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Aims: Type 2 diabetes (T2DM) is associated with alterations of the immune response and T2DM patients have an increased risk for infections and certain sorts of cancers. Although CD14 + HLA-DR -/low cells have emerged as important mediators of immunosuppression in several pathologies, including cancer and non-malignant diseases, the presence of these cells in T2DM is not fully characterized., Methods: In this study, we evaluated the frequency of CD14 + HLA-DR -/low cells in non-obese T2DM patients and their association with glycemic control. Peripheral blood mononuclear cells were isolated from healthy controls (HC, n = 24) and non-obese T2DM patients (n = 25), the population was evaluated by flow cytometry, and an analysis of correlation between cell frequencies and clinical variables was performed., Results: CD14 + HLA-DR -/low monocytes were expanded in patients with T2DM compared to HC regardless of weight. Among the subjects with T2DM, the frequency of CD14 + HLA-DR -/low was higher in patients with poor glycemic control (HbA1c > 9%) compared to those with better glycemic control (HbA1c < 9%) and, positively correlated with the years since the diagnosis of T2DM, the age of the patients and the glycemic index., Conclusions: An increased frequency of CD14 + HLA-DR -/low cells in the blood of T2DM patients was recorded. The influence of hyperglycemia seems to be independent of obesity, but related to glycemic control and age., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

Aims: Monocytes and macrophages express cell-surface markers indicative of their inflammatory and activation status. In this study, we investigated whether these markers are affected or correlated in non-obese T2D subjects, or glycemic/metabolic control variables., Methods: Clinical data was recorded, and peripheral blood drawn from T2D patients (n = 28) and control subjects (n = 27). Isolated monocytes were evaluated by flow cytometry for the expression of CD14, CD16, and the phenotypic markers for the different states of activation spectrum, such as pro-inflammatory (M1) (HLA-DR, CD86), anti-inflammatory/pro-resolving (M2) (CD163, CD206, MERTK, PD-L1) and metabolically-activated (MMe) (CD36, ABCA-1). From a subset of individuals, monocytes-derived macrophages (MDM) were obtained and evaluated for phenotypic markers. A correlation analysis was performed between the clinical variables and the marker expression., Results: The frequency of CD14 ++ CD16 - monocytes was lower in T2D patients and it correlates negatively with poor control in glycemic and metabolic variables. T2D monocytes expressed lower levels of HLA-DR, CD86, PD-L1, and CD163, which correlated negatively with poor metabolic control. In MDM from T2D patients, HLA-DR, CD86 and CD163 expression was lower and it inversely correlated with deficient glycemic or metabolic control parameters., Conclusion: The glycemic/metabolic control associated with T2D influences monocyte and MDM phenotypes toward an immune-suppressive phenotype., Competing Interests: Declaration of competing interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Despite the existing research, the etiology of rheumatoid arthritis (RA), an autoimmune disease remains poorly understood with early and accurate diagnosis difficult to achieve. MicroRNAs (miRNAs) play an important role in biological processes as modulators of transcription and translation. Previous studies have demonstrated a downregulation of several genes in early RA stages and in addition, miRNAs may serve as early biomarkers of subclinical changes in early RA. When comparing the four groups (ANOVA P < 0.01, fold change > 4), we found 253 differentially expressed miRNAs. Of these, 97 miRNAs were identified as overexpressed in early rheumatoid arthritis. The validation of miRNA microarray expression was performed in a set by RT-qPCR and showed strong agreement with microarray expression data. The putative targets of overexpressed microRNAs in early RA were significantly enriched in apoptosis, tolerance loss and Wnt pathways. Moreover, ROC analysis showed values of AUC 0.76 and P < 0.05 for miR 361-5p, identifying this miRNA as a potential biomarker of disease. We identified specific microRNAs associated with early rheumatoid arthritis and proposed them as early biomarkers of disease. Our results provide novel insight into immune disease physiopathology and describe unreported microRNAs in RA with potential for clinical use., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Aim: Diabetes mellitus is a chronic disease that has manifestations other than alterations in endocrine regulation or in metabolic pathways. Several diseases of the oral cavity have been associated with diabetes mellitus type 1 and 2 in young people according to their evolution. Scarce information exists regarding the role of diabetes and its association with the oral health status in paediatric diabetic patients. The aims of the study were to assess the quality of saliva, saliva acidogenicity, dental caries experience, fluorosis and periodontal status in diabetic patients and to evaluate their relationship with metabolic control variables and nutritional plan adherence., Materials and Methods: The study population consisted of 60 paediatric patients with both types of diabetes mellitus. Saliva testing included stimulated flow, pH (using pH indicator strips), buffer capacity and Snyder's Test. DMFT/dmft and dental caries experience were determined on the basis of ICDAS II codes. The periodontal status was assessed by PI and GI and fluorosis by FI. Nutritional plan adherence was established from the subscale "Dietary Control" of the Diabetes Self-Management Profile questionnaire. Medical Data was retrieved from the clinical registers in the Diabetic Clinic., Results: We describe the main characteristics of the oral cavity related variables of our population that might guide the clinical practice in similar settings; we found a dmft/DMFT of 1.71 ± 1.74 and 0.64 ± 1.03, PI of 1.91 ± 0.75, GI of 0.50 ± 0.56 and a fluorosis prevalence of 61%. We identified several correlated variables, which indicate strong associations between the nutritional habits of the patients and co-occurrence of oral cavity physiopathological alterations. Several correlations were found between acidogenic activity of the saliva (Snyder Test) and the percentage of adherence to the nutritional plan and to the dmft index. Furthermore, a significant correlation between the buffering capacity of the saliva and the glycemic control of the participants was found. Neither an association nor a difference among means was found between treatment regime and the plaque index., Conclusion: The results of the present study concluded that there was a significant relationship between diabetes mellitus and an increased prevalence of oral cavity related diseases in the paediatric population. These are also associated with a poor adherence to the nutritional plan.

Regulatory T cells (Tregs), a subset of CD4+ T cells related with immune regulation, have been associated with active and latent tuberculosis infection (LTBI). Treg frequencies were evaluated by multicolor flow cytometry (FC) in peripheral blood mononuclear cells (PBMCs) stimulated with mycobacterial antigens ESAT-6, CFP-10, and TB7.7 to assess their capacity to distinguish subjects with different reactivity to the QuantiFERON-TB® Gold In-Tube (QFT-IT) test and the tuberculin skin test (TST). Increased frequencies of CD4+CD25highCD39+ cells were found for the [TST+, QTF+] compared with the [TST+, QTF-] group. Also, higher frequencies were observed for the [TST+, QTF+] compared with the [TST+, QTF-] and [TST-, QTF-] groups in CD4+CD25highFoxp3+ and CD4+CD25highCD39+Foxp3+ populations. Receiver operating characteristics (ROC curve) analysis confirmed these discriminating results. QFT-IT and TST quantitative values correlated with several Treg population frequencies., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The increasing number of people with type 2 diabetes (DM2) is alarming and if it is taken into account that the relative odds of developing tuberculosis in diabetic patients ranges from 2.44 to 8.33 compared with non-diabetic patients, thus in developing countries where these two diseases are encountering face to face, there is a need for prophylaxis strategies. The role of vitamin D has been widely implicated in growth control of Mycobacterium tuberculosis (Mtb) during primary infection mainly through the induction of certain antimicrobial peptides (AMPs). In this study we evaluated the vitamin D serum levels, CYP27B1-hydroxylase enzyme, vitamin D receptor (VDR) and AMPs gene expression in Healthy donors, DM2 and TB patients. Results showed that DM2 group has lower VDR and AMPs expression levels. When Monocytes Derived Macrophages (MDM) from DM2 patients with low VDR expression were supplemented with vitamin D, MDMs eliminate efficiently M. tuberculosis. This preliminary study suggests the use of vitamin D as prophylaxis for tuberculosis in high DM2 endemic countries., (Copyright © 2014 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.)

There is an increased susceptibility to infections during elderly, mainly because of the decreased efficacy of adaptive immunity to contain microorganisms. Albeit most of the elderly adults develop this deficiency in adaptive immunity only a minor percentage of them developed recurrent infectious diseases, thus innate immunity represents an important barrier to avoid infections in this group of aged people. Since antimicrobial peptides are important molecules of innate immunity in the study we sought to determine whether healthy aging correlates with a proper antimicrobial production. Our results by ELISA and flow cytometry showed that healthy elder individuals produce significant amounts of both cathelicidin and β-defensin-2 (hBD-2) comparable with those found in healthy young individuals. Our results suggest that during healthy aging the maintenance of the antimicrobial peptide innate immune response may be responsible for the protection against infectious diseases., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Five variants of human β-defensins (HBDs) were expressed in Escherichia coli using two vector systems (pET28a(+) and pQE30) with inducible expression by IPTG. The last vector has not been previously reported as an expression system for HBDs. The recombinant peptides were different in their lengths and overall charge. The HBDs were expressed as soluble or insoluble proteins depending on the expression system used, and the final protein yields ranged from 0.5 to 1.6 mg of peptide/g of wet weight cells, with purities higher than 90%. The recombinant HBDs demonstrated a direct correlation between antimicrobial activity and the number of basic charged residues; that is, their antimicrobial activity was as follows: HBD3-M-HBD2 > HBD3 = HBD3-M = HB2-KLK > HBD2 when assayed against E. coli, Staphylococcus aureus and Pseudomonas aeruginosa. Interestingly, HBD2 had the best antimicrobial activity against the Mycobacterium tuberculosis strain H37Rv (1.5 μM) and the heterologous tandem peptide, HBD3-M-HBD2, had the best minimal inhibitory concentration (MIC) value (2.7 μM) against a multidrug resistance strain (MDR) of M. tuberculosis, demonstrating the feasibility of the use of HBDs against pathogenic M. tuberculosis reported to be resistant to commercial antibiotics., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The World Health Organization (WHO) has estimated that there are about 8 million new cases annually of active Tuberculosis (TB). Despite its irregular effectiveness (0-89%), the Bacillus Calmette-Guérin) BCG is the only vaccine available worldwide for prevention of TB; thus, the design is important of novel and more efficient vaccination strategies. Considering that β-defensin-2 is an antimicrobial peptide that induces dendritic cell maturation through the TLR-4 receptor and that both ESAT-6 and Ag85B are immunodominant mycobacterial antigens and efficient activators of the protective immune response, we constructed two DNA vaccines by the fusion of the gene encoding β-defensin-2 and antigens ESAT6 (pDE) and 85B (pDA). After confirming efficient local antigen expression that induced high and stable Interferon gamma (IFN-γ) production in intramuscular (i.m.) vaccinated Balb/c mice, groups of mice were vaccinated with DNA vaccines in a prime-boost regimen with BCG and with BCG alone, and 2 months later were challenged with the mild virulence reference strain H37Rv and the highly virulent clinical isolate LAM 5186. The level of protection was evaluated by survival, lung bacilli burdens, and extension of tissue damage (pneumonia). Vaccination with both DNA vaccines showed similar protection to that of BCG. After the challenge with the highly virulent Mycobacterium tuberculosis strain, animals that were prime-boosted with BCG and then boosted with both DNA vaccines showed significant higher survival and less tissue damage than mice vaccinated only with BCG. These results suggest that improvement of BCG vaccination, such as the prime-boost DNA vaccine, represents a more efficient vaccination scheme against TB., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Foot ulcers are one of the main diabetes complications due to its high frequency and difficulty of complete healing. There are several factors that participate in diabetic ulcers development and limited information exists about the role of antimicrobial peptides (AMP) in its pathogenesis., Objective: The aim of this study was to analyze the expression pattern of the main AMPs: Human Neutrophil Peptide (HNP)-1, Human β-defensin (HBD)-1, HBD-2, HBD-3, HBD-4 and cathelicidin LL-37 in biopsies from diabetic foot ulcers (DFU)., Methods: 20 biopsies from DFU grade 3 according to Wagner's classification and 20 biopsies from healthy donors were obtained. Real time PCR, immunohistochemistry and primary cell cultures were performed., Results: β-Defensins were overexpressed in DFU, whereas LL-37 has low or none expression in comparison with healthy skin. When primary cell culture from these biopsies were performed and infected with Staphylococcus aureus, epidermal cell from diabetic ulcers showed lower LL-37 expression compared with cell cultures from healthy donors skin., Conclusion: These results suggest that though most AMPs are expressed in DFU, this production is not appropriate to promote wound healing and contain secondary infections., (Copyright © 2011 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.)

Tuberculosis (TB) is one of the most important infectious diseases, causing 1.8 million deaths annually worldwide. This problem has increased because of the association with human immmunodeficiency virus and diabetes mellitus type 2, mainly in developing countries. In the past few years it has been highlighted the significance of antimicrobial peptides in the immunopathogenesis of TB ex vivo and in experimental models studies. In this study we analyzed the expression of CAMP, DEFA1, DEFB4, and DEFB103A in patients with latent TB and progressive TB with and without comorbidity with diabetes mellitus type 2. Antimicrobial peptide gene expression increased during progressive TB, which could be used as a biomarker for reactivation. By contrast, patients with diabetes mellitus type 2 have lower antimicrobial peptides gene expression, suggesting that the lack of its proper production in these patients contribute to enhance the risk for TB reactivation., (Copyright © 2011 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)