Lactobacillus rhamnosus and Lactobacillus delbrueckii Ameliorate the Expression of miR-125a and miR-146a in Systemic Lupus Erythematosus Patients.

The microRNAs are non-coding RNA molecules involved in physiological and pathological processes, causing autoimmune diseases such as systemic lupus erythematosus (SLE). Probiotics are living microorganisms that possess beneficial effects on the host immune system and modulate it. The effect of Lactobacillus rhamnosus and Lactobacillus delbrueckii on the expression of miR-125a and miR-146a was studied in peripheral blood mononuclear cells (PBMCs) from newly diagnosed lupus patients in this in vitro study. During this study, 20 recently diagnosed SLE patients and 20 healthy individuals participated. Ficoll method was used to isolate the PBMCs from whole blood, which were cultured for 48 h with Lactobacillus rhamnosus and Lactobacillus delbrueckii. In the next step, total RNA containing microRNA was extracted. cDNA was synthesized for miR-125a and miR-146a genes and analyzed by real-time PCR. Results were presented as fold changes. As compared to healthy controls, SLE patients expressed lower levels of miR-125a and miR-146a. PBMCs treated with Lactobacillus rhamnosus, Lactobacillus delbrueckii, or both probiotics had significantly higher levels of miR-125a and miR-146a compared to the untreated group. Treatment of PBMCs with both L. rhamnosus and L. delbrueckii upregulated the expression of miR-125a and miR-146a in treated cells compared with untreated cells in SLE patients (p = 0.02, p = 0.001). Lactobacillus rhamnosus and Lactobacillus delbrueckii modify lupus patients' immune responses and disease effects by regulating miR-125a and miR-146a.

The effects of Lactobacillus delbrueckii and Lactobacillus rhamnosus on cytokines and their related molecules: An ex vivo study on patients with systemic lupus erythematosus.

Objectives: This study aimed to assess the ex vivo impact of Lactobacillus delbrueckii (L. delbrueckii) and Lactobacillus rhamnosus (L. rhamnosus) on inflammatory and anti-inflammatory cytokines as well as their related molecules on the peripheral blood mononuclear cells (PBMCs) of systemic lupus erythematosus (SLE) patients. Patients and methods: This study was conducted with 20 newly diagnosed SLE patients (18 females, 2 males; mean age: 33.3±12.4 years; range, 18 to 68 years) between September 2017 and September 2018. Extracted PBMCs from each patient were divided into 4 cell groups in our study. Three cell groups act as treatment groups receiving L. rhamnosus (107 CFU/mL), L. delbrueckii (105 CFU/mL) or a mixture of both, and one group act as our untreated control group in the absence of any probiotic agents. All cell groups were cultured in RPMI 1460 medium for 48 h. Then, total RNA was extracted, and cDNA was synthesized. Results: The gene expression levels of forkhead box P3 (FOXP3), transforming growth factor beta (TGF-ß), interleukin (IL)-6, IL-10, and IL-2 were evaluated by a quantitative real-time polymerase chain reaction. The results revealed that expression levels of FOXP3, TGF-ß, IL-10, and IL-2 increased and the level of IL-6 decreased in probiotics-receiving groups compared to the control group. Lactobacillus delbrueckii and L. rhamnosus enhanced the expression of regulatory T cell-related molecules such as FOXP3 and IL-2 and also increased the expression of IL-10. These probiotics also reduced the expression of IL-6 as proinflammatory cytokines in the PBMCs of SLE patients. Conclusion: The results of the present study show that these probiotics could be effective in regulating the balance of cytokine gene expression ex vivo , and due to their beneficial effects, they can be an intriguing option in the production of new complement drugs for SLE.

Immune response to COVID-19 vaccines among people living with human T-cell lymphotropic virus type 1 infection: a retrospective cohort study from Iran.

The effectiveness of COVID-19 vaccination is still unclear in individuals with underlying diseases such as HTLV-1 infection. This retrospective cohort study aimed to evaluate the humoral response of COVID-19 vaccines among people living with HTLV-1 (PLHTLV) in northeastern Iran. From December 2021 to October 2022, eighty-six HTLV-1+ subjects (50 males and 36 females; 47.7 ± 11.2 years) and 90 HTLV-1 seronegative individuals (age- and sex-matched convenient samples) were enrolled. The humoral immune response was evaluated by measuring different COVID-19 Abs in serum samples at least 28 days after receiving 2nd or 3rd doses of COVID-19 vaccines. Throughout all three rounds of immunization, Sinopharm was the most commonly used COVID-19 vaccine across all three immunization rounds. Compared to the HTLV-1- group, a significantly lower frequency of all four Abs activity was observed among PLHTLV:anti-nucleocapsid (66.3% vs 86.7%, p = 0·001), anti-spike (91.9% vs 98.9%, p = 0·027), RBD (90.7% vs 97.8%, p = 0·043), and neutralizing Abs (75.6% vs 95.5%, p < 0·001). Also, the frequency of all Abs in 28 patients with HAM/TSP was higher than that of 58 asymptomatic carriers, although this difference was statistically significant only in the case of anti-spike Abs (p = 0.002). Notably, PLHTLV-vaccinated against COVID-19 demonstrated significantly lower antibody activities, indicating a reduced humoral immune response to COVID-19 vaccines.

Pentraxin 3, a serum biomarker in human T-cell lymphotropic virus type-1-associated myelopathy patients and asymptomatic carriers.

Human T-cell lymphotropic virus type 1 (HTLV-1) can induce a neuroinflammatory condition that leads to myelopathy. Pentraxin 3 (PTX3) is an acute-phase protein that its plasma concentration increases during inflammation. We aimed to determine whether PTX3 serum level is elevated in HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients and HTLV-1 asymptomatic carriers (ACs) and evaluate its association with proviral load and clinical features. The serum level of PTX3 was measured using an enzyme-linked immunosorbent assay in 30 HAM patients, 30 HTLV-1 ACs, and 30 healthy controls. Also, the HTLV-1 proviral load was determined via real-time PCR technique. The findings showed that PTX3 serum level was significantly higher in HAM patients than in both asymptomatic carriers and healthy controls (p values < 0.0001). No correlation between PTX3 and the proviral load was observed in HAM patients and asymptomatic carriers (r = - 0.238, p = 0.205 and r = - 0.078, p = 0.681, respectively). The findings showed that there was no significant correlation between PTX3 and motor disability grading (MDG) (r = - 0.155, p = 0.41) nor urinary disturbance score (UDS) (r = - 0.238, p = 0.20). Higher levels of PTX3 are associated with HTLV-1-associated myelopathy compared to asymptomatic carriers. This finding may support the idea that PTX3 has the potential as a diagnostic biomarker.

XCL1, a serum biomarker in neurological diseases; HTLV-1-associated myelopathy and multiple sclerosis.

The XCL1-XCR1 axis has a potential role in the recruitment of immune cells to the site of inflammation. The present study aimed to examine the relation of XCL1 serum levels with Multiple sclerosis (MS) and HTLV-1-associated myelopathy (HAM), as chronic inflammatory diseases of the central nervous system (CNS). DNA was extracted to evaluate HTLV-1 proviral load (PVL) using real-time PCR. Serum levels of XCL1 was determined by using an ELISA assay. The serum level of XCL1 was significantly higher in patients with HAM than that of asymptomatic carriers (ACs) and healthy controls (HCs) (p < 0.001 and p < 0.0001, respectively) and was also higher in MS patients compared to HCs (p < 0.0001). Moreover, the concentration of XCL1 serum level was significantly different between the ACs and HCs group (p < 0.0001). In conclusion, increased expression of XCL1 might contribute to the migration of autoreactive T cells to the central nervous system and play a critical role in the development and pathogenesis of inflammatory neurological diseases including HAM and MS.

Planning and management to control and eliminate HTLV-1 infection in Iran.

Prevention and treatment of the Human T-cell leukemia virus, type 1 (HTLV-1) which was discovered nearly 40 years ago, still remain challenging. The reported high prevalence of HTLV-1 in some countries around the world triggered an open letter to the World Health Organization (WHO), urging action against HTLV-1 infection in 2018. This highlights the importance of virus elimination strategies to eradicate HTLV-1 infection. In Iran, we have documented our experiences with the virus in order to achieve and promote the possible ways to manage, control, and eliminate HTLV-1. Although there has been considerable progress apropos of HTLV-1, a series of additional challenges need to be tackled to control HTLV-1 infection in Iran.

Evaluation of iron, ferritin, copper, and ceruloplasmin along with proviral load in human T lymphotropic virus type 1-associated myelopathy.

Human T-cell lymphotropic virus type 1 (HTLV-1) infection can cause HTLV-I-associated myelopathy (HAM). In this study, we evaluated the levels of serum iron, ferritin, copper, and ceruloplasmin, and their correlations with HTLV-1 proviral load (PVL) and standard indices of HAM severity. In total, 114 subjects were recruited in this cross sectional study in Qaem Hospital, Mashhad, Iran between 2017 and 2018, including 36 HAM and 32 asymptomatic cases (ACs) and 46 healthy people (HSs). The clinical examination and evaluation of serum levels of biochemical factors and proviral load were performed. The PVL in HAM and ACs were 1835.49 ± 382.81 and 280.97 ± 67.41 copies/104 PBMCs, which statistically differed. Significant differences were also observed in plasma levels of iron, copper, and ceruloplasmin, among the three groups, while ferritin level was not considerably different. For HAM severity, the mean Osame motor disability scale (OMDS) and overactive bladder-validated-8-questionnaire (OABV-8) scores were 4.97 ± 0.38 and 15.75 ± 0.83, respectively, that had no significant correlations with the biochemical variables. Even though the studied elements in HAM group did not affect the severity of the disease, the levels of copper and ceruloplasmin might be determinants of the development and progression of HAM, as they are shown to play role in progression of other neurological diseases.

Dietary Intake and Serum Selenium Levels Influence the Outcome of HTLV-1 Infection.

Human T cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP), as the most common neurological emersion related to HTLV-1, is a debilitating and lifelong treating disease with no definitive treatment. Furthermore, it has been determined that dietary compositions (inflammatory and anti-inflammatory) and some micronutrients (such as vitamin D and selenium) have an effect on inflammatory and immune processes and with this background; the study was done to compare the nutritional status between age- and sex-matched with infected and non-infected HTLV-1. In a multi-center setting, 70 healthy controls (HCs), 35 asymptomatic carriers (ACs), and 35 HAM/TSP patients were recruited in the HTLV-1 Foundation, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran. Nutritional status including anthropometric indices, dietary (micro- and macronutrient) intake, and serum vitamin D, vitamin B12, zinc, and selenium were measured. In anthropometric indices, mean waist circumference (WC) in the carrier group was significantly higher than the patient and the control groups (p = 0.008). In the dietary intake, the patient group received less energy, protein, mono-unsaturated fatty acids (MUFA), and oleic, but more fat than the HTLV-1 carrier and control groups, and these differences were remarkable in three groups (p = 0.002, 0.005, 0.001, 0.01, and 0.001, respectively), whereas the carrier group received more saturated fatty acid and less poly-unsaturated fatty acids (PUFA), linoleic, and linolenic than patient and control groups with a different significant (p = 0.01, 0.007, 0.005, and 0.006, respectively) in three groups. In micronutrient intake, although selenium, zinc, and vitamins B12 and D were lower in the patient group than the carrier and control group, however, no significant differences were observed. In comparison with micronutrient serum concentrations, vitamins B12 and D and selenium in the patient group were lower than the carrier and control groups, but statistically, the considerable difference was found only in the selenium concentration (p = 0.001). The study showed that there were differences in dietary intake (including energy, macronutrients, and fatty acids), WC, and selenium serum levels between HAM/TSP patients and HTLV-1 carriers, suggesting that nutritional statues influence the inflammatory immune response in HTLV-1 infection.

The Role of Chemokines in the Pathogenesis of HTLV-1.

Human T cell leukemia virus type 1 (HTLV-1) is a human retrovirus that is associated with two main diseases: HTLV-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T cell leukemia/lymphoma (ATL). Chemokines are highly specialized groups of cytokines that play important roles in organizing, trafficking, homing, and in the migration of immune cells to the bone marrow, lymphoid organs and sites of infection and inflammation. Aberrant expression or function of chemokines, or their receptors, has been linked to the protection against or susceptibility to specific infectious diseases, as well as increased the risk of autoimmune diseases and malignancy. Chemokines and their receptors participate in pathogenesis of HTLV-1 associated diseases from inflammation in the central nervous system (CNS) which occurs in cases of HAM/TSP to T cell immortalization and tissue infiltration observed in ATL patients. Chemokines represent viable effective prognostic biomarkers for HTLV-1-associated diseases which provide the early identification of high-risk, treatment possibilities and high-yielding clinical trials. This review focuses on the emerging roles of these molecules in the outcome of HTLV-1-associated diseases.

Predictive value of inflammatory markers for functional outcomes in patients with ischemic stroke.

Background: Inflammatory processes have been proposed in the pathophysiology of ischemic stroke. The present study was designed to evaluate the relationship between tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), IL 1 beta (IL-1ß), and high sensitivity C-reactive protein (hsCRP) with the prognosis and functional outcome in patients with less severe ischemic stroke. Methods: We measured the level of IL-1ß, IL-6, hsCRP, and TNF-α on days 1 and 5 after stroke onset by enzyme-linked immunosorbent assay (ELISA). The infarct volume was assessed using Alberta Stroke Program Early CT Score (ASPECTS) and posterior circulation ASPECTS (pcASPECTS) score in brain computed tomography (CT) scan and magnetic resonance imaging (MRI). The severity of stroke was assessed by applying the National Institutes of Health Stroke Scale (NIHSS) and Modified Rankin Scale (MRS) in 24 hours on day 5 and after 3 months from stroke onset. Good outcome was defined as the third month MRS ≤ 2. The association of inflammatory markers and the course of stroke symptoms over time was examined. Results: Forty-four first-ever stroke patients without concurrent inflammatory diseases with a mean age of 65 years were included. The mean NIHSS and MRS in admission time were 6.5 ± 3.5 and 3.07, respectively. The day 1 and the day 5 levels of IL-1ß, IL-6, hsCRP, and TNF-α were not significantly different in good and poor outcome groups (all P-values > 0.05). In addition, they were not significantly associated with the ASPECTS, pcASPECTS, and changes of NIHSS and MRS over time. Conclusion: The levels of hsCRP, IL-1ß, IL-6, and TNF-α are not reliable predictors of functional outcomes in patients with less severe acute ischemic stroke (AIS).

International multicenter randomized, placebo-controlled phase III clinical trial of ß-D-mannuronic acid in rheumatoid arthritis patients.

BACKGROUND: The oral administration of drug ß-D-mannuronic acid (M2000) showed a potent therapeutic effect in phase I/II study in rheumatoid arthritis (RA) patients. Here, our aim is to assess the efficacy and safety of this new drug in RA patients under a multinational, randomized placebo-controlled phase III clinical trial. METHOD: Patients (n = 288) with active disease at baseline and inadequate response to conventional drugs were randomly allocated to three groups; (1) receiving mannuronic acid at a dose of two capsules (500 mg) per day orally for 12 weeks, (2) placebo-controlled, and (3) conventional. The primary endpoints were the America College of Rheumatology 20 response (ACR20), 28-joint disease activity score (DAS28) and Modified Health Assessment Questionnaire-Disability Index (M-HAQ-DI). In addition, the participants were followed-up for safety assessment. RESULTS: In this phase III trial, after 12 weeks of treatment, there was a significant reduction in ACR20 between mannuronic-treated patients compared to placebo and conventional groups. Moreover, there was a similar significant improvement for DAS28 following mannuronic therapy. The statistical analysis showed a significant reduction in the swollen and tender joint count in mannuronic-treated patients compared with the placebo group. On the other side, mannuronic acid showed no-to-very low adverse events in comparison to placebo. CONCLUSION: The results of this multinational, phase III clinical trial provided a potent evidence base for the use of ß-D-mannuronic acid as a new highly safe and efficient drug in the treatment of RA.