Lymphocyte Subpopulations Research Articles

New nomenclature of allergic diseases and hypersensitivity reactions

The review presents a modern view on the mechanisms of initiation and development of hypersensitivity reactions in response to external triggers based on the new nomenclature of allergic diseases proposed in 2023 by EAACI. The new concept of hypersensitivity is considered in detail, which systematizes previous classifications and summarizes newly obtained data on the etiology and mechanisms of development of inflammatory reactions in comparison with various variants of the immune response, based on the concept of phenotypes and endotypes of the disease. The modern concept of allergic reactions includes several types - associated with antibody formation (I-III), cell-mediated (IVa-c) and the Pichler concept, tissue-dependent, caused by defects in the epithelial barrier and metabolically induced immune dysregulation (V-VI), as well as a direct immunoinflammatory reaction to chemicals (VII). In the updated classification of allergic reactions, the adaptive and innate immune responses take a part in the initiation and effector phase of hypersensitivity reactions. The role of regulatory and effector subpopulations of lymphocytes and ILCs in various types of hypersensitivity is outlined. The leading role of epithelial barrier dysfunction in many allergic diseases, as well as the influence of viral infection on their course, is noted. The significance of metabolic dysregulation and its impact on the immune response is indicated. From the updated nomenclature of allergic reactions, it follows that several pathophysiological mechanisms may underlie the development of the same disease. It is interesting that most cellular and humoral factors are involved in various mechanisms of hypersensitivity, which once again confirms the biological universality of the immune response. As a wide range of people become familiar with the new concept and clinical and experimental data accumulate, the updated classification of hypersensitivity types will contribute to a theoretically sound, correct practical approach to the prevention of allergic diseases, improving their diagnosis and treatment.

Abstract 4119680: First-in-Man Treatment of Heart Failure by Repeated Intravenous Infusions of a Cardiovascular Cell-Derived Extracellular Vesicle-Enriched Secretome

Background: Most of the effects of intramyocardially transplanted stem cells can be duplicated by the sole administration of their secretome but this approach has not yet been tested in heart failure (HF). Methods: The SECRET-HF phase I trial (NCT05774509) was designed according to a Bayesian optimal interval scheme to assess the effects of repeated intravenous infusions of a cellular secretome in 12 patients with a non-ischemic dilated cardiomyopathy. The main inclusion criteria are severe symptoms (NYHA Class III despite an optimal guideline-directed medical therapy), a reduced left ventricular (LV) ejection fraction (EF ≤40%) and ineligibility for a heart transplant. The Investigational Medicinal Product was derived from human induced pluripotent stem cells reprogrammed from a healthy donor and differentiated in cardiovascular progenitor cells (CPC). Following CPC culture in a dedicated "vesiculation" medium, the conditioned media were collected, filtered, enriched for extracellular vesicles, concentrated by tangential flow filtration and scaled out into glass vials stored at -80°C. Quality controls were implemented throughout the whole process which was conducted according to current Good Manufacturing Practices. Results: Three patients, out of the 4 of the initial low-dose cohort, have now been treated. All had been previously fitted with an automatic internal cardioverter defibrillator (AICD). The secretome was delivered intravenously 3 times, 3 weeks apart, at a dose of 20 x10 9 particles/kg for each infusion. By November, 2024, the follow-up will be 16, 9, 6 and 2 months for each of them (mean: 8 months). So far, none of the treated patients has experienced a dose-limiting toxicity; in particular, there have been no post-treatments ventricular arrhythmia detected by the AICD, no allo-immunization and no inflammation based on the enumeration of lymphocyte subpopulations by flow cytometry. At 6 months, the first patient improved to NYHA Class II with a decrease in echographic LVEDV and LVESV (from 108 mL/m 2 to 87 mL/m 2 and from 80 mL/m 2 to 60 mL/m 2 , respectively) and a concomitant increase in LVEF from 25% to 32%. At 1 month post-treatment, the second patient also reports a symptomatic improvement (NYHA Class II) with an increase in EF from 21% to 28%. Conclusions: This initial experience supports the safety of repeated intravenous administrations of a cardiovascular cellular secretome as a potential noninvasive and user-friendly treatment of severe HF.

BIOM-73. CYTOKINE DYNAMIC DURING RADIATION THERAPY PREDICTS SURVIVAL IN GLIOBLASTOMA

Abstract Radiation Therapy affects a wide range of circulating lymphocyte subpopulations that are integral to mounting a successful lymphocyte-mediated immune response. Lymphopenia is associated with inferior tumor control and could be addressed to improve outcomes in glioblastoma. RT is one significant and potentially actionable iatrogenic suppressor of immune response that may limit the success of therapy. We hypothesized that a comprehensive evaluation of serial cytokine measurements during concurrent radiation and chemotherapy in glioblastoma will provide information about systemic immune status during treatment. 16 patients were enrolled in a single-institution, observational, immune surveillance study between 2018 and 2019. Peripheral blood was collected prior to starting radiation, and then weekly for a total of 7 timepoints. Plasma was isolated from blood, and cytokine levels were measured with a Luminex 23-cytokine panel. Survival was defined at 2 years since diagnosis. Patients >2 years were called survivors and <2 years were called non-survivors. Cytokine levels were compared with a cohort of 4 healthy controls. All data are log2 transformed using formula log2(x+1). ANOVA was used to find cytokines that differ among 3 groups. Only for those cytokines with significant ANOVA results, pair-wise t-test was performed. We found a total of 12 cytokines that were increased in plasma in glioblastoma patients undergoing radiation compared to control. Top cytokines to show differences were IL-10, M-CSF, TGF-b3 and TIM-3 (p<0.05). The others to show a difference were IP-10, MCP-1, TGF-b2, IL-34, PD-L1, LAG-3, PD-1, and CTLA-4. These cytokines are known to be immunosuppressive, and our results demonstrate a soluble mechanism of immunosuppression in this patient population. This cytokine signature can predict early during treatment the overall survival in patients with glioblastoma.

Clinical and immunological characteristics of high-risk double-hit multiple myeloma

At present, the characteristics of double-hit multiple myeloma (DHMM) are unknown. We retrospectively analyzed the clinical data from 433 new diagnosed MM patients and found that DHMM have a higher β2-MG level and percentage of bone marrow plasma cell. Cox regression analysis showed that the prognosis of DHMM was not limited by clinical indicators. The abnormal proliferation of bone marrow in DHMM is obvious, and the proportion of poorly differentiated plasma cell is high. By collecting specimens from our center and performing flow cytometry to analyze the immunophenotypic and functional characteristics of lymphocyte subpopulations, we found that DHMM had a higher ratio of Tregs cells, and the proportion of iTregs cells was also significantly higher than non-DHMM (P < 0.05). Moreover, DHMM had higher levels of TGF-β1 and IL-10, and TGF-β1 and IL-10 were positively correlated with iTregs (P < 0.05). In addition, DHMM was highly expressed PD-1 on CD8 + T cells and had a higher proportion of CD38highTregs cells. In vitro we have shown that the addition of TGF-β1 antibody or CD38 antibody can effectively inhibit the proportion of CD38high Tregs. This study describes the characteristics of DHMM based on bicentric data, which is helpful to better provide theoretical support for the treatment of DHMM.

Genomic Variants Associated with Haematological Parameters and T Lymphocyte Subpopulations in a Large White and Min Pig Intercross Population.

The breeding of disease-resistant pigs has consistently been a topic of significant interest and concern within the pig farming industry. The study of pig blood indicators has the potential to confer economic benefits upon the pig farming industry, whilst simultaneously providing valuable insights that can inform the study of human diseases. In this study, an F2 resource population of 489 individuals was generated through the intercrossing of Large White boars and Min pig sows. A total of 17 haematological parameters and T lymphocyte subpopulations were measured, including white blood cell count (WBC), lymphocyte count (LYM), lymphocyte count percentage (LYM%), monocyte count (MID), monocyte count percentage (MID%), neutrophilic granulocyte count (GRN), percentage of neutrophils (GRN%), mean platelet volume (MPV), platelet distribution width (PDW), platelet count (PLT), CD4+/CD8+, CD4+CD8+CD3+, CD4+CD8-CD3+, CD4-CD8+CD3+, CD4-CD8-CD3+, and CD3+. The Illumina PorcineSNP60 Genotyping BeadChip was obtained for all of the F2 animals. Subsequently, a genome-wide association study (GWAS) was conducted using the TASSEL 5.0 software to identify associated variants and candidate genes for the 17 traits. Significant association signals were identified for PCT and PLT on SSC7, with 1 and 11 significant SNP loci, respectively. A single nucleotide polymorphism (SNP) on SSC12 was identified as a significant predictor of the white blood cell (WBC) trait. Significant association signals were detected for the T lymphocyte subpopulations, namely CD4+/CD8+, CD4+CD8+CD3+, CD4+CD8-CD3+, and CD4-CD8+CD3+, with the majority of these signals observed on SSC7. The genes CLIC5, TRIM15, and SLC17A4 were identified as potential candidates for influencing CD4+/CD8+ and CD4-CD8+CD3+. A missense variant, c.2707 G>A, in the SLC17A4 gene has been demonstrated to be significantly associated with the CD4+/CD8+ and CD4-CD8+CD3+ traits. Three missense variants (c.425 A>C, c.500 C>T, and c.733 A>G) have been identified in the TRIM15 gene as being linked to the CD4+/CD8+ trait. Nevertheless, only c.425 A>C has been demonstrated to be significantly associated with CD4-CD8+CD3+. In the CLIC5 gene, one missense variant (c.957 T>C) has been identified as being associated with the CD4+/CD8+ and CD4-CD8+CD3+ traits. Additionally, significant association signals were observed for CD4+CD8+CD3+ and CD4+CD8-CD3+ on SSC2 and 5, respectively. Subsequently, a gene ontology (GO) enrichment analysis was conducted on all genes within the quantitative trait loci (QTL) intervals of platelet count, CD4+/CD8+, and CD4-CD8+CD3+. The MHC class II protein complex binding pathway was identified as the most significant pathway among the three immune traits. These results provide guidance for further research in the field of breeding disease-resistant pigs.

Hypofractionated radiotherapy with simultaneous integrated boost for localized prostate cancer patients: effects on immune system and prediction of toxicity.

The other side of radiotherapy (RT), in addition to the cytotoxic effect, is the ability to modulate the immune system in terms of activation or suppression, also depending on the dose and fractionation delivered. This immune RT effect can be detected both locally in the irradiated tumor site and in the peripheral blood. The aim of this study was to assess the consequence of pelvic irradiation on peripheral immune cells and cytokine secretions in localized prostate cancer (PC) patients undergoing pelvic irradiation with a simultaneous moderately hypofractionated prostate/prostate bed boost by Volumetric Modulated Arc Therapy (VMAT). Furthermore, we analyzed whether there was a correlation between these peripheral immune parameters and acute and late genitourinary (GU) and gastrointestinal (GI) toxicity. Thirty-eight PC patients were treated with pelvis irradiation (dose per fraction 1.8 Gy) and simultaneous hypofractionated (median dose per fraction: 2.7 Gy) prostate/prostate bed boost. A longitudinal analysis was performed for 12 months on peripheral blood to assess changes in 9 different lymphocyte subpopulations by flow cytometry and 10 circulating cytokines by Multiplex Luminex assay and ELISA. Our analysis revealed that basal IFN-γ serum values were significantly lower in the definitive (curative intent for patients with prostate) patient group respect to the post-operative one. All the lymphocyte subsets and IFN-α, IFN-β and Il-2 peripheral concentrations displayed significant variations between the different time points considered. The immune cell population that suffers the greatest RT toxicity in the blood was B lymphocyte. We found an interesting correlation between basal TGF-β1 and late GU toxicity. In particular, TGF-β1 concentrations before RT were significantly higher in patients that experienced grade 2-3 of late GU toxicity, respect to grade 0-1. Exploring possible correlations between some clinical/biological findings and radiation planning parameters, we found no statistical significance. Our study analyzed, in the context of hypofractionated radiotherapy in prostate cancer, different parameters of the peripheral immune system. We have highlighted longitudinally the peripheral behavior of the different lymphocyte subpopulations and of a group of 10 cytokines during the first year after RT. One of the analyzed cytokines, such as TGF-β1, has proven to be promising predictive factor of severe late GU toxicity.

Вплив імуносупресивної терапії на стан імунного захисту в дітей

For the treatment of rheumatological diseases, autoimmune lymphoproliferative syndrome and nephrotic syndrome in children, glucocorticosteroid therapy with/without cytostatics is used. Immunosuppression is a serious side effect of these medications. Aim - to investigate immunological parameters in children receiving immunosuppressive therapy in order to determine vaccination tactics. Materials and methods. 50 healthy children (comparison group) and 34 children who received immunosuppressive therapy for rheumatological pathology, autoimmune lymphoproliferative syndrome or nephrotic syndrome (study group) participated in the study. Patients who received high-dose immunosuppressive therapy (n=16) made up the subgroup I, low-dose immunosuppressive therapy (n=18) - the subgroup II. Determination of subpopulations of blood lymphocytes was carried out by the method of flow cytometry, serum immunoglobulins - by the method of radial immunodiffusion. Statistical analysis was performed using the SPSS 23.0 software package. Results. In children who received immunosuppressive therapy, a significant increase in the number of T-lymphocytes (CD3+), a decrease in B-lymphocytes (CD19+) and NK cells (CD3-CD16/56+) was established, while the average levels of serum IgA, IgM, IgG did not differ from the indicators of healthy children, which demonstrates the preservation of humoral immunity. However, in children who received high-dose immunosuppressive therapy, a dose-dependent decrease in the level of serum IgA, IgM, and IgG was found, respectively, by 1.7, 1.3 times, and by 18.9%. Conclusions. It is advisable to vaccinate children before starting immunosuppressive therapy for rheumatological pathology or nephrotic syndrome. The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of all participating institutions. The informed consent of the patient was obtained for conducting the studies. No conflict of interests was declared by the authors.

New concept for the prevention of acute respiratory infections

Medical personnel and family members of patients with acute respiratory diseases (ARD) are at increased risk of infection during epidemics or pandemics. In this regard, it is necessary to develop and implement accessible preventive measures. The aim of the study was to evaluate the effectiveness of the use of IFNα-2b for the prevention of acute respiratory viral infections in persons located at the source of infection (medical personnel and members of their families). Patients (n = 31) with acute respiratory infections and 117 people from their environment (family members in constant contact with patients) were examined. The subjects underwent a clinical examination and laboratory tests a clinical blood test and a study of the content of the main populations and subpopulations of lymphocytes in the blood. Persons in contact with ARD patients were divided into three groups: persons who received the drug “Grippferon” for 7 days; persons who received the drug “Grippferon” in a prophylactic dose for 7 days; persons in contact with patients with ARD but who have not received the drug “Grippferon”. When assessing the state of the immune system, it was found that the most common type of immune reaction in patients and their people around was activation of innate immunity (48.39% and 66.67%, respectively). At the same time, immunodeficiency in the group of patients with ARD was detected much more often than in persons in contact with them. In addition, patients were more likely to have monocytosis (1.4 times), T lymphocytopenia (2.1 times) and an increase in the number of regulatory T lymphocytes (7.6 times). More than 50% of those examined in both groups showed an increase in the number of NK cells in the blood. An examination of persons in contact with patients with ARD after 7 days of using the “Grippferon” in different doses revealed that the lowest frequency of acute respiratory viral infections symptoms was found in the group receiving IFN at a therapeutic dose. In the group receiving IFN in a prophylactic dose, the frequency of acute respiratory viral infection (ARVI) symptoms was detected in almost 40% of those examined. More than 80% of people from the group who did not receive the “Grippferon” had symptoms of ARVI after a week of contact with patients with ARD. Thus, the use of IFN in therapeutic doses during the epidemic for persons in contact with patients is proposed as a new concept for the prevention of ARD.

Indicators of the cytokine profile and standard immunogram in the controlled and uncontrolled course of bronchial asthma in children

Bronchial asthma in children is a multifactorial disease, but it is based on atopic inflammation, which is the focus of the main methods of research and therapy of this pathology. However, if we evaluate not only the fact of the appearance of bronchial asthma in a particular patient, but also consider its course in more detail, and especially the possibility of achieving control over the disease, then indicators of not only atopic inflammation, but also local inflammation in general, acquire great influence, which is one of the reasons for the continuing high percentage of uncontrolled and partially controlled course bronchial asthma in children. The purpose of this work is to identify changes in cytokine status indicators and immunograms – markers of the risk of uncontrolled bronchial asthma. 167 patients with bronchial asthma were examined, who, based on a standard clinical and instrumental examination, according to the criteria of clinical recommendations, were divided into two groups – controlled (70 people) and partially controlled and uncontrolled (97 children). All of them had their cytokines and IgA, IgM, IgG, IgE levels determined, in blood serum by ELISA, subpopulations of lymphocytes by flow cytometry, indicators of neutrophilic phagocytosis by light microscopy. In the group with uncontrolled asthma, the following significant differences were noted: a decrease in the level of IL-7, IL-9 and an increase in IL-8, there is also a higher level of B lymphocytes, IgE and IgM, and a lower level of IgA, similar changes, but less pronounced, were previously detected in other studies when comparing patients with bronchial asthma and conditionally healthy, as well as mild and severe course diseases. There were no significant differences in the other studied indicators. It is noteworthy that the greater influence on the control of the disease in bronchial asthma is not exerted by atopic cytokines responsible for the very fact of atopic inflammation, but by cytokines of general inflammation, such as IL-7, IL-8, IL-9, regulating the severity of inflammation in general, the role of IL-8 as a cytokine of granulocyte chemotaxis regulating local inflammation is especially interesting.

Monitoring Immune Dysfunction in Critically Ill Patients with Carbapenem-Resistant Acinetobacter baumannii Sepsis Treated with Regimens Including Cefiderocol: A Pilot Study to Identify Accessible Biomarkers to Stratify Patients' Prognosis.

Background: Multidrug-resistant Acinetobacter baumannii (CRAB) infections are a serious problem in critical care. This study aims to develop an early prognostic score for immune paralysis, using practical and cost-effective parameters, to predict ICU mortality in patients with CRAB infections being treated with Cefiderocol. Methods: We carried out an observational pilot study on consecutive patients hospitalized in the ICU with ensuing septic Acinetobacter baumannii infections treated with Cefiderocol monotherapy or Cefiderocol including combinations. We investigated the predictive power of lymphocyte counts, lymphocyte subpopulations, serum cholinesterase levels, and reactivation of herpes viruses. Results: Overall, 36 of 39 patients entered in our analysis: 20 survivors and 16 deceased. A total of 12 patients developed bacteremia, 19 patients had HAP/VAP, and 5 patients had a soft tissue infection. Univariate analyses of factors associated with unfavorable outcome revealed a significant association for age (OR: 1.5, CI: 1.11-2.02), SAPS II (OR: 1.05, CI: 1.01-1.1), SOFA score (OR: 1.37, CI: 1.06-1.76), lymphocytopenia (OR: 32.5, CI: 3.45-306.4), viral reactivation (OR: 9.75, CI: 1.72-55.4), and cholinesterase drop <1600 U/L (OR: 39.7, CI: 5.8-271.6). At variance, monotherapy or associations with Cefiderocol were not associated. In the final multivariable model, the only independent predictors of death were age (OR: 1.42, CI: 0.98-2.05), lymphocytopenia (OR: 18.2, CI: 0.87-371), and cholinesterase drop to below 1600 U/L (OR: 9.7, CI: 0.77-123.7). Conclusions: Age, lymphocytopenia, and serum cholinesterase drops, which were nearly significantly associated with an unfavorable outcome, may help pinpoint patients with acute immune paralysis during sepsis. Knowledge of such an immune state may in turn directly influence patients' care.

Correlation between elderly patients with COPD and the impact on immunity in tuberculosis patients: A retrospective study.

The prevalence of chronic obstructive pulmonary disease (COPD) and tuberculosis (TB) is increasing globally, yet their comprehensive impact on the immune system remains underexplored. This study aimed to provide a thorough assessment of the immune status of patients with COPD and tuberculosis (TB-COPD), including their pulmonary conditions, immune cell responses, and changes in lymphocyte subpopulations. A total of 151 patients with TB-COPD patients were included, and clinical data were compared between the TB-COPD group and a group of TB patients without COPD (TB-NCOPD). Lung imaging findings and peripheral blood immune cell levels were compared between the 2 groups. Flow cytometry was used to analyze the absolute counts of lymphocyte subpopulations. The incidence of pulmonary lobe lesions and cavitation in the TB-COPD group aged 70 years or older was significantly higher than that in the control group. At the immune cell level, patients with TB-COPD showed a significant reduction in total lymphocytes, CD4+ T lymphocytes and CD4+/CD8+ ratio. Regardless of COPD status, the CD4+ T cell count in the CMV-infected group was significantly lower than that in the uninfected group (P < .05). Additionally, the CD4+/CD8+ ratio in the COPD + TB CMV + group was significantly lower than that in the uninfected group. Analysis of lymphocyte subpopulations revealed a decrease in the counts of CD4+ T lymphocytes in patients with TB-COPD, potentially associated with the chronic inflammatory state induced by COPD. The one-month treatment outcomes showed that the improvement rate in the control group was 70.58%, which was significantly higher than the 38.92% in the COPD + TB group (P < .001). We observed a significant increase in the number of pulmonary cavity patients in the TB-COPD group, suggesting that COPD may be a potential risk factor for the formation of pulmonary cavities in patients with TB. At the immune cell level, TB-COPD patients showed a notable decrease in lymphocytes and CD4+ T lymphocytes, implying that COPD combined with pulmonary TB may significantly affect the immune system, leading to a reduction in the counts of key immune cells.

Expression of Concern: Multiple In Vitro and In Vivo Regulatory Effects of Budesonide in CD4+ T Lymphocyte Subpopulations of Allergic Asthmatics.

Expression of Concern: Multiple In Vitro and In Vivo Regulatory Effects of Budesonide in CD4+ T Lymphocyte Subpopulations of Allergic Asthmatics.

The effects of chronic fatigue and chronic stress on alterations in immune cell responses to acute psychosocial stress

Fatigue is a common and debilitating symptom of a broad spectrum of diseases. Previous research has shown that individuals suffering from chronic forms of fatigue experience significantly more stress compared to healthy individuals, suggesting that stress is a potential pathophysiological factor in the onset and maintenance of chronic fatigue. Individually, chronic experiences of fatigue and stress have been associated with disruptions in adaptive immunity. However, how chronic fatigue and chronic stress together affect immune regulation is not fully understood. Here, we investigated the unique and combined contribution of chronic fatigue and chronic stress on immune cell redistribution in response to, and recovery from, acute psychosocial stress. Eighty women with high or low levels of chronic fatigue and varying levels of chronic stress were exposed to a psychosocial laboratory stressor. Blood samples were collected 10 min before and then at 10, 40, and 100 min after the end of stress. The main lymphocyte subpopulations (CD3+, CD3 + CD4+, CD3 + CD8+, CD16 + CD56+, and CD19 + cells) were enumerated via flow cytometry. Acute stress resulted in an increase in CD8 + and CD16+/CD56 + cells, a decline in CD4 + cells, and no effects on CD19 + B lymphocytes. Importantly, the magnitude of immune cell redistribution during stress reactivity (CD3+, CD4+, CD16+/CD56 + ) and recovery (CD3 + ) was contingent on fatigue and chronic stress levels of individuals. Notably, in contrast to low-fatigued individuals, who showed steeper changes in cell populations, increasing levels of chronic stress did not impact immune cell migration responses in high-fatigued individuals. Our findings demonstrate the compounded blunting effects of fatigue and chronic stress on adaptive immune functioning, highlighting a potential pathway for vulnerability and detrimental effects on long-term health.

Lymphocytes Change Their Phenotype and Function in Systemic Lupus Erythematosus and Lupus Nephritis.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease, characterized by considerable changes in peripheral lymphocyte structure and function, that plays a critical role in commencing and reviving the inflammatory and immune signaling pathways. In healthy individuals, B lymphocytes have a major role in guiding and directing defense mechanisms against pathogens. Certain changes in B lymphocyte phenotype, including alterations in surface and endosomal receptors, occur in the presence of SLE and lead to dysregulation of peripheral B lymphocyte subpopulations. Functional changes are characterized by loss of self-tolerance, intra- and extrafollicular activation, and increased cytokine and autoantibody production. T lymphocytes seem to have a supporting, rather than a leading, role in the disease pathogenesis. Substantial aberrations in peripheral T lymphocyte subsets are evident, and include a reduction of cytotoxic, regulatory, and advanced differentiated subtypes, together with an increase of activated and autoreactive forms and abnormalities in follicular T cells. Up-regulated subpopulations, such as central and effector memory T cells, produce pre-inflammatory cytokines, activate B lymphocytes, and stimulate cell signaling pathways. This review explores the pivotal roles of B and T lymphocytes in the pathogenesis of SLE and Lupus Nephritis, emphasizing the multifaceted mechanisms and interactions and their phenotypic and functional dysregulations.

Characterization of systemic lupus erythematosus subtypes using cluster analysis: insights from lymphocyte subpopulations.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease, in which lymphocyte subsets were dysregulated. Incorporating lymphocyte subpopulations in cluster analysis offers a pathway for personalized and precise treatment, targeting specific abnormalities for more effective management. We conducted Gaussian clustering analysis on clinical data, serological data, urine test results, and lymphocyte subpopulations for SLE patients hospitalized from September 2008 to December 2019. A total of 1863 SLE patients from Xi'Jing Hospital were included. After excluding those without complete assessments, 1281 patients underwent flow cytometry for lymphocyte subsets. Five SLE clusters emerged: Cluster 1 with severe kidney involvement, high SLEDAI scores, and infection rates, often accompanied by rashes and edema; cluster 2 with high urinary protein but better renal function; cluster 3 with normal lymphocyte count and low positive antibodies; cluster 4 with frequent psychiatric symptoms and pulmonary arterial hypertension (PAH); and cluster 5 with fever, arthritis, hematologic involvement, and high IgG levels despite decreased B cells. All enrolled SLE patients were ultimately categorized into five distinct clinical phenotype groups, with lymphocyte testing being meaningful for patient stratification. This finding shed light on the intricate heterogeneity of SLE, emphasizing the need for a personalized medicine approach. Targeting specific abnormalities in lymphocyte subsets holds promise for more effective and precise management of SLE. Key Points • A comprehensive analysis of SLE patients, including lymphocyte subpopulations, revealed five distinct clusters with varying clinical characteristics, emphasizing the heterogeneity of the disease. • This heterogeneity underscores the need for a personalized medicine approach in SLE management, targeting specific lymphocyte subset abnormalities for more effective and precise treatment.

Antiretroviral therapy combined with Shenling Guben Granules for the treatment of HIV infection with immune reconstitution deficiency: A randomized, double-blind, placebo-controlled study

Background: Even with long-term complete suppression of the virus through Antiretroviral therapy (ART), people infected with HIV cannot attain optimal immune reconstitution. This phenomenon is called immune reconstitution deficiency, there are no effective therapeutic interventions for immune reconstitution deficiency in modern medicine. Objective: To evaluate the efficacy and safety of ART with Shenling Guben Granules Traditional Chinese medicine in boosting immunological reconstitution compared with ART alone. Methods: This was a randomized, double-blind, placebo-controlled, multi-center clinical trial evaluating the efficacy and safety of ART combined with Chinese medicine. The individuals aged 18–65 years with poor immune reconstitution following ART were included in this trial. The primary outcome was a change in the absolute value of CD4+ T lymphocytes after 72 weeks of combined ART and Chinese medicine administration. Secondary outcomes included changes in CD4+ T lymphocyte functional subpopulations, activated T lymphocyte subpopulations, CD4+ T lymphocyte proliferation, and T lymphocyte apoptosis from baseline to after 72 weeks. We also evaluated efficacy at 24- and 48-week intervals to better understand the dynamics of the trial drug’s efficacy. Results: There was a significant increase in CD4+ cell counts in groups treated with the Shenling Guben Granules after 24 weeks, 48 weeks, and 72 weeks of treatment (P&lt;0.05), and the difference in CD4+ cell counts at 24 weeks of treatment was statistically significant (P=0.010). After 48 and 72 weeks of therapy, the CD4+CD38+ cell counts in the Shenling Guben Granules group were significantly higher than in the control group (P&lt;0.05). In the subgroup analysis of CD4+ cell counts ≥200 cells/mm3, the CD4+ cell counts in the treatment group were higher than the control group after treatment for 24, 48, and 72 weeks (P&lt;0.05). Discussion: CD4 cell counts in HIV/AIDS patients with immunological reconstitution insufficiency can be improved to a certain extent using Shenling Guben Granules. The greater the CD4 cell count at the start, the better the therapy response. Furthermore, Shenling Guben Granules have the efficacy and safety to prevent aberrant immunological activation. A large sample size, long-term follow-up, and multiple efficacy indicators were employed to assess the therapy’s safety. Our findings will lead to new therapeutic alternatives for HIV/AIDS patients suffering from immune reconstitution deficiency. Clinical Trial Registry: Name of the registry: Sundy on promote the reconstruction of Inadequate responders in HIV/AIDS patients after combined antiretroviral therapy by Shen Ling Gu Ben Granules;Chictr.org.cn Identifier: ChiCTR1800015290, registered on March 21, 2018( http://www.chictr.org.cn/registry.aspx).

Long-term modifications of the peripheral immune repertoire after switching from sequestering disease-modifying treatments in multiple sclerosis

Background: Scarce data are available on the long-term immunological effects of multiple sclerosis (MS) disease-modifying treatments (DMTs). Objectives: This study aimed to investigate the long-term modifications of the peripheral immune repertoire on interruption of a sequestering DMT (natalizumab, fingolimod) and switch to another high-efficacy DMT. Methods: Lymphocyte subpopulations were assessed, every 6 months up to 48 months, in patients switched from fingolimod or natalizumab to ocrelizumab, and in patients switched from fingolimod to natalizumab, compared to patients switched to ocrelizumab or natalizumab from a moderate-efficacy DMT and to naive patients. Results: We included 389 MS patients (200 ocrelizumab and 189 natalizumab). After adjusting for baseline variables, patients switched from fingolimod to ocrelizumab showed lower CD3 + and CD4 + lymphocytes up to 48 months after switch (with lower percentage of naive CD4 +), and increased odds of total, CD3+, CD4+ lymphopenia. Patients switched from natalizumab to ocrelizumab showed higher CD3 + lymphocytes up to 36 months after switch, and higher CD4+, CD8+ lymphocytes up to 24 months. The frequency of infections was not influenced by previous treatment. Conclusions: A long-term persistence of the residual effects of the exposure to sequestering DMTs (fingolimod and less natalizumab) on the peripheral immune repertoire was observed after switching to another high-efficacy DMT.

Peripheral blood lymphocyte subpopulations as predictive biomarkers for first-line programmed death 1 inhibitors efficacy in esophageal squamous cell carcinoma: A retrospective study.

Esophageal cancer (EC) poses a significant global health burden, necessitating effective treatment strategies. Immune checkpoint inhibitors have emerged as a promising therapeutic option for EC, but the identification of predictive biomarkers remains crucial for optimizing patient outcomes. We conducted a retrospective analysis of medical records from advanced esophageal squamous cell carcinoma patients treated with first-line programmed death 1 inhibitors. Peripheral blood lymphocyte subpopulations were evaluated using flow cytometry, while hematological tests provided data on neutrophil, lymphocyte, and monocyte counts. Cox regression and logistic regression analyses were employed to explore the association between lymphocyte subpopulations, baseline characteristics, and progression-free survival (PFS). Among the 100 initially included patients, 70 met eligibility criteria. Multivariate Cox regression analysis revealed a significant association between high CD16+CD56+ lymphocyte proportions and longer PFS, independent of other clinical variables. Similarly, a high CD4+/CD8+ ratio was correlated with prolonged PFS. Kaplan-Meier survival curves supported these findings. Logistic regression analysis indicated no significant differences in the CD4+/CD8+ ratio and CD16+CD56+ lymphocytes concerning baseline characteristics, suggesting their potential as independent prognostic markers. Our study highlights the predictive value of peripheral blood CD16+CD56+ lymphocytes and the CD4+/CD8+ ratio for the efficacy of programmed death 1 inhibitors in advanced esophageal squamous cell carcinoma patients. These findings underscore the importance of peripheral blood biomarkers in guiding personalized immunotherapy strategies and improving outcomes for EC patients.

Therapeutic effects of S-allyl-L-cysteine in a mouse endometriosis model and its immunomodulatory effects via regulation of T cell subsets and cytokine expression.

Endometriosis is a female hormone-dependent gynecological disorder characterized by chronic inflammation. Therefore, the development of novel treatment strategies that can diminish the side effects of the long-term use of hormone-based drugs has been emphasized. S-Allyl-L-cysteine (SAC) is the major constituent of aged garlic extracts. Although the therapeutic effects resulting from the antioxidant properties of SAC have been extensively studied in inflammatory diseases, the therapeutic efficacy of SAC in endometriosis has not been described. In this study, we investigated the therapeutic potential of SAC for endometriosis using a mouse model. An endometriosis mouse model was surgically induced, and oral treatment with 30mg/kg SAC was administered daily for 28 days. The development of endometriotic lesions was assessed by histological analysis, and the expression profiles of adhesion-, apoptosis-, and inflammation-related genes were evaluated by PCR. Flow cytometric analysis of mouse spleen was conducted to assess changes in lymphocyte subpopulations. SAC treatment significantly inhibited endometriotic lesion growth. Transcriptional expression analysis revealed the antiadhesion and apoptosis-promoting effects of SAC. In particular, SAC showed an effective immune modulatory response by altering splenic CD4+ and CD8+ T cell subsets and inflammatory cytokine production in the spleen and endometriotic lesions. This study newly elucidates the inhibitory effects of SAC on the growth of endometriosis in a mouse model and describes its immunomodulatory effects.

Субпопуляционный состав лимфоцитов костного мозга при хроническом лимфоцитарном лейкозе у пациентов с различным ответом на противоопухолевое лечение

AIM. To analyze the bone marrow lymphocyte subpopulation based on targeted assessment of PD-1, PD-L1, and LAG-3 marker expression in chronic lymphocytic leukemia (CLL) patients with different responses to chemotherapy. MATERIALS &amp; METHODS. In 33 CLL patients, PD-1, PD-L1, and LAG-3 antigen expression on В-, Т-, and NK-cells of the bone marrow (BM) was analyzed by flow cytofluorometry prior to treatment and after 6 cycles of chemotherapy with rituximab. Patients were aged 58–68 years (median 64 years); there were 14 women and 19 men. Hematologic response was assessed by measurements of minimal residual disease (MRD). On this basis, patients were divided into two groups: group 1 (n = 20) with satisfactory hematologic response (MRD &lt; 1 %) and group 2 (n = 13) with unsatisfactory hematologic response (MRD ≥ 1 %). RESULTS. Prior to treatment, the count of PD-1-, LAG-3-, CD38-, and ZAP-70-expressing BM tumor B-cells was lower in patients of group 1 than in those of group 2. After treatment, their decrease was more pronounced in group 1. Prior to treatment, patients in group 1 had a higher count of BM T-lymphocytes with CD3+, CD4+, CD8+, CD8+/CD28+, CD8+/CD28–, and CD8+/CD38+ phenotype including PD-1- but neither PD-L1- nor LAG-3-expressing T-cells. After treatment, increased T-cells with CD3+, CD4+, CD8+, Treg, CD8+/CD28+, and CD8+/CD28– phenotype including PD-1+ T-lymphocytes were detected in both groups but more pronounced in group 2. In this group, CD3+ и CD4+ T-lymphocytes maintained LAG-3 expression. Prior to treatment, all patients showed decreased NK-cells in BM. After treatment, group 1 showed a higher count of NK-cells with CD3–/CD16+/CD56+ and CD3–/CD16+/CD56+/PD-1+ phenotype and a lower count of NK-cells with CD3–/CD16+/CD56+/LAG-3+ phenotype. PD-L1 expression in NK-cells was not detected, whereas in Т- and В-cells it was moderate prior to treatment and was not identified after hematologic response was achieved. CONCLUSION. The values determined by the targeted assessment of PD-1 and LAG-3 expression in BM В-, Т-, and NK-cells prior to chemotherapy may well be used in clinical practice as additional prognostic factors in CLL. PD-1 and LAG-3 overexpression in Т-lymphocytes and NK-cells in CLL patients with MRD-positive status after chemotherapy can be regarded as evidence of the functional deficiency of these cells.