Immunologic Research最新文献

Background: Pomalidomide, a third-generation oral immunomodulatory drug, exhibits efficacy in patients with relapsed multiple myeloma or those refractory to bortezomib and lenalidomide (RRMM).

Methods: In this clinical context, we employed flow cytometry and CDR3 spectratyping to monitor the dynamics of the T-cell repertoire during Pomalidomide treatment, aiming to investigate its potential to reverse the immunological abnormalities characteristic of RRMM.

Results: By flow cytometry at baseline we found a significant decrease in CD4 + frequency in MM patients, while CD8 + frequency were significantly higher in patients when compared to controls. Most T cell populations remained stable across all time points, except for CD4 + frequency, which notably decreased from t1 to subsequent assessments. Our investigation revealed as most relevant finding the notable increase in CD4 + expansions and the growing prevalence of patients manifesting these expansions. This pattern is even more evident in patients receiving their treatment until t3 and therefore still responding to treatment with Pomalidomide. We also conducted a comparison of spectratyping data before and after treatment, substantially demonstrating a relatively stable pattern throughout the course of Pomalidomide treatment.

Conclusions: These observations imply that Pomalidomide treatment influences the T-cell repertoire, particularly in the CD4 + subpopulation during the later stages of treatment, raising speculation about the potential involvement of these lymphocyte expansions in mechanisms related to antitumor immunity.

We report a pediatric patient with prolidase deficiency, caused by a mutation in the PEPD gene, which encodes the enzyme prolidase D, with a lupus-like clinic and marked dysmorphic features along with pulmonary, neurological, skeletal, and immune system involvement. In addition to being the first known case in the literature where Friedrich’s ataxia and prolidase deficiency were observed together, we aimed to highlight that this diagnosis should be considered in patients with autoimmunity and additional systemic findings such as treatment-resistant skin lesions, intellectual disability, and pulmonary manifestations. Furthermore, we sought to compare this case with others documented in the literature.

Asthma is featured by persistent airway inflammation. Long noncoding RNAs (lncRNAs) are reported to play critical roles in asthma. However, the function of Opa interacting protein 5-antisense 1 (OIP5-AS1) in pyroptosis during the development of asthma remains unexplored. The blood samples of asthma patients (n = 32) as well as the baseline characteristics of asthma patients or healthy people were collected. An in vivo model of asthma was established using house dust mites (HDM). To mimic asthma in vitro, BEAS-2B cells were treated with HDM. Cell pyroptosis and apoptosis were examined by flow cytometry. The levels of interleukin-1 beta (IL-1β) and interleukin-18 (IL-18) were detected by enzyme-linked immunosorbent assay (ELISA). The binding among messenger RNAs (mRNAs) was assessed by chromatin immunoprecipitation (ChIP), dual luciferase report assay, RNA immunoprecipitation (RIP), co-immunoprecipitation (Co-IP), and RNA pull-down assay, respectively. The cellular localization was observed by fluorescence in situ hybridization (FISH) staining. The level of OIP5-AS1 was upregulated in asthma patients. HDM induced pyroptosis and increased the levels of IL-18, IL-1β, and lactate dehydrogenase (LDH) in BEAS-2B cells, which was obviously reversed by OIP5-AS1 knockdown. Consistently, the expressions of NOD-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), c-caspase 1, and pyroptosis-related gasdermin D-1 (GSDMD-1) in BEAS-2B cells were upregulated by HDM treatment, while these phenomena were partially abolished by silencing of OIP5-AS1. Moreover, HDM promoted the progression of asthma in vivo, which was rescued by the downregulation of OIP5-AS1. OIP5-AS1 silencing decreased HDM-induced cell pyroptosis by inactivation of NLRP3. More importantly, OIP5-AS1 promoted the mRNA stability of yes-associated protein (YAP) via binding with eukaryotic translation initiation factor 4A3 (EIF4A3), and OIP5-AS1 was transcriptionally upregulated by doublesex and mab-3 related transcription factor 3 (DMRT3). DMRT3-mediated OIP5-AS1 aggravated the progression of asthma by mediation of the EIF4A3/YAP axis, which might provide a new therapeutic strategy against asthma.

Vaccines are an identified cause of autoimmune/inflammatory syndrome induced by adjuvants (ASIA syndrome). In this research, we aimed to investigate the remarkable features of patients, whom we classified as ASIA syndrome, developing rheumatoid arthritis (RA) after BNT162b2 vaccination. Patients who were asymptomatic before the BNT162b2 vaccination, developed chronic arthritis within 3 months after the vaccination, and fulfilled the 2010 American College of Rheumatology/European League Against Rheumatism RA classification criteria were enrolled in the study. Demographic, laboratory, clinical, and treatment characteristics were reviewed retrospectively. We identified ten patients developing RA following BNT162b2 vaccination. The median age was 54.5 years and six of them were female. The median time between vaccination and onset of symptoms was 7 days; seven patients had acute arthritis, and four had intermittent arthritis at the onset of the disease. Only three patients had a disease onset in the small joints of the hands. All patients had radiological erosions on hand X-rays. We reported a case series of patients, classifiable as having ASIA syndrome, who developed RA with radiological erosions after the BNT162b2 vaccine. The onset of the disease in joints different from the typically expected ones, along with the early development of erosions in hand X-rays, suggests that these cases may follow a course distinct from classic RA. RA that develops following mRNA vaccination may have an aggressive course, but studies with larger sample sizes are needed.

This study aims to explore the relationship between serum soluble interleukin-2 receptor alpha (sIL-2Rα) levels and histologic features in immunoglobin A nephropathy (IgAN), and evaluate its predicting values on disease progression and remission status. IgAN patients were included retrospectively. Lee classification, Oxford classification and histological scoring were evaluated. Patients’ estimated filtration rate (eGFR) and proteinuria remission status were collected during 6-month follow-up. Logistic regression was used to determine the risk factors and predicting value. Receiver operating characteristic (ROC) curve were used to determine the predicting value for outcome. One hundred seventy-two subjects were included in this study. Individuals in moderate-to-severe tubulointerstitial inflammatory cell infiltration group manifested with significantly elevated serum sIL-2Rα levels than those in non-to-mild group. Serum sIL-2Rα levels were positively correlated with infiltration scores. Serum sIL-2Rα was an independent risk factor for moderate-to-severe inflammatory cell infiltration [sIL-2Rα: OR 1.29 (1.015–1.640, p = 0.038)]. ROC curve analysis regarding predictive value for moderate-to-severe inflammatory cell infiltration of sIL-2Rα suggested area under curve was 0.859 (0.801–0.918, p = 0.000) when sIL-2Rα combined with eGFR < 60 mL/(min·1.73 m²), 24-h proteinuria excretion > 1.0 g, and hemoglobin. It showed good sensitivity (71.6%) and specificity (87.6%). Additionally, sIL-2Rα levels at kidney biopsy were strong predictive factor for kidney function loss 6 months after kidney biopsy [OR 4.161 (1.013–17.088, p = 0.048)]. High serum sIL-2Rα was significantly associated with serious inflammatory cell infiltration in IgAN, and it showed strong predictive value for disease prognosis. Serum sIL-2Rα could be a useful noninvasive biomarker to evaluate the extent of histological injury and disease prognosis in IgAN.

Diffuse large B-cell lymphoma (DLBCL) is a common malignancy among people living with HIV. Macrophage enrichment of the tumour microenvironment (TME) is a prognostic factor in DLBCL among immunocompetent people, with some studies reporting that macrophage enrichment predicts a superior response to rituximab therapy. The macrophage phenotype is also important, with reportedly poorer outcomes with enrichment of anti-inflammatory (M2) macrophages. To date, the relationship between the type/number of tumour macrophages and outcomes in HIV-associated DLBCL (HIV-DLBCL) has been poorly explored. In this study, we assessed tumour macrophage numbers in a South African cohort of patients with DLBCL and a high HIV-seropositivity rate. Immunohistochemistry for CD68 and CD163 was performed on the diagnostic biopsies of 79 patients with DLBCL. Relevant information was documented from the clinical records, including disease stage, international-prognostic index score, HIV-related parameters, C-reactive protein, ferritin levels and immune cell numbers (monocytes, lymphocytes and neutrophils). Survival analysis was performed using Kaplan–Meier survival estimates, and the correlation between tumour macrophage numbers and a variety of immunological parameters was assessed using Spearman’s rho. Of the 79 patients included, 87.2% were living with HIV, and rituximab therapy was used in 46.9%. Tumour macrophage numbers were not related to HIV status, but low pro-inflammatory (M1) macrophage numbers (CD68 + CD163 −) were significantly associated with poorer outcomes (HR 2.02, p = 0.03). M2 macrophage (CD68 + CD163 +) enrichment was not predictive of survival but was associated with improved response to rituximab therapy (HR 0.19; p = 0.002). Macrophage numbers were marginally correlated with ferritin levels, which showed modest performance as a peripheral blood biomarker of the TME macrophage status (AUC 0.6 at a level of 374 µg/L), and high ferritin levels were associated with a superior response to rituximab-therapy (HR 0.28, p = 0.034). Pro-inflammatory macrophages are important in tumour control in HIV-DLBCL, while M2 macrophage enrichment improves the response to rituximab therapy. Ferritin shows promise as a biomarker for identifying patients more likely to benefit from rituximab therapy.

Multiple myeloma (MM) is a malignancy of plasma cells accompanied by immune dysfunction. This study aimed to provide a comprehensive and dynamic characterization of the peripheral immune environment in MM patients and find its diagnostic and prognostic values for therapy. The peripheral immune profiles of MM inpatients and healthy controls were assessed by flow cytometry. A longitudinal study of immune subsets was observed during cycles of chemotherapy. The diagnostic and prognostic models were established based on immune subsets by the absolute shrinkage and selection operator (LASSO) and multivariate regression. MM patients possessed an impeded immune landscape, including reduced activation of B cells, increased effective T cells and regulatory T cells (Tregs), augmented CD16 expression on monocytes and dendritic cell percentages, decreased CD56^dimCD16⁺ natural killer cells (NKs), and amplified CD56^bright and HLA-DR⁺ natural killer T cells (NKTs). Chemotherapy has different dynamic effects on specific cells, of which 2 cycles is the key turning point. NKT, dendritic cells, naïve Tc and Th cells, HLA-DR⁺ Tc cells, CD56^dim NKTs, CD16⁺⁺ monocytes, and CD25⁺ B cells could have the diagnostic value, and a prognostic model including neutrophils, naïve Tc cells, CD56^brightCD16^dim NKs, and CD16⁺ dendritic cells was established with acceptable accuracy. Our data showed dynamic and abnormal peripheral immune profiles in MM patients, which had prognostic values and could provide the basis for clinical therapy.

The complex relationship between natural killer (NK) cells and dendritic cells (DCs) within the tumor microenvironment significantly impacts the success of cancer immunotherapy. Recent advancements in cancer treatment have sought to bolster innate and adaptive immune responses through diverse modalities, aiming to tilt the immune equilibrium toward tumor elimination. Optimal antitumor immunity entails a multifaceted interplay involving NK cells, T cells and DCs, orchestrating immune effector functions. Although DC-based vaccines and NK cells' cytotoxic capabilities hold substantial therapeutic potential, their interaction is frequently hindered by immunosuppressive elements such as myeloid-derived suppressor cells (MDSCs) and regulatory T cells. Chemokines and cytokines, such as CXCL12, CCL2, interferons, and interleukins, play crucial roles in modulating NK/DC interactions and enhancing immune responses. This review elucidates the mechanisms underlying NK/DC interaction, emphasizing their pivotal roles in augmenting antitumor immune responses and the impediments posed by tumor-induced immunosuppression. Furthermore, it explores the therapeutic prospects of restoring NK/DC crosstalk, highlighting the significance of molecules like Sema3E/PlexinD1 in this context, offering potential avenues for enhancing the effectiveness of current immunotherapeutic strategies and advancing cancer treatment paradigms. Harnessing the dynamic interplay between NK and DC cells, including the modulation of Sema3E/PlexinD1 signaling, holds promise for developing more potent therapies that harness the immune system's full potential in combating cancer.

Systemic lupus erythematosus (SLE) is a chronic multifactorial autoimmune disease. It is now widely demonstrated that oxidative stress (OS) plays an important role in the modulation of the pathogenesis of this disease. Mitochondrial DNA (mtDNA) is highly vulnerable to OS and it is known a decrease of mtDNA copy number in SLE patients. However, to date, it has not been investigated if this decrease is associated with a dysregulation of mitochondrial homeostasis genes. Our aim is to evaluate the amount of mtDNA copy number and the expression of the genes more involved in the mitochondrial homeostasis pathways, in peripheral blood mononuclear cells (PBMCs) of SLE patients and healthy controls. We analysed the amount of mtDNA in PBMCs of 72 SLE patients and 61 healthy controls by qPCR. Then, we investigated the expression variability of TFAM and SIRT1 (biogenesis), MFN1 and MFF (fusion/fission) and PRKN2 (mitophagy) genes in a subgroup of SLE patients and healthy controls. Interestingly, we have observed a highly significant decrease in mtDNA copies in SLE patients compared to healthy controls (P < 0.0001). In addition, we have shown that the expression levels of SIRT1, MFN1 and PRKN2 genes were significantly decreased in SLE patients with respect to healthy controls (P = 0.00001 for SIRT1, P = 0.0150 for MFN1 and P = 0.0009 for PRKN2). Lastly, we have reported a positive correlation between PRKN2 expression level and mtDNA copy number (P = 0.019, r = 0.475). In conclusion, our data confirm the impairment of mtDNA copy number in the disease and show for the first time a dysregulation of the mitochondrial homeostasis genes. These results could provide additional support to the important role of mitochondria in SLE development.