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      Hematological and immunological profiles of podoconiosis patients in West Gojjam Zone, Ethiopia: A comparative cross-sectional study

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          Abstract

          Background

          Podoconiosis is a geo-chemically induced, non-infectious, familial, chronic lymphedema of the legs that occurs among barefoot people in rural, farming communities with extreme poverty. Despite a growing body of research surrounding the disease, the pathogenesis of the disease is relatively unknown. This study aims to investigate the immunological and hematological profiles of individuals affected by podoconiosis in comparison to healthy controls.

          Methodology/Principal findings

          A comparative cross-sectional study was conducted in West Gojjam Zone of Ethiopia involving adult individuals clinically diagnosed with podoconiosis (n = 53) and healthy controls (n = 67) from the same area. A survey was conducted to gather information on sociodemographic, lifestyle characteristics, and clinical features of the disease. About nine ml whole blood samples were collected for hematological and immunological testing, which included IL-4, TNF-α, IL-6, IL-17, IL-10, TGF β and IFN-γ. Overall, we observed significant differences in hematological parameters between individuals with podoconiosis and healthy controls. Specifically, we found a notable reduction in white blood cell count, with an adjusted mean difference (AMD) of -1.15 (95% CI: -2.09 to -0.21; p = 0.017). Additionally, the differential white blood count showed a decrease in absolute neutrophils (AMD = -3.42, 95% CI: -4.15 to -2.69; p < 0.001) and absolute eosinophils (AMD = -0.20, 95% CI: -0.37 to -0.03; p = 0.019). Conversely, we noted an increase in absolute lymphocytes (AMD = 0.98, 95% CI: 0.50 to 1.46; p < 0.001) and monocytes (AMD = 0.54, 95% CI: 0.22 to 0.85; p = 0.001). However, we didn’t observe a significant difference in cytokine profile between podoconiosis patients and healthy controls

          Conclusions/Significance

          The decrease in neutrophil counts among podoconiosis cases compared to healthy controls may provide insight into the potential disease pathogenesis, suggesting the involvement of autoimmune-related mechanisms, as it demonstrates a similar hematological profile to other autoimmune disorders.

          Author summary

          Podoconiosis, a non-infectious form of elephantiasis, is a neglected tropical disease whose immunopathology remains poorly understood. This study aimed to investigate the hematological and immunological aspects of podoconiosis. Our findings revealed significant hematological changes, particularly a reduction in absolute neutrophil counts in podoconiosis cases, which may suggest an autoimmune process. We hypothesize that chronic inflammation activates immune cells (lymphocytes, macrophages, or monocytes), which may contribute to the destruction of circulating neutrophils. We also found reduced hemoglobin levels in podoconiosis patients, possibly due to mechanisms such as hemolysis, iron sequestration, and cytokine-mediated inhibition of erythropoiesis. However, future mechanistic research is needed to confirm our observations and elucidate the role of reduced neutrophils in the pathogenesis of podoconiosis.

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          Most cited references42

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          Macrophage Cytokines: Involvement in Immunity and Infectious Diseases

          The evolution of macrophages has made them primordial for both development and immunity. Their functions range from the shaping of body plans to the ingestion and elimination of apoptotic cells and pathogens. Cytokines are small soluble proteins that confer instructions and mediate communication among immune and non-immune cells. A portfolio of cytokines is central to the role of macrophages as sentries of the innate immune system that mediate the transition from innate to adaptive immunity. In concert with other mediators, cytokines bias the fate of macrophages into a spectrum of inflammation-promoting “classically activated,” to anti-inflammatory or “alternatively activated” macrophages. Deregulated cytokine secretion is implicated in several disease states ranging from chronic inflammation to allergy. Macrophages release cytokines via a series of beautifully orchestrated pathways that are spatiotemporally regulated. At the molecular level, these exocytic cytokine secretion pathways are coordinated by multi-protein complexes that guide cytokines from their point of synthesis to their ports of exit into the extracellular milieu. These trafficking proteins, many of which were discovered in yeast and commemorated in the 2013 Nobel Prize in Physiology or Medicine, coordinate the organelle fusion steps that are responsible for cytokine release. This review discusses the functions of cytokines secreted by macrophages, and summarizes what is known about their release mechanisms. This information will be used to delve into how selected pathogens subvert cytokine release for their own survival.
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            Anemia of inflammation

            Anemia of inflammation (AI), also known as anemia of chronic disease (ACD), is regarded as the most frequent anemia in hospitalized and chronically ill patients. It is prevalent in patients with diseases that cause prolonged immune activation, including infection, autoimmune diseases, and cancer. More recently, the list has grown to include chronic kidney disease, congestive heart failure, chronic pulmonary diseases, and obesity. Inflammation-inducible cytokines and the master regulator of iron homeostasis, hepcidin, block intestinal iron absorption and cause iron retention in reticuloendothelial cells, resulting in iron-restricted erythropoiesis. In addition, shortened erythrocyte half-life, suppressed erythropoietin response to anemia, and inhibition of erythroid cell differentiation by inflammatory mediators further contribute to AI in a disease-specific pattern. Although the diagnosis of AI is a diagnosis of exclusion and is supported by characteristic alterations in iron homeostasis, hypoferremia, and hyperferritinemia, the diagnosis of AI patients with coexisting iron deficiency is more difficult. In addition to treatment of the disease underlying AI, the combination of iron therapy and erythropoiesis-stimulating agents can improve anemia in many patients. In the future, emerging therapeutics that antagonize hepcidin function and redistribute endogenous iron for erythropoiesis may offer additional options. However, based on experience with anemia treatment in chronic kidney disease, critical illness, and cancer, finding the appropriate indications for the specific treatment of AI will require improved understanding and a balanced consideration of the contribution of anemia to each patient's morbidity and the impact of anemia treatment on the patient's prognosis in a variety of disease settings.
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              Immune modulation of some autoimmune diseases: the critical role of macrophages and neutrophils in the innate and adaptive immunity

              Macrophages and neutrophils are key components involved in the regulation of numerous chronic inflammatory diseases, infectious disorders, and especially certain autoimmune disease. However, little is known regarding the contribution of these cells to the pathogenesis of autoimmune disorders. Recent studies have aimed to clarify certain important factors affecting the immunogenicity of these cells, including the type and dose of antigen, the microenvironment of the cell-antigen encounter, and the number, subset, and phenotype of these cells, which can prevent or induce autoimmune responses. This review highlights the role of macrophage subsets and neutrophils in injured tissues, supporting their cooperation during the pathogenesis of certain autoimmune diseases.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: Formal analysisRole: Writing – original draftRole: Writing – review & editing
                Role: Formal analysisRole: SoftwareRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS Negl Trop Dis
                PLoS Negl Trop Dis
                plos
                PLOS Neglected Tropical Diseases
                Public Library of Science (San Francisco, CA USA )
                1935-2727
                1935-2735
                17 December 2024
                December 2024
                : 18
                : 12
                : e0012732
                Affiliations
                [1 ] Department of Medical Laboratory Science, Debre Markos University, Debre Markos, Ethiopia
                [2 ] Department of Medical Laboratory Sciences, Addis Ababa University, Addis Ababa, Ethiopia
                [3 ] Department of Biology, Colgate University, Hamilton, New York, United States of America
                [4 ] Department of Biomedical Data Science, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, United States of America
                Instituto Butantan, BRAZIL
                Author notes

                The authors have declared that no competing interests exist.

                Author information
                https://orcid.org/0000-0002-9512-4369
                Article
                PNTD-D-24-00819
                10.1371/journal.pntd.0012732
                11687886
                39689160
                2761ec22-3eb4-4a78-adfe-cab97afa438d

                This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

                History
                : 11 June 2024
                : 26 November 2024
                Page count
                Figures: 1, Tables: 4, Pages: 17
                Funding
                Funded by: Colgate University Research Council
                Award Recipient :
                Funded by: IOCC
                Award Recipient :
                We obtained financial support from the International Orthodox Christian Charity (IOCC), Ethiopia, for data collection and laboratory analyses. The Colgate University Research Council grant covered the cost of the cytokine measurements. BT received funding from the Colgate University Research Council, while AA, AT, and KD received funds from IOCC. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
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                2024-12-31
                All the data are available from the Addis Ababa University repository ( https://etd.aau.edu.et/server/api/core/bitstreams/aa6b0e83-289b-45e6-b314-03375c9423eb/content).

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