    How can you protect yourself from getting infected with Leishmania? ›

    Apply insect repellent to exposed skin and under the ends of sleeves and pant legs.
    When indoors:
    1. Stay in well-screened or air-conditioned areas.
    2. Keep in mind that sand flies are much smaller than mosquitoes and therefore can get through smaller holes.
    3. Spray living/sleeping areas with an insecticide to kill insects.

    What is responsible for transmission of leishmaniasis? ›

    Leishmaniasis is transmitted by the bite of infected female phlebotomine sand flies. The sand flies inject the infective stage (i.e., promastigotes) from their proboscis during blood meals .

    Which cells of your body are infected by Leishmania? ›

    Although Leishmania parasites interact and infect a variety of host cell types, macrophages and dendritic cells (DCs) are arguably the most important cells that regulate the outcome of infection.

    What is CD4 T cell response? ›

    CD4+T cells are crucial in achieving a regulated effective immune response to pathogens. Naive CD4+T cells are activated after interaction with antigen-MHC complex and differentiate into specific subtypes depending mainly on the cytokine milieu of the microenvironment.

    What are the responses of T helper 2 cell? ›

    Abstract. T helper 2 (TH2) cells orchestrate protective type 2 immune responses, such as those that target helminths and facilitate tissue repair, but also contribute to chronic inflammatory diseases, such as asthma and allergy.

    What is Th1 Th2 response in autoimmune disease? ›

    Th1 cells promote cellular immunity and are involved in the development of autoimmune diseases; Th2 cells mediate humoral immunity and are involved in allergic immune responses.

    What is the difference between Th1 and Th2 response leishmaniasis? ›

    Th1-type cellular immune responses play an important role in defense against infection with Leishmania parasites, whereas activation of Th2-type cells results in progressive disease (4, 5).

    What is the difference between Th1 and Th2 in Leishmania? ›

    Th1 and Th2 cells can be distinguished by the cytokines they secrete: Th1 cells secrete activators of cell-mediated immunity such as interferon (IFN)-γ, while Th2 cells secrete cytokines such as interleukin (IL)-4 which promote antibody responses.

    What is the most severe form of Leishmania? ›

    There are three main forms of the disease: cutaneous leishmaniasis (CL), visceral leishmaniasis (VL), also known as kala-azar, and mucocutaneous leishmaniasis (MCL). CL is the most common form, VL is the most severe form and MCL is the most disabling form of the disease.

    What is the most serious form of leishmaniasis? ›

    Visceral leishmaniasis (VL), also known as kala-azar, is fatal if left untreated in over 95% of cases.

    Can leishmaniasis go away on its own? ›

    The skin sores of cutaneous leishmaniasis usually heal on their own, even without treatment. But this can take months or even years, and the sores can leave ugly scars.

    What are the symptoms of Leishmania in humans? ›

    Visceral leishmaniasis symptoms include:
    • Fever. This can start suddenly and come and go for several weeks.
    • Chills.
    • Cold sweats.
    • Swollen lymph nodes.
    • Swollen abdomen (belly) from an enlarged spleen.
    • Weight loss.
    • Fatigue.
    • Weakness.
    Dec 12, 2022

    What is the new treatment for Leishmania? ›

    Liposomal amphotericin B is an effective treatment for cutaneous leishmaniasis and mucosal leishmaniasis, but requires administration by trained health-care professionals and cold chain transport. Miltefosine is a phospholipid analogue and is currently the only oral drug available.

    What is the best treatment for Leishmania? ›

    Liposomal amphotericin B is FDA-approved for treatment of visceral leishmaniasis and generally is the treatment of choice for U.S. patients.

    Can mosquitoes spread Leishmania? ›

    It is prevalent in tropical and subtropical countries and become a challenge to a highly endemic area of East Africa including Ethiopia [2, 3]. It is transmitted via the bite of infected female anopheles mosquito.

    Which of the following is a vector for the parasite that transmits leishmaniasis? ›

    Lutzomyia longipalpis sand flies are the major natural vector of Leishmania infantum parasites, responsible for transmission of visceral leishmaniasis in the New World.

    What is the main host of leishmaniasis? ›

    Their primary hosts are vertebrates; Leishmania commonly infects hyraxes, canids, rodents, and humans.

    What are the stages of the leishmaniasis disease? ›

    The Two Life Stages of Leishmania: Amastigote (A) and Promastigotes (B). Leishmaniasis is a parasitic disease caused by hemoflagellate, Leishmania spp. The parasite is transmitted through the bites of an infected female phlebotomine sandfly. Leishmaniasis is prevalent throughout the world and in at least 88 countries.

    What is the reservoir host for Leishmania parasites affecting humans? ›

    There are two main sources of human leishmaniases, zoonotic leishmaniases, in which the reservoir hosts are wild animals, commensals or domestic animals, and anthroponotic leishmaniases, in which the reservoir host is human.

    What is the prognosis for leishmaniasis? ›

    Outlook (Prognosis)

    Cutaneous leishmaniasis may lead to disfigurement. Death is usually caused by complications (such as other infections), rather than from the disease itself. Death often occurs within 2 years.

    What are the 3 signals for CD4 T cell activation? ›

    Primary T cell activation involves the integration of three distinct signals delivered in sequence: (1) anti- gen recognition, (2) costimulation, and (3) cytokine- mediated differentiation and expansion.

    What disease CD4 T cells are affected? ›

    CD4+ T cells play an essential role in the pathogenesis of autoimmune disorders. The aberrant CD4+ T cell responses have been demonstrated in patients with autoimmune disorders, including inflammatory bowel diseases (IBD), 1 systemic lupus erythematosus (SLE),2 and rheumatoid arthritis (RA).

    What causes CD4 T cell dysfunction? ›

    Virus-specific CD4 T cell dysfunction results from a combination of an exhaustion program and skewing in Thelper lineage differentiation which impact function.. The CD4 and CD8 T cell exhaustion programs present similarities and distinct features.

    What is type 2 inflammatory disease? ›

    As mentioned, it is now well documented that type 2 inflammatory responses are at the basis of atopic dermatitis (AD), asthma, and CRSwNP, as well as for eosinophilic esophagitis, some forms of COPD, and other conditions [4-6].

    Is Th2 anti-inflammatory? ›

    Th2-related cytokinees (IL-4 and IL-10) are associated with humoral immunity and anti-inflammatory properties.

    Why is Th2 anti-inflammatory? ›

    The Th2-type cytokines include interleukins 4, 5, and 13, which are associated with the promotion of IgE and eosinophilic responses in atopy, and also interleukin-10, which has more of an anti-inflammatory response. In excess, Th2 responses will counteract the Th1 mediated microbicidal action.

    Is Hashimoto's Th1 or Th2 dominant? ›

    Because Graves' hyperthyroidism is directly caused by thyroid-stimulating antibodies (TSAbs), it is logical to assume that the disease belongs to the Th2 category. Conversely, the dominance of cellular immunity and thyroid tissue damage in Hashimoto's thyroiditis implies a Th1 origin.

    What is the difference between Th1 and Th2 inflammation? ›

    Th1 diseases are characterized by a strong Th1 response, while Th2 diseases are characterized by a weak or absent Th1 response. Th1 cytokines like IFNγ and TNFα promote inflammation, while Th2 cytokines like IL-21 and IL-22 inhibit inflammation.

    What is the difference between Th1 and Th2 lupus? ›

    Th1 cells protect against intracellular pathogens, activate phagocytes, induce IgG2a antibodies, and promote delayed-type hypersensitivity responses, whereas Th2 cells protect against extracellular pathogens, activate eosinophils, induce IgE-mediated allergic reactions, and promote other humoral responses in which IgG1 ...

    What is humoral immunity in Leishmania? ›

    Humoral immunity is characterized by the production of antibodies capable of promoting neutralization, opsonization, and activation of the complement system. In this scenario, B lymphocytes produce antibodies that play an important role in Leishmania infection although neglected for a long time.

    What are the mechanisms of human immunity to fungal infections? ›

    Host defence mechanisms against fungi involve innate immunity and adaptive immunity. The two systems are intimately linked and controlled by sets of molecules and receptors that act to generate a highly coordinate and unitary process for protection against fungal pathogens.

    What adaptations does leishmaniasis have? ›

    Once inside the macrophage, Leishmania is protected from phagolysosome degradation by a variety of adaptations to inhibit cellular defense mechanisms. These include the inhibition of phagosome-endosome fusion, hydrolytic enzymes, cell signaling pathways, nitric oxide production, and cytokine production.

    What is the role of cytokines in leishmaniasis? ›

    IL-8 is a strong proinflammatory cytokine that plays an essential role in the recruitment and activation of neutrophils in the course of inflammation. This cytokine is secreted by tissue-resident macrophages in response to Leishmania infections and plays a key role in the initial stages of infection or tissue damage.

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