This study aimed to investigate the expression condition of a proliferation-inducing ligand (APRIL) in lacrimal gland lesions of patients with IgG4-associated ophthalmic diseases (IgG4-ROD) and mucosa-associated lymphoid tissue (MALT) lymphoma.

Fifteen patients with IgG4-ROD, 3 with MALT lymphoma, and 1 with elevated IgG4 with lacrimal gland lesions, treated in West China Hospital of Sichuan University from April 2022 to November 2023, were included. Immunofluorescence staining was used to detect the expression of APRIL in the specimen of lacrimal gland.

The average expression level of APRIL in patients with lacrimal gland lesions of IgG4-ROD and MALT lymphoma were 8471.12 pixels/HPF and 2950.78 pixels/HPF respectively. The positive rates of APRIL were 10.49% and 7.23% respectively. CD138 and APRIL were colocalized, and the positive rate of their colocalization was 8.83%, and the positive areas of colocalization coincidence was 946.84 pixels/HPF in patients with IgG4-ROD. CD20 and APRIL were colocalized, and the positive rate of their colocalization was 7.04%, and the positive areas of colocalization coincidence was 949.78 pixels/HPF in patients with MALT lymphoma. We also found that the expression level and the positive rate of APRIL were positively correlated with the level of serum IgG4 in IgG4-ROD patients (r=0.5820, P=0.029; r= 0.6261, P=0.017; respectively). In addition, the positive rate and the positive areas of CD138 and APRIL colocalization were also positively correlated with serum IgG4 level (r=0.6420, P=0.013; r= 0.5673, P=0.034; respectively).

APRIL is highly expressed in lacrimal gland lesions of patients with IgG4-ROD and MALT lymphoma. This overexpression may facilitate the enrichment of CD138+ plasma cells and is associated with elevated serum IgG4 levels in patients with IgG4-ROD. Additionally, it may promote the proliferation of CD20+ B lymphocytes in patients with MALT lymphoma.APRIL may play a certain role in the possible transformation of IgG4-ROD into MALT lymphoma.

BAFF, a vital B cell survival and differentiation factor, has three receptors: B-cell maturation antigen (BCMA), transmembrane activator and CAML interactor (TACI) and BR3. Although B cells are greatly reduced in B6.Baff-/- (which harbour no BAFF) and B6.Br3-/- mice (which harbour supra-normal levels of BAFF), the distributions of B cell subsets and relationships between Foxp3+ and CD4+ cells in these mice differ. Using a large panel of B6 congenic knockout and/or transgenic mice, we demonstrate that (1) supra-normal levels of BAFF per se do not explain the phenotypic differences between B6.Baff-/- and B6.Br3-/- mice; (2) B cells are expanded in B6.Taci-/- mice, with preferential expansion of follicular (FO) B cells at the expense of CD19+CD21-/loCD23-/lo B cells but without the preferential expansion of Foxp3+ cells observed in B6 mice bearing a Baff transgene; (3) despite no expansion in total B cells, percentages of FO B cells and marginal zone B cells are higher and percentages of CD19+CD21-/loCD23-/lo B cells are lower in young B6.Bcma-/- mice, consistent with the inability of B6.Br3-/-.Taci-/- mice to recapitulate the B cell profile of B6.Baff-/- mice; and (4) percentages of Foxp3+ cells in B6.Br3-/-.Taci-/- mice are intermediate between those in B6.Br3-/- and B6.Taci-/- mice despite the B cell profile of B6.Br3-/-.Taci-/- mice strongly resembling that of B6.Br3-/- mice. Collectively, our findings point to a non-redundant role for each of the BAFF receptors in determining the ultimate lymphocyte profile of the host. This may have clinically relevant ramifications in that the degree that a candidate therapeutic agent blocks engagement of any given individual BAFF receptor may affect its clinical utility.

Autoimmune diseases (AIDs) are common diseases in the world. Some cases are difficult to cure and can only delay the progression of the diseases. The B lymphocyte stimulator (BLyS)/a proliferation-inducing ligand (APRIL) plays an important role in B cell homeostasis, regulation of both innate and adaptive immune responses. After binding to their receptors, BLyS/APRIL primarily affects the survival and development of marginal, transitional, and mature B cells. Of note, elevated BLyS/APRIL is seen in many AIDs, such as systemic lupus erythematosus, rheumatoid arthritis, immunoglobulin A nephropathy, etc. Moreover, there is evidence that blocking these two cytokines can control the number of serum autoantibodies, promote the depletion of B lymphocytes, inhibit the activation of T cells and dendritic lymphocytes, and reduce inflammatory stress. Currently, some clinical studies are underway targeting BLyS/APRIL inhibitors for the treatment of AIDs. However, due to the scattered knowledge on the relationship between BLyS/APRIL and AIDs, it is necessary to sort out the existing data. Therefore, in this review, we describe the basic biological characteristics and functions of BLyS/APRIL in AIDs, summarize the potential clinical applications of related inhibitors, especially monoclonal antibodies and recombinant fusion proteins targeting BLyS/APRIL in AIDs, and also outline promising research directions.

Dysregulated signaling from TNF and TNFR proteins is implicated in several immune-mediated inflammatory diseases (IMIDs). This review centers around seven IMIDs (rheumatoid arthritis, systemic lupus erythematosus, Crohn's disease, ulcerative colitis, psoriasis, atopic dermatitis, and asthma) with substantial unmet medical needs and sheds light on the signaling mechanisms, disease relevance, and evolving drug development activities for five TNF/TNFR signaling axes that garner substantial drug development interest in these focus conditions. The review also explores the current landscape of therapeutics, emphasizing the limitations of the approved biologics, and the opportunities presented by small-molecule inhibitors and combination antagonists of TNF/TNFR signaling.

Rheumatoid arthritis (RA) is a systemic autoimmune disease driven by highly active autoantibody-producing B cells. Activation of B cells is maintained within ectopic germinal centres found in affected joints. Fibroblast-like synoviocytes (FLS) present in inflamed joints support B-cell survival, activation, and differentiation. CD27+ memory B cells and naive B cells show very different responses to activation, particularly by CD40 ligand (CD40L). We show that FLS-dependent activation of human B cells is dependent on interleukin-6 (IL-6) and CD40L. FLS have been shown to activate both naive and memory B cells. Whether the activating potential of FLS is different for naive and memory B cells has not been investigated. Our results suggest that FLS-induced activation of B cells is dependent on IL-6 and CD40L. While FLS are able to induce plasma cell differentiation, isotype switching, and antibody production in memory B cells, the ability of FLS to activate naive B cells is significantly lower.

The mucosal immune system is a critical first line of defense to infectious diseases, as many pathogens enter the body through mucosal surfaces, disrupting the balanced interactions between mucosal cells, secretory molecules, and microbiota in this challenging microenvironment. The mucosal immune system comprises of a complex and integrated network that includes the gut-associated lymphoid tissues (GALT). One of its primary responses to microbes is the secretion of IgA, whose role in the mucosa is vital for preventing pathogen colonization, invasion and spread. The mechanisms involved in these key responses include neutralization of pathogens, immune exclusion, immune modulation, and cross-protection. The generation and maintenance of high affinity IgA responses require a delicate balance of multiple components, including B and T cell interactions, innate cells, the cytokine milieu (e.g., IL-21, IL-10, TGF-β), and other factors essential for intestinal homeostasis, including the gut microbiota. In this review, we will discuss the main cellular components (e.g., T cells, innate lymphoid cells, dendritic cells) in the gut microenvironment as mediators of important effector responses and as critical players in supporting B cells in eliciting and maintaining IgA production, particularly in the context of enteric infections and vaccination in humans. Understanding the mechanisms of humoral and cellular components in protection could guide and accelerate the development of more effective mucosal vaccines and therapeutic interventions to efficiently combat mucosal infections.

Enhanced IgG4 antibody (Ab) response is a prominent feature of type 1 autoimmune pancreatitis (AIP). Innate immune responses associated with IgG4 Ab production are poorly defined. We have previously reported that peripheral blood mononuclear cells (PBMCs) isolated from patients with type 1 AIP produce large amounts of IgG4 Abs upon stimulation with bacterial cell wall components. In addition, we showed that activation of plasmacytoid dendritic cells producing interferon (IFN)-α, interleukin (IL)-33, and B cell-activating factor (BAFF) upon sensing intestinal bacteria mediates the development of experimental AIP. In this study, we attempted to clarify the role of innate immunity against fungi in inducing enhanced IgG4 Ab responses in type 1 AIP. PBMCs isolated from healthy controls and patients with type 1 AIP were stimulated with a broad range of bacterial and fungal cell wall components. The concentrations of IgG1, IgG4, and cytokines were measured using enzyme-linked immunosorbent assays. Cell wall components derived from bacteria and fungi induced IgG1 and IgG4 Ab production in patients with type 1 AIP. Various types of microbe-associated molecular pattern motifs enhanced IgG4 Ab production in patients with type 1 AIP compared with the limited motifs in healthy controls. The enhanced IgG1 and IgG4 Ab production that followed in response to bacterial and fungal cell wall components was parallel to that of IFN-α, IFN-γ, IL-10, IL-33, and BAFF. In conclusion, cell wall components derived from fungi as well as bacteria promote IgG4 Ab responses in patients with type 1 AIP.

Immunoglobulin A nephropathy (IgAN) is the most prevalent primary glomerular disease worldwide and it remains a leading cause of kidney failure. Clinical manifestations of IgA are exacerbated by infections, and emerging data suggest that aberrant mucosal immune responses are important contributors to the immunopathogenesis of this disease. However, the exact stimuli, location and mechanism of nephritis-inducing IgA production remains unclear. In this focused review we explore recent developments in our understanding of the contribution of the mucosal immune system and mucosal-derived IgA-producing cells to the development of IgAN.

B cell-activating factor (BAFF) is a critical TNF-family cytokine that regulates homeostasis and peripheral tolerance of B2 cells. BAFF overproduction promotes autoantibody generation and autoimmune diseases. During obesity, BAFF is predominantly produced by white adipose tissue (WAT), and IgG autoantibodies against adipocytes are identified in the WAT of obese humans. However, it remains to be determined if the autoantibodies formed during obesity affect WAT remodeling and systemic insulin resistance. Here, we show that IgG autoantibodies are generated in high-fat diet (HFD)-induced obese mice that bind to apoptotic adipocytes and promote their phagocytosis by macrophages. Next, using murine models of obesity in which the gonadal WAT undergoes remodeling, we found that BAFF neutralization depleted IgG autoantibodies, increased the number of dead adipocytes, and exacerbated WAT inflammation and insulin resistance. RNA sequencing of the stromal vascular fraction from the WAT revealed decreased expression of immunoglobulin light-chain and heavy-chain variable genes suggesting a decreased repertoire of B cells after BAFF neutralization. Further, the B cell activation and the phagocytosis pathways were impaired in the WAT of BAFF-neutralized mice. In vitro, plasma IgG fractions from BAFF-neutralized mice reduced the phagocytic clearance of apoptotic adipocytes. Altogether, our study suggests that IgG autoantibodies developed during obesity, at least in part, dampens exacerbated WAT inflammation and systemic insulin resistance.

Cytokines from the Tumour Necrosis Factor (TNF) family are important regulators of both physiological and pathological processes. The discovery of novel TNF ligands and receptors, BAFF and APRIL, have opened up new possibilities for scientists to explore the effect of these cytokines on the human immune system. The role of BAFF/APRIL system in B lymphocytes is particularly important for survival and maintenance of homeostasis. Aberrant expression of the system is associated with various immunological disorders. Hence, this study provides a comprehensive overview of the past and present BAFF/APRIL system research development in a bibliometric perspective. To our best knowledge, this is the first ever bibliometric analysis conducted focusing on the BAFF/APRIL system. A total of 1055 relevant documents were retrieved from WoSCC. Microsoft Excel, VOSviewer, and Biblioshiny of R studio were bibliometric tools used to analyse the scientific literature. From 1999, the annual publications showed an upward trend, with Journal of Immunology being the most productive journal. USA leads the race for BAFF/APRIL system research developments. Pascal Schneider, a senior researcher affiliated with University of Lausanne, Switzerland was recognised as the most productive author and institution in the BAFF/APRIL system research field. The research focus transitioned from focusing on the role of the system in B cell biology, to immunological disorders and finally to development of BAFF/APRIL targeting drugs. Despite several studies elucidating briefly the pathway mechanism of BAFF/APRIL system in B-cell selection, substantial research on the mechanism of action in disease models and T cell activation and development of immunomodulating drugs from natural origins remains largely unexplored. Therefore, future research focusing on these areas are crucial for the deeper understanding of the system in disease manifestations and progression allowing a better treatment management for various immunological disorders.

Inborn errors of immunity (IEIs) refer to a heterogeneous category of diseases with defects in the number and/or function of components of the immune system. Immunoglobulin A (IgA) deficiency is the most prevalent IEI characterized by low serum level of IgA and normal serum levels of IgG and/or IgM. Most of the individuals with IgA deficiency are asymptomatic and are only identified through routine laboratory tests. Others may experience a wide range of clinical features including mucosal infections, allergies, and malignancies as the most important features. IgA deficiency is a multi-complex disease, and the exact pathogenesis of it is still unknown.

This review compiles recent research on genetic and epigenetic factors that may contribute to the development of IgA deficiency. These factors include defects in B-cell development, IgA class switch recombination, synthesis, secretion, and the long-term survival of IgA switched memory B cells and plasma cells.

A better and more comprehensive understanding of the cellular pathways involved in IgA deficiency could lead to personalized surveillance and potentially curative strategies for affected patients, especially those with severe symptoms.

Lrba is a cytoplasmic protein involved in vesicular trafficking. Lrba-deficient (Lrba-/-) mice exhibit substantially higher levels of IgA in both serum and feces than wild-type (WT) mice. Transforming growth factor β1 (TGFβ1) and its receptors (TGFβR I and II) is essential for differentiating IgA+ B cells. Furthermore, increased IgA production suggests a potential connection between Lrba and the TGFβR signaling pathway in IgA production. However, the specific function of Lrba in B cell biology remains unknown.

Given the increased IgA levels in Lrba-/- mice, the goal in this work was to explore the lymph organs where the switch to IgA occurs, and if TGFβR function is affected.

Non-immunized Lrba-/- mice were compared with Lrba+/+ mice. IgA levels in the serum and feces, as well as during peripheral B cell development, were determined. IgA+ B cells and plasma cells were assessed in the small intestine and secondary lymphoid organs, such as the spleen, mesenteric lymph nodes, and Peyer's patches. The TGFβR signaling pathway was evaluated by determining the expression of TGFβR on B cells. Additionally, SMAD2 phosphorylation was measured under basal conditions and in response to recombinant TGFβ. Finally, confocal microscopy was performed to investigate a possible interaction between Lrba and TGFβR in B cells.

Lrba-/- mice exhibited significantly higher levels of circulating IgA, IgA+ B, and plasma cells than in peripheral lymphoid organs those in WT mice. TGFβR expression on the membrane of B cells was similar in both Lrba-/- and Lrba+/+ mice. However, intracellular TGFβR expression was reduced in Lrba-/- mice. SMAD2 phosphorylation showed increased levels under basal conditions; stimulation with recombinant TGFβ elicited a poorer response than in that in Lrba+/+ B cells. Finally, we found that Lrba colocalizes with TGFβR in B cells.

Lrba is essential in controlling TGFβR signaling, subsequently regulating SMAD2 phosphorylation on B cells. This mechanism may explain the increased differentiation of IgA+ B cells and production of IgA-producing plasma cells.

Intestinal homeostasis is maintained by the response of gut-associated lymphoid tissue to bacteria transported across the follicle associated epithelium into the subepithelial dome. The initial response to antigens and how bacteria are handled is incompletely understood. By iterative application of spatial transcriptomics and multiplexed single-cell technologies, we identify that the double negative 2 subset of B cells, previously associated with autoimmune diseases, is present in the subepithelial dome in health. We show that in this location double negative 2 B cells interact with dendritic cells co-expressing the lupus autoantigens DNASE1L3 and C1q and microbicides. We observe that in humans, but not in mice, dendritic cells expressing DNASE1L3 are associated with sampled bacteria but not DNA derived from apoptotic cells. We propose that fundamental features of autoimmune diseases are microbiota-associated, interacting components of normal intestinal immunity.

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.

Primary IgA nephropathy (IgAN) is a common glomerular disorder defined by predominant mesangial IgA deposition. Once thought to follow a progressive course in 10-20% of those diagnosed, emerging evidence now suggests most will progress to kidney failure over their lifetimes. Although the lack of safe and effective treatments to impede disease progression continues to present a challenge, the landscape of IgAN has dramatically evolved over the last 2 years. Driven by fundamental changes to accepted end points for IgAN clinical trials as well as fascinating new insights into the pathophysiology of IgAN, a swathe of novel and repurposed therapies are currently being evaluated. Already, two novel drugs, targeted-release formulation budesonide and sparsentan, have received conditional approvals for the treatment of IgAN, with sodium glucose co-transporter 2 inhibitors establishing themselves as further options. Soon to join this ensemble are likely to be treatments that modulate the complement system and B-cell activity; several are currently undergoing clinical trials in IgAN with promising interim results. In this review, we provide an overview of evolving epidemiological insights, disease mechanisms, emerging therapies, and contemporary challenges surrounding the management of IgAN.

To evaluate corneal epithelial changes and related factors in chronic ocular graft-versus-host disease (oGVHD) patients.

21 patients (35 eyes) with chronic oGVHD and 8 patients (12 eyes) without oGVHD after bone marrow transplantation were recruited for assessment involving in vivo confocal microscopy (IVCM) analysis, ocular surface parameter determination and tear cytokine level analysis. The IVCM corneal epithelial scoring system was used to evaluate corneal epithelial changes.

There was a significant difference in the corneal epithelial score (p = .001) between the two groups. The corneal epithelial scores were significantly correlated with the corneal fluorescein staining scores (CFS, r = 0.463, p < .001), Schirmer's test (r = -0.389, p = .009) and tear cytokine levels of EGF (r = -0.491, p < .001) and APRIL (r = -0.318, p = .030).

The depth of corneal epithelial defects can be estimated by the CFS. Corneal epithelial changes of chronic oGVHD are considered to be associated with lacrimal deficiency and a lack of EGF.

Metabolic Dysfunction-Associated Steatotic Liver (MASL), previously named nonalcoholic fatty liver (NAFL), is a multifactorial disease in which metabolic, genetic, and environmental risk factors play a predominant role. Obesity and type 2 diabetes act as triggers of the inflammatory response, which contributes to the progression of MASL to Metabolic Dysfunction-Associated Steatohepatitis and the development of hepatocellular carcinoma. In the liver, several parenchymal, nonparenchymal, and immune cells maintain immunological homeostasis, and different regulatory pathways balance the activation of the innate and adaptative immune system. PD-1/PD-L1 signaling acts, in the maintenance of the balance between the immune responses and the tissue immune homeostasis, promoting self-tolerance through the modulation of activated T cells. Recently, PD-1 has received much attention for its roles in inducing an exhausted T cells phenotype, promoting the tumor escape from immune responses. Indeed, in MASLD, the excessive fat accumulation dysregulates the immune system, increasing cytotoxic lymphocytes and decreasing their cytolytic activity. In this context, T cells exacerbate liver damage and promote tumor progression. The aim of this review is to illustrate the main pathogenetic mechanisms by which the immune system promotes the progression of MASLD and the transition to HCC, as well as to discuss the possible therapeutic applications of PD-1/PD-L1 target therapy to activate T cells and reinvigorate immune surveillance against cancer.

Type 1 interferons (IFN-I) are of increasing interest across a wide range of autoimmune rheumatic diseases. Historically, research into their role in rheumatoid arthritis (RA) has been relatively neglected, but recent work continues to highlight a potential contribution to RA pathophysiology.

We emphasise the importance of disease stage when examining IFN-I in RA and provide an overview on how IFN-I may have a direct role on a variety of relevant cellular functions. We explore how clinical trajectory may be influenced by increased IFN-I signalling, and also, the limitations of scores composed of interferon response genes. Relevant environmental triggers and inheritable RA genetic risk relating to IFN-I signalling are explored with emphasis on intriguing data potentially linking IFN-I exposure, epigenetic changes, and disease relevant processes. Whilst these data cumulatively illustrate a likely role for IFN-I in RA, they also highlight the knowledge gaps, particularly in populations at risk for RA, and suggest directions for future research to both better understand IFN-I biology and inform targeted therapeutic strategies.

IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Approximately 30% to 45% of patients progress to kidney failure (KF) within 20 to 25 years of diagnosis, and there has long been a lack of effective treatments. The therapeutic landscape in IgAN is rapidly evolving, driven in large part by the acceptance of the surrogate clinical trial end point of proteinuria reduction by regulatory authorities for the accelerated approval of new therapies. Two drugs, targeted release formulation (TRF)-budesonide (nefecon) and sparsentan, have recently been approved under this scheme. Advancing insights into the pathophysiology of IgAN, including the roles of the mucosal immune system, B-cells, the complement system, and the endothelin system have driven development of therapies that target these factors. This review outlines current, recently approved, and emerging therapies for IgAN.

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.

Type I interferon (IFN) is a class of proinflammatory cytokines with a dual role on malignant transformation, tumor progression, and response to therapy. On the one hand, robust, acute, and resolving type I IFN responses have been shown to mediate prominent anticancer effects, reflecting not only their direct cytostatic/cytotoxic activity on (at least some) malignant cells, but also their pronounced immunostimulatory functions. In line with this notion, type I IFN signaling has been implicated in the antineoplastic effects of various immunogenic therapeutics, including (but not limited to) immunogenic cell death (ICD)-inducing agents and immune checkpoint inhibitors (ICIs). On the other hand, weak, indolent, and non-resolving type I IFN responses have been demonstrated to support tumor progression and resistance to therapy, reflecting the ability of suboptimal type I IFN signaling to mediate cytoprotective activity, promote stemness, favor tolerance to chromosomal instability, and facilitate the establishment of an immunologically exhausted tumor microenvironment. Here, we review fundamental aspects of type I IFN signaling and their context-dependent impact on malignant transformation, tumor progression, and response to therapy.

One-third of patients with severe hemophilia A develop neutralizing antibodies to the factor VIII (FVIII) protein in response to intravenous replacement therapy. Patients may also generate natural, nonneutralizing antibodies to FVIII before FVIII exposure. These patients are at increased risk of developing neutralizing antibodies to FVIII. However, natural anti-FVIII antibodies are also present in healthy human donors.

To further characterize the natural antihuman (h) FVIII antibody repertoire in mice and humans.

An in-house ELISA was developed using a purified polyclonal immunoglobulin (Ig) standard to quantify anti-hFVIII Ig in cell culture supernatant or plasma from mice (wild-type and FVIII-/-) and adult human donors.

All naïve wild-type and FVIII-/- mice, as well as healthy human donors, possess natural anti-hFVIII antibodies. Mice only have natural anti-hFVIII IgM, which is present in germ-free mice, suggesting that they are germline encoded. Although murine marginal zone B cells (MZBs) contribute 44% to all circulating natural IgM, they contribute disproportionately to the anti-hFVIII IgM repertoire (82%). This naturally occurring murine MZB-derived IgM is not B-domain specific and is reduced by intravenously administered hFVIII, suggesting that it may form immune complexes immediately upon hFVIII administration. Natural anti-hFVIII antibodies of IgG, IgM, and IgA isotypes can be detected in adult human donors. There were increased levels of B-domain-favoring anti-hFVIII IgG in 14% of healthy donors, which were markedly different from the rest of the "low-titer" population.

There is a preponderance of natural anti-hFVIII antibodies in both mice and healthy adult human donors.

Memory B cells and antibody-secreting cells are the two prime effector B cell populations that drive infection- and vaccine-induced long-term antibody-mediated immunity. The antibody-mediated immunity mostly relies on the formation of specialized structures within secondary lymphoid organs, called germinal centers (GCs), that facilitate the interactions between B cells, T cells, and antigen-presenting cells. Antigen-activated B cells may proliferate and differentiate into GC-independent plasmablasts and memory B cells or differentiate into GC B cells. The GC B cells undergo proliferation coupled to somatic hypermutation of their immunoglobulin genes for antibody affinity maturation. Subsequently, affinity mature GC B cells differentiate into GC-dependent plasma cells and memory B cells. Here, we review how the NFκB signaling system controls B cell proliferation and the generation of GC B cells, plasmablasts/plasma cells, and memory B cells. We also identify and discuss some important unanswered questions in this connection.

The pathogenesis of thrombocytopenia in chronic hepatitis C (CHC) conceivably involves autoimmunity; however, the dynamics of autoantibodies and other autoimmune mechanisms remain unclear. In this study, we examined the changes in the frequency of anti-glycoprotein (GP) IIb/IIIa antibody-producing B cells and the levels of plasma B-cell-activating factor (BAFF), a proliferation-inducing ligand (APRIL), and interleukin (IL)-21 following treatment of CHC with direct-acting antiviral agents (DAA). We recruited 28 patients with CHC who underwent treatment with DAA for 8-12 weeks and subsequently tested negative for serum hepatitis C virus RNA. Thirty healthy controls were recruited for comparison. Platelet counts increased significantly (p = .016), and the frequency of anti-GPIIb/IIIa antibody-producing B cells decreased significantly (p = .002) in CHC patients with thrombocytopenia at the end of treatment (EOT) than before DAA treatment (baseline). However, these changes were not observed in CHC patients without thrombocytopenia. Plasma BAFF levels in CHC patients with thrombocytopenia significantly decreased from baseline to EOT (p = .002). Anti-GPIIb/IIIa antibody-producing B cells were positively correlated with plasma BAFF levels in these patients (r = 0.669, p = .039). These results suggest that DAA treatment suppresses the autoimmune response against platelets and improves thrombocytopenia.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the loss of immune tolerance. Lupus nephritis (LN) is one of the most common manifestations of severe organ damage in SLE, and also an important cause of disability and death. Its pathogenesis is associated with immune abnormalities such as immune cells, cytokines, and immune complex deposition. Traditional immunosuppressive therapy has been unable to meet the treatment needs of patients while bringing them toxic effects. In recent years, targeted therapies have emerged, and several novel biologics have gradually entered people's sight. This review will briefly introduce the pathogenesis of LN and the mechanism of biological targets, and summarize and analyze the clinical trials of new biologics for treating LN. Although not all biologics show positive results in clinical trials, the experience learned from these trials can help researchers adjust and plan future trial programs to seek better treatment methods.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is an unabated risk factor for end-stage liver diseases with no available therapies. Dysregulated immune responses are critical culprits of MASLD pathogenesis. Independent contributions from either the innate or adaptive arms of the immune system or their unidirectional interplay are commonly studied in MASLD. However, the bidirectional communication between innate and adaptive immune systems and its impact on MASLD remain insufficiently understood. Given that both innate and adaptive immune cells are indispensable for the development and progression of inflammation in MASLD, elucidating pathogenic contributions stemming from the bidirectional interplay between these two arms holds potential for development of novel therapeutics for MASLD. Here, we review the immune cell types and bidirectional pathways that influence the pathogenesis of MASLD and highlight potential pharmacologic approaches to combat MASLD based on current knowledge of this bidirectional crosstalk.

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.

Ovarian cancer (OC), a highly lethal cancer in women, has a 48% 5-year overall survival rate. Prior studies link the presence of IL-17 and Th17 T cells in the tumor microenvironment to improved survival in OC patients. To determine if Th17-inducing vaccines are therapeutically effective in OC, we created a murine model of Th17-inducing dendritic cell (DC) (Th17-DC) vaccination generated by stimulating IL-15 while blocking p38 MAPK in bone marrow-derived DCs, followed by antigen pulsing.

ID8 tumor cells were injected intraperitoneally into mice. Mice were treated with Th17-DC or conventional DC (cDC) vaccine alone or with immune checkpoint blockade (ICB). Systemic immunity, tumor associated immunity, tumor size and survival were examined using a variety of experimental strategies.

Th17-DC vaccines increased Th17 T cells in the tumor microenvironment, reshaped the myeloid microenvironment, and improved mouse survival compared with cDC vaccines. ICB had limited efficacy in OC, but Th17-inducing DC vaccination sensitized it to anti-PD-1 ICB, resulting in durable progression-free survival by overcoming IL-10-mediated resistance. Th17-DC vaccine efficacy, alone or with ICB, was mediated by CD4 T cells, but not CD8 T cells.

These findings emphasize using biologically relevant immune modifiers, like Th17-DC vaccines, in OC treatment to reshape the tumor microenvironment and enhance clinical responses to ICB therapy.

The progression determinants of IgA nephropathy (IgAN) are still not fully elucidated. We have previously demonstrated that the mucosal activation of toll-like receptor (TLR) 9, which senses microbial unmethylated CpG DNA, influences progression by producing aberrantly glycosylated IgA. However, numerous recent reports of patients with IgAN presenting with gross hematuria after the mRNA vaccination for coronavirus disease 2019 suggest that the RNA-sensing system also exacerbates IgAN. Here, we investigated whether TLR7, which recognizes microbial RNA, is also involved in IgAN progression using a murine model and tonsil tissue from 53 patients with IgAN compared to samples from 40 patients with chronic tonsillitis and 12 patients with sleep apnea syndrome as controls. We nasally administered imiquimod, the ligand of TLR7, to IgAN-prone ddY mice and found that TLR7 stimulation elevated the serum levels of aberrantly glycosylated IgA and induced glomerular IgA depositions and proteinuria. Co-administered hydroxychloroquine, which inhibits TLRs, canceled the kidney injuries. In vitro, stimulating splenocytes from ddY mice with imiquimod increased interleukin-6 and aberrantly glycosylated IgA levels. The expression of TLR7 in the tonsils was elevated in patients with IgAN and positively correlated with that of a proliferation-inducing ligand (APRIL) involved in the production of aberrantly glycosylated IgA. Mechanistically, TLR7 stimulation enhanced the synthesis of aberrantly glycosylated IgA through the modulation of enzymes involved in the glycosylation of IgA. Thus, our findings suggest that nucleotide-sensing TLR9 and TLR7 play a crucial role in the pathogenesis of IgAN. Hence, nucleotide-sensing TLRs could be reasonably strong candidates for disease-specific therapeutic targets in IgAN.

Gut bacteria produce various metabolites from dietary fiber, the most abundant of which are short-chain fatty acids (SCFAs) such as acetate, propionate, and butyrate. Many biological functions, such as host metabolism and the immune system, are regulated by SCFAs because they act on a wide variety of cell types. A growing body of documents has shown that microbiota SCFAs directly regulate B-cell growth, proliferation, and immunoglobulin (Ig) production. As histone deacetylase (HDAC) inhibitors, SCFAs alter gene expression to enhance the expression of critical regulators of B cell growth. In particular, microbiota SCFAs increase the production of acetyl coenzyme A (acetyl-CoA), adenosine triphosphate (ATP), and fatty acids in B cells, which provide the energy and building blocks needed for the growth of plasma B cells. SCFAs play a significant role in promoting the involvement of B cells in host immunity during both homeostatic conditions and disease states. In this context, SCFAs stimulate B-cell activation and promote the differentiation of plasma B cells in response to B cell receptor (BCR)-activating antigens or co-stimulatory receptor ligands. The result may be increased production of IgA. Microbiota SCFAs were found to lower both overall and antigen-specific IgE levels, indicating their potential to mitigate IgE-related allergic reactions, much like their effect on class-switch recombination (CSR) towards IgG and IgA. Therefore, in the future, the therapeutic advantage should be to use specific and diffusible chemicals, such as SCFAs, which show a strong immunoregulatory function of B cells. This review focuses on the role of microbiota-produced SCFAs in regulating B cell development and antibody production, both in health and diseases.

Rhupus 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 rhupus, the underlying cause of the disease remains unknown due to its complex pathogenesis. The objective of this study was to investigate the role of tumour necrosis factor (TNF) in the production of inflammatory molecules by peripheral blood mononuclear cells (PBMCs) from patients with rhupus.

The study involved five healthy controls, seven patients with rhupus and seven patients with SLE. PBMCs were obtained from each participant and stimulated with recombinant human TNF for 24 hours. The levels of various molecules secreted by the cells, such as cytokines and chemokines, were measured using immunobead-based assays on xMAP technology.

The production levels of some molecules were higher in TNF-stimulated PBMCs from patients with rhupus and SLE than in unstimulated cells. In addition, the levels of certain molecules, including gp130/sIL-6Rb, a proliferation-inducing ligand (APRIL), interferon-β, matrix metalloproteinase-3 and interleukin (IL)-12, were higher in PBMCs from patients with rhupus even without TNF stimulation. Similarly, the levels of gp130/sIL-6Rb and APRIL were higher in TNF-stimulated PBMCs from patients with rhupus than in healthy controls. These results were further validated against patients with RA using enzyme-linked immunosorbent assay.

These findings suggest that the spontaneous production of molecules by cells from patients with rhupus may contribute to the development of the disease, and that TNF may play a role in this process by regulating the secretion of gp130/sIL-6Rb and APRIL.

The gut immune system is shaped by the continuous interaction with the microbiota. Here we dissect temporal, spatial and contextual layers of gut B cell responses. The microbiota impacts on the selection of the developing pool of pre-immune B cells that serves as substrate for B cell activation, expansion and differentiation. However, various aspects of the gut B cell response display unique features. In particular, occurrence of somatically mutated B cells, chronic gut germinal centers in T cell-deficient settings and polyreactive binding of gut IgA to the microbiota questioned the nature and microbiota-specificity of gut germinal centers. We propose a model to reconcile these observations incorporating recent work demonstrating microbiota-specificity of gut germinal centers. We speculate that adjuvant effects of the microbiota might modify permissiveness for B cell to enter and exit gut germinal centers. We propose that separating aspects of time, space and place facilitate the occasionally puzzling discussion of gut B cell responses to the microbiota.

Type I interferons (IFNs) have recently received a lot of attention with the elucidation of the pathogenesis of systemic lupus erythematosus (SLE). Type I IFNs are associated with many SLE symptoms and play a role in the pathogenesis of autoimmune diseases that may occur concurrently with SLE, such as Sjögren's syndrome, antiphospholipid syndrome, myositis, scleroderma, and interferonopathy. Type I IFNs could be the link between these diseases. However, direct measurement of type I IFN levels and the IFN gene signature is currently unavailable in clinical practice. This review discusses type I IFN signalling in SLE, investigates the role of type I IFN in the clinical manifestations and symptoms associated with SLE and other IFN-related diseases, and discusses the clinical tests that can be used to diagnose SLE and measure disease activity. In addition, the role of type I IFN-blocking therapies as potential treatments for SLE is discussed.

Lactic acid bacteria (LAB) exert health-beneficial effects by regulating innate immunity in the intestinal tract. Due to growing health awareness, the demand for LAB and studies have focused on identifying beneficial LAB strains is increasing, especially those that stimulate innate immunity. In this study, the LAB strain D279 (NITE_BP-03645, Latilactobacillus sakei) was isolated from among 741 LAB strains that were analyzed for their ability to induce interleukin 12 (IL-12) production and was subsequently characterized. D279 induced the highest expression of IL-12 among the screened LABs. Furthermore, D279 significantly activated antiviral genes and preferentially induced interferon (IFN)λ expression in vitro, which plays a critical role in the epithelial tissue, thereby conferring strong anti-influenza potency without inflammation. However, it decreased the IFNα levels. The administration of pasteurized D279 to mice resulted in strong anti-influenza potency, with higher natural killer (NK) cell activity and a lower viral load in the lung than in the control. Importantly, none of the D279-administered mice were sacrificed during the viral infection tests. These results suggest that D279 administration confers beneficial effects by regulating innate immunity and that it may be relevant for commercial use in the future.

NF-κB signaling is essential to an effective innate and adaptive immune response. Many immune-specific functional and developmental outcomes depend in large on NF-κB. The formidable task of sorting out the mechanisms behind the regulation and outcome of NF-κB signaling remains an important area of immunology research. Here we briefly discuss the role of NF-κB in regulating cell fate decisions at various times in the path of B cell development, activation, and the generation of long-term humoral immunity.

Considering the important role of the Peyer's patches (PPs) in gut immune balance, understanding of the detailed mechanisms that control and regulate the antigens in PPs can facilitate the development of immune therapeutic strategies against the gut inflammatory diseases.

In this review, we summarize the unique structure and function of intestinal PPs and current technologies to establish in vitro intestinal PP system focusing on M cell within the follicle-associated epithelium and IgA⁺ B cell models for studying mucosal immune networks. Furthermore, multidisciplinary approaches to establish more physiologically relevant PP model were proposed.

PPs are surrounded by follicle-associated epithelium containing microfold (M) cells, which serve as special gateways for luminal antigen transport across the gut epithelium. The transported antigens are processed by immune cells within PPs and then, antigen-specific mucosal immune response or mucosal tolerance is initiated, depending on the response of underlying mucosal immune cells. So far, there is no high fidelity (patho)physiological model of PPs; however, there have been several efforts to recapitulate the key steps of mucosal immunity in PPs such as antigen transport through M cells and mucosal IgA responses.

Current in vitro PP models are not sufficient to recapitulate how mucosal immune system works in PPs. Advanced three-dimensional cell culture technologies would enable to recapitulate the function of PPs, and bridge the gap between animal models and human.

In this review, we will summarize the growing body of knowledge on the age-related changes of human splenic B cell composition and molecular evidence of immune maturation and discuss the contribution of these changes on splenic protective function. From birth on, the splenic marginal zone (sMZ) contains a specialized B cell subpopulation, which recruits and archives memory B cells from immune responses throughout the organism. The quality of sMZ B cell responses is augmented by germinal center (GC)-dependent maturation of memory B cells during childhood, however, in old age, these mechanisms likely contribute to waning of splenic protective function.

Marginal zone (MZ) B cells are one of the main actors of T-independent (TI) responses in mice. To identify the B cell subset(s) involved in such responses in humans, we vaccinated healthy individuals with Pneumovax, a model TI vaccine. By high-throughput repertoire sequencing of plasma cells (PCs) isolated 7 days after vaccination and of different B cell subpopulations before and after vaccination, we show that the PC response mobilizes large clones systematically, including an immunoglobulin M component, whose diversification and amplification predated the pneumococcal vaccination. These clones could be mainly traced back to MZ B cells, together with clonally related IgA+ and, to a lesser extent, IgG+CD27+ B cells. Recombinant monoclonal antibodies isolated from large PC clones recognized a wide array of bacterial species from the gut flora, indicating that TI responses in humans largely mobilize MZ and switched B cells that most likely prediversified during mucosal immune responses against bacterial antigens and acquired pneumococcal cross-reactivity through somatic hypermutation.

Systemic lupus erythematosus (SLE) is characterized by increased expression of type I interferon (IFN)-regulated genes in 50%-75% of patients. We report that out of 501 patients with SLE analyzed, 73 (14%) present autoantibodies against IFNα (anti-IFN-Abs). The presence of neutralizing-anti-IFN-Abs in 4.2% of patients inversely correlates with low circulating IFNα protein levels, inhibition of IFN-I downstream gene signatures, and inactive global disease score. Hallmarks of SLE pathogenesis, including increased immature, double-negative plasmablast B cell populations and reduction in regulatory B cell (Breg) frequencies, were normalized in patients with neutralizing anti-IFN-Abs compared with other patient groups. Immunoglobulin G (IgG) purified from sera of patients with SLE with neutralizing anti-IFN-Abs impedes CpGC-driven IFNα-dependent differentiation of B cells into immature B cells and plasmablasts, thus recapitulating the neutralizing effect of anti-IFN-Abs on B cell differentiation in vitro. Our findings highlight a role for neutralizing anti-IFN-Abs in controlling SLE pathogenesis and support the use of IFN-targeting therapies in patients with SLE lacking neutralizing-anti-IFN-Abs.

B cell-activating factor (BAFF) contributes to the pathogenesis of autoimmune diseases including systemic lupus erythematosus (SLE). Although several anti-BAFF Abs and derivatives have been developed for the treatment of SLE, the specific sources of BAFF that sustain autoantibody (auto-Ab) producing cells have not been definitively identified. Using BAFF-RFP reporter mice, we identified major changes in BAFF-producing cells in two mouse spontaneous lupus models (Tlr7 Tg mice and Sle1), and in a pristane-induced lupus (PIL) model.

First, we confirmed that similar to their wildtype Tlr7 Tg and Sle1 mice counterparts, BAFF-RFP Tlr7 Tg mice and BAFF-RFP Sle1 mice had increased BAFF serum levels, which correlated with increases in plasma cells and auto-Ab production. Next, using the RFP reporter, we defined which cells had dysregulated BAFF production. BAFF-producing neutrophils (Nphs), monocytes (MOs), cDCs, T cells and B cells were all expanded in the spleens of BAFF-RFP Tlr7 Tg mice and BAFF-RFP Sle1 mice compared to controls. Furthermore, Ly6C^hi inflammatory MOs and T cells had significantly increased BAFF expression per cell in both spontaneous lupus models, while CD8^- DCs up-regulated BAFF expression only in the Tlr7 Tg mice. Similarly, pristane injection of BAFF-RFP mice induced increases in serum BAFF levels, auto-Abs, and the expansion of BAFF-producing Nphs, MOs, and DCs in both the spleen and peritoneal cavity. BAFF expression in MOs and DCs, in contrast to BAFF from Nphs, was required to maintain homeostatic and pristane-induced systemic BAFF levels and to sustain mature B cell pools in spleens and BMs. Although acting through different mechanisms, Nph, MO and DC sources of BAFF were each required for the development of auto-Abs in PIL mice.

Our findings underscore the importance of considering the relative roles of specific myeloid BAFF sources and B cell niches when developing treatments for SLE and other BAFF-associated autoimmune diseases.

Immunoglobulin A (IgA) is the most abundant Ig in mucosae where it plays key roles in host defense against pathogens and in mucosal immunoregulation. Whereas intense research has established the different roles of secretory IgA in the gut, its function has been much less studied in the lung. This review will first summarize the state-of-the-art knowledge on the distribution and phenotype of IgA⁺ B cells in the human lung in both homeostasis and disease. Second, it will analyze the studies looking at cellular and molecular mechanisms of homing and priming of IgA⁺ B cells in the lung, notably following immunization. Lastly, published data on observations related to IgA and IgA⁺ B cells in lung and airway disease such as asthma, cystic fibrosis, idiopathic pulmonary fibrosis, or chronic rhinosinusitis, will be discussed. Collectively it provides the state-of-the-art of our current understanding of the biology of IgA-producing cells in the airways and identifies gaps that future research should address in order to improve mucosal protection against lung infections and chronic inflammatory diseases.

T cell-independent (TI) B cell responses to nonprotein Ags involve multiple cues from the innate immune system. Neutrophils express complement receptors and activated neutrophils can release BAFF, but mechanisms effectively linking neutrophil activation to TI B cell responses are incompletely understood. Using germline and conditional knockout mice, we found that TI humoral responses involve alternative pathway complement activation and neutrophil-expressed C3a and C5a receptors (C3aR1/C5aR1) that promote BAFF-dependent B1 cell expansion and TI Ab production. Conditional absence of C3aR1/C5aR1 on neutrophils lowered serum BAFF levels, led to fewer Peyer's patch germinal center B cells, reduced germinal center B cells IgA class-switching, and lowered fecal IgA levels. Together, the results indicate that sequential activation of complement on neutrophils crucially supports humoral TI and mucosal IgA responses through upregulating neutrophil production of BAFF.