A Proliferation-inducing Ligand Research Articles

Serum BAFF (B-cell activating factor) and APRIL (a proliferation-inducing ligand) levels in the first trimester may predict the future development of GDM (gestational diabetes mellitus)

BackgroundGestational diabetes mellitus (GDM) is a prevalent condition with an unclear pathogenesis. B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) are potential key players in GDM. Participants, materials, and methodsIn a longitudinal observational study, we monitored women from the first trimester through 24–28 weeks of gestation, focusing on the development of GDM. Serum levels of BAFF and APRIL, as well as their mRNA expression, were evaluated in both the first and third trimesters. Furthermore, we assessed cytokines, adipokines, and placental hormones in the serum. ResultsIn the first trimester, participants who later developed GDM exhibited elevated serum BAFF and reduced serum APRIL levels, although the mRNA expression of these molecules was similar to controls. Serum BAFF exhibited significant positive correlations with metabolic markers and placental hormones. Conversely, serum APRIL was negatively correlated with insulin resistance and inflammatory markers but positively correlated with adiponectin. In the early third trimester, GDM participants continued to display higher serum BAFF levels and lower serum APRIL levels than controls. There was no significant difference in mRNA expression of BAFF between GDM and control groups. Conversely, APRIL mRNA expression was significantly lower in the GDM group. The predictive potential of first-trimester BAFF and APRIL levels for future GDM development was explored, with both molecules demonstrating strong predictive capability. Discussion and conclusionThis study suggests that elevated serum BAFF and reduced serum APRIL levels during pregnancy may be associated with the development of GDM. These biomarkers can serve as potential early predictors for GDM.

Immunomodulatory effects of BAFF and APRIL cytokines in post-pulmonary infection lung cancer: Implications for drug resistance and progression.

Lung cancer is a complicated and challenging disease and is one of the most common causes of cancer-related mortality worldwide. Within the lung microenvironment, specific cytokines, including the B cell activation factor (BAFF) and the A proliferation-inducing ligand (APRIL), are produce by various cells, notably airway epithelial cells, in response allergic inflammation or pulmonary infection. These cytokines play a critical role in maintaining local immune responses and fostering the survival of immune cells. The BAFF and APRIL system have been connected in a range of malignancies and have shown their potential in inducing drug resistance and promoting cancer progression. This review highlights recent studies on the involvement of BAFF and APRIL in various cancers, focusing mainly on their role in lung cancer, and discusses the possibility of these molecules in contributing to drug resistance and cancer progression following pulmonary infection. We suggest consideration the targeting BAFF and APRIL or their respective receptors as promising novel therapies for effective treatment of lung cancer, especially post pulmonary infection. However, it remains important to conduct further investigations to fully elucidate the precise mechanisms underlying how the BAFF and APRIL systems enhance cancer survival and drug resistance subsequent pulmonary infections.

Myelitis associated with COVID-19: clinical, radiological, and laboratory characteristics

Aim: The current study aimed to describe various types of myelitis associated with a novel coronavirus infection [coronavirus disease 2019 (COVID-19)] as well as to analyze cytokine profiles and cerebrospinal fluid (CSF) parameters in affected patients and to compare them to patients with other immune-mediated disorders—multiple sclerosis (MS), in order to identify possible common pathogenetic pathways and consequently treatment targets. Methods: Clinical, radiological, and laboratory characteristics were studied based on patients’ history. CSF from patients with myelitis associated with COVID-19 (11 patients) was compared with CSF of healthy controls (HC) (7 patients) and patients with MS (37 patients) from the non-COVID era. CSF cytological examination, protein levels and oligoclonal bands (OCBs) evaluation, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus detection and cytokine profiling using Bio-Plex Pro Human Inflammation Panel 1, 37-Plex were performed. Results: In total 11 patients with different types of myelitis developed up to 3 months after COVID-19 were enrolled in the study. Radiological findings were diverse: short transverse myelitis (lesion of fewer than 3 segments) (n = 6), longitudinal extensive transverse myelitis (LETM) (n = 2), multifocal spinal cord lesions (n = 1), and myelitis involving dorsal and lateral columns (n = 2). The most pronounced response to treatment was observed in patients with partial transverse myelitis and patients with anti-myelin oligodendrocyte glycoprotein (MOG) antibodies (MOG Abs). Multiple comparisons have demonstrated decreased levels of interleukin-10 (IL-10), interferon-α2 (IFN-α2), IFN-β, and thymic stromal lymphopoietin (TSLP), and increased IL-19 and B cell activating factor (BAFF) in patients with COVID-19 myelitis (CM) compared to the MS group. The highest BAFF and a proliferation-inducing ligand (APRIL) concentrations were found in patients with the most profound neurological disability. Conclusions: Myelitis associated with COVID-19 is clinically and radiologically heterogeneous. Evaluation of cytokine profiles in patients with myelitis associated with COVID-19 revealed their relative similarity with ones of MS patients, except for a few cytokines. BAFF/APRIL system as well as IL-10 is well-known for the role in the development and progression of autoimmune diseases, however, their links with COVID-19 and effects on the development of immune-mediated central nervous system (CNS) disorders after SARS-CoV-2 remain to be further studied.

Effects of highly effective modulator therapy on the dynamics of the respiratory mucosal environment and inflammatory response in cystic fibrosis.

While the widespread initiation of elexacaftor/tezacaftor/ivacaftor (ETI) has led to dramatic clinical improvements among persons with cystic fibrosis (pwCF), little is known about how ETI affects the respiratory mucosal inflammatory and physiochemical environment, or how these changes relate to lung function. We performed a prospective, longitudinal study of adults with CF and chronic rhinosinusitis (CF-CRS) followed at our CF center (n = 18). Endoscopic upper respiratory tract (paranasal sinus) aspirates from multiple visit dates, both pre- and post-ETI initiation, were collected and tested for cytokines, metals, pH, and lactate levels. Generalized estimating equations were used to identify relationships between ETI and upper respiratory tract (URT) biomarker levels, and between URT biomarkers and lung function or clinical sinus parameters. ETI was associated with decreased upper respiratory mucosal cytokines B-cell activating factor (BAFF), IL-12p40, IL-32, IL-8, IL-22 and soluble tumor necrosis factor-1 (sTNFR1), and an increase in a proliferation-inducing ligand (APRIL) and IL-19. ETI was also associated with decreased URT levels of copper, manganese, and zinc. In turn, lower URT levels of BAFF, IL-8, lactate, and potassium were each associated with ~1.5% to 4.3% improved forced expiratory volume in 1 s (FEV1 ), while higher levels of IFNγ, iron, and selenium were associated with ~2% to 10% higher FEV1 . Our observations suggest a dampening of inflammatory signals and restriction in microbial nutrients in the upper respiratory tract with ETI. These findings improve our understanding of how ETI impacts the mucosal environment in the respiratory tract, and may give insight into the improved infectious and inflammatory status and the resulting clinical improvements seen in pwCF.

Refractory lupus hepatitis successfully treated with telitacicept who failed to belimumab: A case report and literature review.

Background: Systemic lupus erythematosus (SLE)-associated hepatitis ("lupus hepatitis") was one of the most frequent causes of liver function abnormalities in patients with SLE. Lupus hepatitis (LH) is commonly treated with conventional treatment, including non-steroidal anti-inflammatory drugs, corticosteroids, and immunomodulators. However, in refractory cases, other treatment options may be required.Methodology: We report the case of a patient with lupus hepatitis refractory to both conventional therapy and belimumab who was successfully treated with telitacicept, a new dual B lymphocyte stimulator (BLyS)/APRIL (a proliferation-inducing ligand) inhibitor.Literature review was performed on PubMed search forum.Result: The specific search term was "telitacicept", 23 papers were searched, among them 10 case reports/series articles reporting telitacicept treatment were elected.Apart from our literature reporting the effectiveness of telitacicept in treating LH, there is no report on it in treating LH.Conclusion: This case suggests that telitacicept should be an effective and safe treatment for LH refractory, even to those who failed to belimumab based on the standard treatment, and can reduce the dosage of glucocorticoids.However, further investigations, particularly prospective randomized controlled trials, are warranted to verify our findings and ensure patient safety.

The role of BAFF and APRIL in IgA nephropathy: pathogenic mechanisms and targeted therapies.

Immunoglobulin A nephropathy (IgAN), characterized by mesangial deposition of galactose-deficient-IgA1 (Gd-IgA1), is the most common biopsy-proven primary glomerulonephritis worldwide. Recently, an improved understanding of its underlying pathogenesis and the substantial risk of progression to kidney failure has emerged. The "four-hit hypothesis" of IgAN pathogenesis outlines a process that begins with elevated circulating levels of Gd-IgA1 that trigger autoantibody production. This results in the formation and deposition of immune complexes in the mesangium, leading to inflammation and kidney injury. Key mediators of the production of Gd-IgA1 and its corresponding autoantibodies are B-cell activating factor (BAFF), and A proliferation-inducing ligand (APRIL), each playing essential roles in the survival and maintenance of B cells and humoral immunity. Elevated serum levels of both BAFF and APRIL are observed in patients with IgAN and correlate with disease severity. This review explores the complex pathogenesis of IgAN, highlighting the pivotal roles of BAFF and APRIL in the interplay between mucosal hyper-responsiveness, B-cell activation, and the consequent overproduction of Gd-IgA1 and its autoantibodies that are key features in this disease. Finally, the potential therapeutic benefits of inhibiting BAFF and APRIL in IgAN, and a summary of recent clinical trial data, will be discussed.

Effect of Telitacicept on Circulating Gd-IgA1 and IgA-Containing Immune Complexes in IgA Nephropathy

IntroductionTelitacicept, a transmembrane activator and cyclophilin ligand (CAML) interactor (TACI) fusion protein targeting B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL), has proven efficacy in treating Immunoglobulin A (IgA) nephropathy. However, serum biomarkers that could predict the clinical response during the treatment remain unclear. MethodsPlasma samples from 24 participants in the Phase 2 clinical trial were collected at baseline and after 4, 12, and 24 weeks, and 8 participants in the placebo group, 9 in the 160 mg group, and 7 in the 240 mg group. We measured the levels of Galactose deficient-IgA1(Gd-IgA1) , IgA-containing immune complexes, C3a, C5a, and sC5b-9. The association between the changes in these markers and proteinuria reduction was analyzed. ResultsAfter 24 weeks of treatment, Gd-IgA1 decreased by 43.9% (95% CI: 29.8%, 55.1%), IgG-IgA immune complex by 31.7% (14.4%, 45.5%), and poly-IgA immune complex by 41.3% (6.5%, 63.1%) in the 160 mg group; Gd-IgA1 decreased by 50.4% (38.6%, 59.9%), IgG-IgA immune complex decreased by 42.7% (29.5%, 53.4%), and poly-IgA immune complex decreased by 67.2% (48.5%,79.1%) in the 240 mg group. There were no significant changes in the circulatory C3a, C5a, or sC5b-9 levels during telitacicept treatment. Decreases in both plasma Gd-IgA1 and IgG-IgA or poly-IgA immune complexes were associated with proteinuria reduction. In turn, IgG-IgA or poly-IgA immune complexes showed a dose-dependent effect, consistent with proteinuria reduction during telitacicept treatment1. ConclusionTelitacicept lowered both circulating Gd-IgA1 and IgA-containing immune complexes, while IgA immune complex levels were more consistent with decreased proteinuria.

Probiotics induce intestinal IgA secretion in weanling mice potentially through promoting intestinal APRIL expression and modulating the gut microbiota composition.

Intestinal infections are strongly associated with infant mortality, and intestinal immunoglobulin A (IgA) is important to protect infants from intestinal infections after weaning. This study aims to screen probiotics that can promote the production of intestinal IgA after weaning and further explore their potential mechanisms of action. In this study, probiotics promoting intestinal IgA production were screened in weanling mouse models. The results showed that oral administration of Bifidobacterium bifidum (B. bifidum) FL228.1 and Bifidobacterium bifidum (B. bifidum) FL276.1 significantly enhanced IgA levels in the small intestine and upregulated the expression of a proliferation-inducing ligand (APRIL) and its upstream regulatory factor toll-like receptor 4 (TLR4). Furthermore, B. bifidum FL228.1 upregulated the relative abundance of Lactobacillus, while B. bifidum FL276.1 increased the relative abundance of Marvinbryantia and decreased Mucispirillum, further elevating intestinal IgA levels. In summary, B. bifidum FL228.1 and B. bifidum FL276.1 can induce IgA production in the intestinal tract of weanling mice by promoting intestinal APRIL expression and mediating changes in the gut microbiota, thus playing a significant role in enhancing local intestinal immunity in infants.

Anti-inflammatory role of APRIL by modulating regulatory B cells in antigen-induced arthritis.

APRIL (A Proliferation-Inducing Ligand), a member of the TNF superfamily, was initially described for its ability to promote proliferation of tumor cells in vitro. Moreover, this cytokine has been related to the pathogenesis of different chronic inflammatory diseases, such as rheumatoid arthritis. This study aimed to evaluate the ability of APRIL in regulating B cell-mediated immune response in the antigen-induced arthritis (AIA) model in mice. AIA was induced in previously immunized APRIL-transgenic (Tg) mice and their littermates by administration of antigen (mBSA) into the knee joints. Different inflammatory cell populations in spleen and draining lymph nodes were analyzed using flow cytometry and the assay was performed in the acute and chronic phases of the disease, while cytokine levels were assessed by ELISA. In the acute AIA, APRIL-Tg mice developed a less severe condition and a smaller inflammatory infiltrate in articular tissues when compared with their littermates. We also observed that the total cellularity of draining lymph nodes was decreased in APRIL-Tg mice. Flow cytometry analysis revealed an increase of CD19+IgM+CD5+ cell population in draining lymph nodes and an increase of CD19+CD21hiCD23hi (B regulatory) cells in APRIL-Tg mice with arthritis as well as an increase of IL-10 and CXCL13 production in vitro.

Neutrophil depletion attenuates antibody-mediated rejection in a renal transplantation mouse model.

Antibody-mediated rejection (AMR) can cause graft failure following renal transplantation. Neutrophils play a key role in AMR progression, but the exact mechanism remains unclear. We investigated the effect of neutrophils on AMR in a mouse kidney transplantation model. The mice were divided into five groups: syngeneic transplantation (Syn), allograft transplantation (Allo), and three differently treated AMR groups. The AMR mouse model was established using skin grafts to pre-sensitize recipient mice. Based on the AMR model, Ly6G-specific monoclonal antibodies were administered to deplete neutrophils (NEUT-/- + AMR) and TACI-Fc was used to block B-cell-activating factor (BAFF)/a proliferation-inducing ligand (APRIL) signaling (TACI-Fc + AMR). Pathological changes were assessed using hematoxylin-eosin and immunohistochemical staining. Banff values were evaluated using the Banff 2015 criteria. Donor-specific antibody (DSA) levels were assessed using flow cytometry, and BAFF and APRIL concentrations were measured using ELISA. Compared to the Syn and Allo groups, a significantly increased number of neutrophils and increased C4d and IgG deposition were observed in AMR mice, accompanied by elevated DSA levels. Neutrophil depletion inhibited inflammatory cell infiltration and reduced C4d and IgG deposition. Neutrophil depletion significantly decreased DSA levels after transplantation and suppressed BAFF and APRIL concentrations, suggesting a mechanism for attenuating AMR-induced graft damage. Similar results were obtained after blockading BAFF/APRIL using a TACI-Fc fusion protein. In summary, neutrophil infiltration increased in the AMR mouse renal transplantation model. Neutrophil depletion or blockading the BAFF/APRIL signaling pathway significantly alleviated AMR and may provide better options for the clinical treatment of AMR.

Human gingival fibroblasts are a source of B cell‐activating factor during periodontal inflammation

AbstractBackgroundHost‐modulating therapy is a possible treatment for individuals that respond poorly to conventional periodontal therapy. B cells, abundant in periodontitis lesions, require the cytokines B cell‐activating factor (BAFF) and A proliferation‐inducing ligand (APRIL) for survival and maturation. Although mRNA levels of BAFF and APRIL are increased in tissue from periodontitis lesions, it is unknown if periodontal resident cells express BAFF and/or APRIL during periodontal inflammation. In this study, we aim to analyze the expression of BAFF and APRIL in human gingival fibroblasts after stimulation with proinflammatory cytokines. Furthermore, we perform protein analysis in tissues and serum from periodontitis patients and healthy controls.MethodsHuman gingival fibroblasts were cultured and stimulated with the proinflammatory cytokines’ tumor necrosis factor‐alpha (TNF‐α) and interleukin‐1 beta (IL‐1β). The mRNA expression of BAFF and APRIL was analyzed by real‐time quantitative polymerase chain reaction (qPCR), and the protein was detected in tissue sections using immune staining. Serum levels of BAFF were analyzed with enzyme‐linked immunosorbent assay (ELISA).ResultsIn gingival fibroblasts, TNF‐α upregulated BAFF mRNA, but APRIL was unaffected. IL‐1β affected neither BAFF nor APRIL expression. BAFF protein was detected in the oral epithelium and in cells of the underlying connective tissue in periodontitis tissue, and BAFF protein was increased in the serum of periodontitis patients.ConclusionPeriodontal resident cells express BAFF during periodontal inflammation and participate in providing a favorable milieu for the survival and action of B cells.

B cell activating factor levels are linked to distinct B cell markers in multiple sclerosis and following B cell depletion and repopulation

Recent studies have highlighted the important role of B cells in the pathogenesis of multiple sclerosis (MS). B cell activating factor (BAFF) and A proliferation inducing ligand (APRIL) play a major role in B cell survival and homeostasis. Here, we studied the association of BAFF and APRIL with B cell immune markers in MS and following B cell depletion and repopulation. We found that BAFF but not APRIL was significantly higher in plasma in untreated MS compared to controls. BAFF increased after rituximab treatment and decreased again during repopulation displaying an inverse correlation with B cell numbers, and more specifically switched memory B cell numbers. Cerebrospinal fluid BAFF inversely correlated with IgG index. BAFF displayed an inverse association to anti-EBV-CA antibodies. In summary, our study identified immune cells and factors that might regulate or be regulated by BAFF and APRIL levels in MS, and during B cell depletion and repopulation.

Advances in the treatment of IgA nephropathy with biological agents.

Immunoglobulin A nephropathy (IgAN) is the most common primary glomerular disease, and the "four-hit" theory represents its currently accepted pathogenic mechanism. Mucosal immunity triggered by infections in the respiratory tract, intestines, or other areas leads to antigen presentation, T cell stimulation, B cell maturation, and the production of IgA-producing plasma cells. The proteins B-lymphocyte stimulator (BLyS) and aproliferation-inducing ligand (APRIL) are involved in this process, and alternative complement and lectin pathway activation are also part of the pathogenic mechanism. Kidney DiseaseImproving Global Outcomes guidelines indicate that a specific effective treatment for IgAN is lacking, with renin-angiotensin-aldosterone system inhibitors being the primary therapy. Recent research shows that biological agents can significantly reduce proteinuria, stabilize the estimated glomerular filtration rate, and reverse some pathological changes, such as endocapillary proliferation and crescent formation. There are four main categories of biological agents used to treat IgA nephropathy, specifically anti-CD20 monoclonal antibodies, anti-BLyS or APRIL monoclonal antibodies, monoclonal antibodies targeting both BLyS and APRIL (telitacicept and atacicept), and monoclonal antibodies inhibiting complement system activation (narsoplimab and eculizumab). However, further research on the dosages, treatment duration, long-term efficacy, and safety of these biological agents is required.

The contribution of a proliferation-inducing ligand (APRIL) and other TNF superfamily members in pathogenesis and progression of IgA nephropathy.

Advances in our understanding of the pathogenesis of immunoglobulin A nephropathy (IgAN) have led to the identification of novel therapeutic targets and potential disease-specific treatments. Specifically, a proliferation-inducing ligand (APRIL) has been implicated in the pathogenesis of IgAN, mediating B-cell dysregulation and overproduction of pathogenic galactose-deficient IgA1 (Gd-IgA1). Animal and clinical studies support the involvement of APRIL in the pathogenesis and progression of IgAN. An elevated level of APRIL is found in IgAN when compared with controls, which correlates with the level of Gd-IgA1 and associates with more severe disease presentation and worse outcomes. Conversely, anti-APRIL therapy reduces pathogenic Gd-IgA1 and IgA immune complex formation and ameliorates the severity of kidney inflammation and injury. Genome-wide association studies in IgAN have identified TNFSF13 and TNFRSF13B, a cytokine ligand-receptor gene pair encoding APRIL and its receptor, respectively, as risk susceptibility loci in IgAN, further supporting the causal role of the APRIL signalling pathway in IgAN. Several novel experimental agents targeting APRIL, including atacicept, telitacicept, zigakibart and sibeprenlimab, are currently under investigation as potential therapies in IgAN. Preliminary results suggest that these agents are well-tolerated, and reduce levels of Gd-IgA1, with corresponding improvement in proteinuria. Further studies are ongoing to confirm the safety and efficacy of anti-APRIL approaches as an effective therapeutic strategy in IgAN.

Povetacicept (ALPN-303), a Potent Dual BAFF/APRIL Antagonist in Development for the Treatment of Autoimmune Cytopenias, Suppresses Disease in a Mouse Model of Autoimmune Hemolytic Anemia

Introduction: B cell activating factor (BAFF) and a proliferation inducing ligand (APRIL) play key roles in B cell development, survival, and differentiation into antibody-secreting cells (ASC). Given their importance in ASC survival and antibody production, inhibition of BAFF and/or APRIL (particularly in combination) is a promising approach for the treatment of a variety of autoimmune or autoantibody-related diseases including autoimmune cytopenias like warm autoimmune hemolytic anemia (wAIHA), immune thrombocytopenia (ITP), and cold agglutinin disease (CAD). Significantly higher levels of both BAFF and APRIL have been observed in the serum of patients with AIHA and ITP compared to healthy subjects, and polymorphisms in BAFF and TACI have been associated with ITP [Abdel-Hamid et al., Am J Med, 2011; Xu et al., Int J Hematol., 2015; Emmerich, et al., Br J Haematol, 2007; Peng, et al., J Thromb Haemost, 2017; Yu, et al., Blood Adv, 2021]. Belimumab, an anti-BAFF antibody, has demonstrated encouraging efficacy in the treatment of ITP associated with systemic lupus erythematosus [De Marchi, et al., Clin Exp Rheumatol, 2017] and in combination with rituximab in patients with ITP [Mahévas, et al., Haematologica, 2021]. Currently, there are no BAFF and/or APRIL inhibitors approved to treat AIHA or ITP. Povetacicept (ALPN-303) is an engineered, potent dual BAFF/APRIL antagonist. We previously evaluated the impact of BAFF/APRIL co-inhibition preclinically in the accelerated HODxOTII transgenic mouse model of AIHA, in which povetacicept treatment significantly suppressed plasma cells in the spleen and bone marrow, reduced pathogenic anti-RBC autoantibodies, and significantly increased hematocrit [Dillon et al., ASH 2022 abstract #3763]. Here, we have evaluated povetacicept in a second preclinical model of AIHA, a rat red blood cell (RRBC)-to-mouse model of erythrocyte autoimmunity. Methods: In the RRBC model, C57BL/6NJ mice were immunized weekly with 2 x 10 8 Wistar rat RBC for 10 weeks, leading to development of anti-mouse RBC autoantibodies. Groups of mice were treated twice weekly via intraperitoneal injection with povetacicept or a matched Fc isotype control. Analyses included anti-RRBC alloantibodies and autoantibodies bound to mouse erythrocytes (measured via direct anti-globulin test [DAT]). While significant anemia does not occur in this model, serum lactate dehydrogenase (LDH) was also measured as an index measure of subclinical hemolysis. Immune cell subset analysis of splenocytes by flow cytometry was also performed. Results: As compared to Fc control, povetacicept treatment significantly reduced levels of anti-RRBC and DAT of IgM and IgG isotypes and significantly limited serum LDH elevations at various timepoints during the study ( Figure 1). Furthermore, at 10 weeks, numbers of T follicular helper (Tfh) cells, total B cells, germinal center (GC) B cells, and plasma cells were significantly lower in spleens of povetacicept-treated mice ( Figure 2). Conclusions: Povetacicept effectively reduced pathogenic autoantibodies and key B cell populations (e.g., ASC) and limited serum LDH elevations in this mouse model of erythrocyte autoimmunity. These data suggest that povetacicept may reduce multiple pathogenic inflammatory processes including autoantibody production and may be an effective treatment for AIHA and other autoimmune cytopenias. Povetacicept is currently being evaluated in an open-label study (RUBY-4; NCT05757570) of adults with autoimmune cytopenias (ITP, AIHA, and CAD).

Bone Marrow CD8 + Tissue-Resident Memory T Cell Promote B Cell Differentiation and Inhibit Platelet Production in Patients with Immune Thrombocytopenia

Immune thrombocytopenia (ITP) is a prevalent autoimmune disease in which enhanced anti-platelet T cell activity and dysfunction of CD8 + T cells are involved(Audia et al., 2013; Semple & Freedman, 1991). Persistent secretion of antibodies by long-lived plasma cells and memory B cells in the bone marrow contributes to ITP pathogenesis (Roeser, Lazarus, & Mahevas, 2023). However, the role of memory T cells, especially tissue-resident memory T cells (TRM), in ITP remains underexplored. TRM develop in specific tissues and play crucial role in local immunity. TRM exert their effects through mechanisms including the induction of local humoral responses, contributing to autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis (Chang et al., 2021; Gu, Song, Roh, Jung, & Kim, 2021). Bone marrow contains one of the largest pools of memory CD8 + T cells. However, the involvement of bone marrow TRM in ITP pathogenesis remains poorly understood. In this study, we observed a significantly higher proportion of CD8 + TRM (CD8 +CD45RA -CD45RO +CD69 +) in the bone marrow of ITP patients compared to healthy controls. However, no significant differences were observed in CD4 + TRM, CD8 + TCM and CD8 + TEM between the two groups. CD8 + TRM from ITP patients exhibited increased levels of IFN-γ, NLRP3, IL-1β, TNF-α, and decreased levels of IL-10 compared to those from healthy controls. Furthermore, CD8 + TRM proportions were significantly higher in glucocorticoid responders than non-responders, suggesting a potential role of CD8 + TRMs in mediating glucocorticoid therapeutic effects. Transcriptome sequencing revealed upregulated genes, including IGLC2, ASAP2, HIST2H2AA4, IGLV2-11, C1QA, ATP5MC1, IL5RA, and CYC1, and downregulated genes, including CCR9, HSPE1P18, RGCC, and ITGAE, in TRM cells from ITP patients compared to controls. GO/KEGG analysis of the top 500 upregulated genes highlighted pathways associated with B cell-associated immunity. To explore the effect of TRM on B cells, bone marrow CD19 + B cells were co-cultured with autologous TRM or memory T cells without TRM (TM) in the presence of IgM, and the proportion of memory B cells (CD19 +CD27 +CD38 -) and plasma cells (CD19 -CD24 -CD38 +) were measured by flow cytometry. The supernatants were collected, and cytokines and IgG level were tested by ELISA. Results showed that TRMs from ITP patients promoted the differentiation of memory B cells and IgG antibody production compared with those from healthy controls. However, no significant difference was observed in the proportion of naive B cells and plasma cells between the two groups. TRM, but not TM augmented B cell differentiation into memory B cells or plasma cells both in ITP patients and healthy controls. Additionally, TRM-primed B cells showed a stronger effect on antibody production and resulted in a higher level of IgG in supernatant compared with TM primed B cells. In line with these findings, the levels of B cell activating factor (BAFF), a proliferation inducing ligand (APRIL), and sCD40L, which were critical cytokines for B cell survival and differentiation, were significantly higher in supernatants from ITP patients than those from healthy controls. Moreover, the levels of BAFF, APRIL and CD40L in co-culture system with TRM were significantly increased compared to the system with TM, providing insights into the impact of TRM on B cell differentiation and function. To further investigate the role of TRM in regulating platelet production in ITP patients, we cocultured TRM with CD34 +cells in the presence of thrombopoietin (TPO), stem cell factor (SCF) and interleukin (IL)-3. Results showed that TRM did not suppress the production of CD41 + megakaryocytes from CD34 + cells, but reduced megakaryocyte apoptosis and increased the percentage of polyploidy (≥4N) megakaryocytes compared with TM. Additionally, TRM inhibited reticulated platelet formation and platelet production. Notably, dexamethasone (DXM) modulation alleviated certain suppressive effects on platelet production. In summary, our findings reveal the involvement of impaired bone marrow CD8 + TRM in the pathogenesis of ITP through the promotion of B cell differentiation and inhibition of platelet production. These results shed new light on the potential of immune therapy targeting TRM in the management of ITP.

A PRoliferation-Inducing Ligand (APRIL) in the Pathogenesis of Immunoglobulin A Nephropathy: A Review of the Evidence.

A PRoliferation-Inducing Ligand (APRIL), the thirteenth member of the tumor necrosis factor superfamily, plays a key role in the regulation of activated B cells, the survival of long-lived plasma cells, and immunoglobulin (Ig) isotype class switching. Several lines of evidence have implicated APRIL in the pathogenesis of IgA nephropathy (IgAN). Globally, IgAN is the most common primary glomerulonephritis, and it can progress to end-stage kidney disease; yet, disease-modifying treatments for this condition have historically been lacking. The preliminary data in ongoing clinical trials indicate that APRIL inhibition can reduce proteinuria and slow the rate of kidney disease progression by acting at an upstream level in IgAN pathogenesis. In this review, we examine what is known about the physiologic roles of APRIL and evaluate the experimental and epidemiological evidence describing how these normal biologic processes are thought to be subverted in IgAN. The weight of the preclinical, clinical, and genetic data supporting a key role for APRIL in IgAN has galvanized pharmacologic research, and several anti-APRIL drug candidates have now entered clinical development for IgAN. Herein, we present an overview of the clinical results to date. Finally, we explore where more research and evidence are needed to transform potential therapies into clinical benefits for patients with IgAN.

Association of Asymmetric and Symmetric Dimethylarginine with Inflammation in the Population-Based Study of Health in Pomerania.

The amino acids arginine (Arg), asymmetric (ADMA) and symmetric dimethylarginine (SDMA) are related to nitric oxide (NO) metabolism and potential markers of two different disease entities: cardiovascular disease such as atherosclerosis and systemic inflammation in critically ill patients with sepsis. Although very different in their pathophysiological genesis, both entities involve the functional integrity of blood vessels. In this context, large population-based data associating NO metabolites with proinflammatory markers, e.g., white blood cell count (WBC), high-sensitivity C-reactive protein (hsCRP), and fibrinogen, or cytokines are sparse. We investigated the association of Arg, ADMA and SDMA with WBC, hsCRP, and fibrinogen in 3556 participants of the Study of Health in Pomerania (SHIP)-TREND study. Furthermore, in a subcohort of 456 subjects, 31 inflammatory markers and cytokines were analyzed. We identified Arg and SDMA to be positively associated with hsCRP (β coefficient 0.010, standard error (SE) 0.002 and 0.298, 0.137, respectively) as well as fibrinogen (β 5.23 × 10-3, SE 4.75 × 10-4 and 0.083, 0.031, respectively). ADMA was not associated with WBC, hsCRP, or fibrinogen. Furthermore, in the subcohort, Arg was inversely related to a proliferation-inducing ligand (APRIL). SDMA was positively associated with osteocalcin, tumor necrosis factor receptor 1 and 2, and soluble cluster of differentiation 30. Our findings provide new insights into the involvement of Arg, ADMA, and SDMA in subclinical inflammation in the general population.

Abnormal immune function of B lymphocyte in peripheral blood of Parkinson's disease

BackgroundParkinson's disease (PD) is associated with peripheral inflammation and abnormal peripheral blood lymphocyte immune responses. Peripheral blood B-lymphocyte subset distributions and whether they are associated with PD are unclear. MethodsSixty-one PD patients and sixty-one one-to-one paired healthy controls (HCs) were enrolled. We used flow cytometry to perform immunophenotyping of peripheral B-lymphocyte, in vitro stimulation and measured serum cytokine. The relationship between variables and PD were assessed. ResultsThe percentage of naive B cells in blood of PD patients was decreased, whereas the percentages of regulatory B cells (Bregs), plasma blast cells (PBCs), and double-negative (DN) B cells were increased. The absolute counts of B-lymphocyte and naive B cells in blood of PD patients were decreased. Regression analysis revealed that alterations in the absolute counts of B-lymphocyte and the percentage of Bregs and DN B cells were associated with PD. After stimulation, the percentages of Bregs, PBCs, and switched memory (SwM) B cells increased in PD patients. Additionally, increases in GM-CSF-producing B-cell, IFN-γ-producing B-cell, and TNF-α-producing B-cell percentages were noted in PD. Serum levels of a proliferation-inducing ligand (APRIL), B-cell activating factor (BAFF) and soluble CD40 ligand (sCD40L) were elevated in PD and correlated negatively with the UPDRS III score. ConclusionsAbnormal B-lymphocyte immune responses in peripheral blood may contribute to PD development. Alterations in the absolute counts of B-lymphocyte and the percentage of Bregs and DN B cells are associated with PD. Furthermore, APRIL, BAFF, and sCD40L could be potential targets for intervention in PD.

Mononuclear cells from patients with rhupus are influenced by TNF in their production of gp130/sIL-6Rb and APRIL

ObjectiveRhupus is a rare disease that shares characteristics of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). While several studies have explored the clinical and immunological profiles of patients with...