OBJECTIVE: Chronic graft-versus-host disease (cGVHD) is a significant complication following allogenic hematopoietic stem cell transplantation, often necessitating therapeutic interventions such as rituximab (RTX) and cyclosporin A (CsA). This study aims to elucidate the mechanisms by which RTX and CsA jointly address B-cell dysregulation in cGVHD, providing a theoretical foundation and scientific rationale for the treatment and prognostic evaluation of this condition.
METHODS: A total of 30 cGVHD mouse models were established by subjecting recipient mice to total body irradiation followed by injection of a mixed suspension of bone marrow cells and splenocytes from donor mice. From Day 2 to Day 29 post-model establishment, the mice received subcutaneous administration of RTX and CsA. Throughout the study, body weight, clinical cGVHD scores, and survival rates were monitored. Blood samples were collected via the orbital venous plexus. Serum levels of B-cell activating factor (BAFF) and pro-inflammatory factors were measured using enzyme-linked immunosorbent assay (ELISA), and the ratio of regulatory B cells (Bregs) in the blood sample was assessed via flow cytometry.
RESULTS: Mice with cGVHD exhibited a 14.5% decrease in body weight, elevated clinical scores, and more severe symptoms compared to the control group. Notably, all mice in both the cGVHD and control groups survived until the conclusion of the study. Induction of cGVHD resulted in B-cell dysregulation, evidenced by elevated serum BAFF levels and a decreased proportion of Bregs. However, treatment with RTX combined with CsA ameliorated B-cell dysregulation and significantly reduced serum levels of pro-inflammatory factors in cGVHD mice, with decreases of 39.78% in TNF-α and 37.89% in IL-6.
CONCLUSIONS: The combination of RTX and CsA effectively mitigates B-cell dysregulation in cGVHD, thereby reducing the severity and progression of the disease.

OBJECTIVE: The aim of this study was to investigate the relationship between circulating levels of B cell activating factor (BAFF) and the presence and severity of coronary artery disease (CAD) and acute myocardial infarction (AMI) in humans, as its biological functions in this context remain unclear.
METHODS: Serum BAFF levels were measured in a cohort of 723 patients undergoing angiography, including 204 patients without CAD (control group), 220 patients with stable CAD (CAD group), and 299 patients with AMI (AMI group). Logistic regression analyses were used to assess the association between BAFF and CAD or AMI.
RESULTS: Significantly elevated levels of BAFF were observed in patients with CAD and AMI compared to the control group. Furthermore, BAFF levels exhibited a positive correlation with the SYNTAX score (r = 0.3002, P < 0.0001) and the GRACE score (r = 0.5684, P < 0.0001). Logistic regression analysis demonstrated that increased BAFF levels were an independent risk factor for CAD (adjusted OR 1.305, 95% CI 1.078-1.580) and AMI (adjusted OR 2.874, 95% CI 1.708-4.838) after adjusting for confounding variables. Additionally, elevated BAFF levels were significantly associated with a high GRACE score (GRACE score 155 to 319, adjusted OR 4.297, 95% CI 1.841-10.030). BAFF exhibited a sensitivity of 75.0% and specificity of 71.4% in differentiating CAD patients with a high SYNTAX score, and a sensitivity of 75.5% and specificity of 72.8% in identifying AMI patients with a high GRACE score.
CONCLUSIONS: Circulating BAFF levels serve as a valuable diagnostic marker for CAD and AMI. Elevated BAFF levels are associated with the presence and severity of these conditions, suggesting its potential as a clinically relevant biomarker in cardiovascular disease.

B-cell activating factor belonging to the TNF family (BAFF), also known as B-lymphocyte stimulator (BLyS), plays a crucial role in B-cell development. It has multiple receptors, including BCMA, TACI, and BAFF-R, with diverse roles in different cell types. BAFF induces B-cell proliferation and immunoglobulin secretion, and acts as a survival factor for immature, naive, and activated B cells. Consequently, BAFF-deficient mice often show suppressed humoral responses, while BAFF-overexpressing mice show the higher number of mature B cells and may develop autoimmune-like manifestations and B-cell lymphoproliferative diseases. Elevated BAFF levels are also associated with various hematological malignancies, and its expression correlates with disease progression in some cases. Therefore, BAFF-targeted therapies, such as belimumab, atacicept, and tabalumab, are being explored in clinical trials for conditions like chronic lymphocytic leukemia (CLL) and multiple myeloma. Belimumab, an anti-BAFF monoclonal antibody, is being investigated in combination with rituximab/venetoclax for CLL. Atacicept, a decoy receptor for BAFF and APRIL, showed tolerability in a phase 1b trial for CLL. Tabalumab, another monoclonal antibody targeting BAFF, did not demonstrate significant efficacy in a phase 2 study for relapsed/refractory multiple myeloma. BAFF ligand-based CAR-T cells are designed to target BAFF receptors and show promise in preclinical studies, particularly for B-cell malignancies. The review emphasizes the importance of understanding the roles of BAFF and its receptors in the microenvironment of hematologic malignancies. Targeting BAFF and its receptors presents potential therapeutic avenues, and ongoing clinical trials provide valuable insights.

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.

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.

A PRoliferation Inducing Ligand (APRIL) is a key member of the tumor necrosis factor (TNF)-superfamily of cytokines, and plays a central role in B cell survival, proliferation and immunoglobulin class switching. Recently, there has been increasing interest in the role of APRIL and the related cytokine B cell activating factor (BAFF) in several glomerular diseases, due to their importance in the above processes. The therapeutic inhibition of APRIL represents a potentially attractive immunomodulatory approach, that may abrogate deleterious host immune responses in autoimmune diseases while leaving other important functions of humoral immunity intact, such as memory B cell function and responses to vaccination, in contrast to B cell depleting strategies. In this review, we describe the physiological roles of APRIL in B cell development and their relevance to glomerular diseases, and outline emerging clinical trial data studying APRIL inhibition, with a focus on IgA nephropathy where the clinical development of APRIL inhibitors is in its most advanced stage.

UNASSIGNED: Allergic Rhinitis (AR), a prevalent condition in otorhinolaryngology, is mediated by Type 1 hypersensitivity through IgE, characterized by Type 2 inflammatory response and eosinophil infiltration in the nasal mucosa. Since AR disease exhibits significant heterogeneity in symptom severity, an objective assessment of AR severity may facilitate better individualized treatment.
UNASSIGNED: To explore the changes in peripheral blood IL-9, Th9, and BAFF levels of allergic rhinitis (AR) in patients and the clinical significance associated with it.
UNASSIGNED: A retrospective study selected 80 AR patients admitted from January 2022 to October 2022 as the case group, dividing them into mild and moderate-to-severe groups based on symptom scores. Concurrently, 50 patients without AR, who were treated for nasal bone fractures or underwent septoplasty, were selected as the group for comparison. Alterations in the expression levels of peripheral blood IL-9, Th9, and BAFF were analyzed and compared among the different groups. The diagnostic value of serum BAFF for the severity of AR was analyzed using the receiver operating characteristic (ROC) curve.
UNASSIGNED: Noticeable variations were observed in clinical variables among the three groups such as, total IgE levels, peripheral blood eosinophil count and proportion, TNSS, and VAS (P< 0.05), while no statistically significant differences were observed in other variables (P> 0.05). The comparison of IL-9, Th9, and BAFF among the three groups revealed statistically significant differences (P< 0.05). Analysis using multivariate logistic regression revealed that IL-9 (OR = 2.365), Th9 (OR = 2.186), BAFF (OR = 2.307) were influencing factors of moderate-to-severe AR (P< 0.05). The ROC curve indicated that the AUC for the diagnosis of moderate-to-severe AR by IL-9, Th9, BAFF were 0.770, 0.734, 0.761, respectively, and the combined detection AUC was 0.888, an area under the curve higher than individual testing.
UNASSIGNED: Changes in peripheral blood IL-9, Th9, and BAFF levels in AR patients may function as indicators to assess the level of severity in diagnostic procedures.

Immune dysregulation is an important aspect of schizophrenia (SZ) and bipolar disorders (BD) pathophysiology, including not only inflammatory but also autoimmune process reflective of abnormal humoral immune responses. Given that B cell-activating factor (BAFF) is an integral aspect of B lymphocyte regulation, the current study investigated BAFF in SZ and BD. 255 SZ patients, 407 BD patients and 185 healthy controls (HC) were investigated across three aspects of soluble BAFF (sBAFF) by (i) comparing sBAFF circulatory levels across SZ, BD and HC, (ii) determining potential correlations between the circulating levels of sBAFF and the genotype distribution of a functionally relevant polymorphism, namely the TNFSF13B 3\'UTR insertion-deletion polymorphism (GCTGT>A), (iii) analyzing relationships between both sBAFF levels and 3\'UTR insertion-deletion genotypes and disease risk, patients clinical characteristics and circulating levels of potent inflammatory molecules. In addition, in subsets of patients, we also searched for possible correlations between sBAFF levels and stigma of past infectious events as well as positivity for circulating systemic autoantibodies or those directed against central nervous system (CNS) structures. Studying blood derived serum and DNA, weobserved that circulating sBAFF levels were significantly higher in SZ and BD patients, versus HC (p = 5.3*10-10and p = 4.4*10-09). Patients experiencing acute episodes, versus stable patients, in between acute episodes, exhibited higher sBAFF levels (p = 0.017).In SZ patients, positive correlations were observed between elevated sBAFF levels and: (i) elevated positive psychotic symptoms (PANSS pos), (ii) history of childhood trauma (physical abuse), and (iii) low scores on global functioning (GAF) (p = 0.024, p = 0.024, and p = 0.041).We also found that the distribution of the BAFF Ins/Del genotypes was significantly correlated with circulating sBAFF levels in SZ and BD patients (p = 0.0004). Elevated sBAFF levels were also correlated with increased levels of pro-inflammatory markers in both SZ and BD cohorts (p < 0.001). Regarding infectious stigma, only patients seropositive, versus seronegative, for herpes simplex virus (HSV)1 immunoglobulin (Ig)G antibodies exhibited a significant association with high sBAFF levels (p = 0.013). In contrast, positivity for systemic or CNS autoantibodies was significantly associated with reduced sBAFF levels, compared to patients without autoantibodies (p = 0.0017). Overall, our findings indicate that BAFF may be a promising trans-nosographic biomarker of inflammation that is likely to offer predictive, diagnostic, and prognostic tools for the management of SZ and BD. The results therefore have practicable clinical utility given the availability of immunotherapeutic treatment options including targeted monoclonal antibodies against BAFF.

Human adenovirus (HAdV) pneumonia poses a major health burden for young children, however, factors that contribute to disease severity remain elusive. We analyzed immune cells from bronchoalveolar lavage (BAL) of children with HAdV pneumonia and found that CD19+CD21low B cells were significantly enriched in the BAL and were associated with increased autoantibody concentrations and disease severity. Myeloid cells, PD-1+CD4+ T helper cells and CD21low B cells formed tertiary lymphoid structures within the respiratory tracts. Myeloid cells promoted autoantibody production by expressing high amounts of B cell activating factor (BAFF). In contrast, PD-1+CD4+ T helper cells induced production of IgG1 and IgG3 antibodies but suppressed autoreactive IgGs by initiating B cell receptor editing. In summary, this study reveals cellular components involved in protective versus autoreactive immune pathways in the respiratory tract, and these findings provide potential therapeutic targets for severe HAdV lower respiratory tract infections.

Chronic viral infections cause thymic involution yet the potential for broader, longer-term impact on thymic composition remains unexplored. Here we show that chronic, but not acute, lymphocytic choriomeningitis virus infection promotes a unique population of immature B cells in the thymus. We show that chronic viral infection promotes signals within the thymus, including the expression of B-cell activating factor (BAFF), that favor the maturation of this population as these cells acquire expression of CD19 and immunoglobulin M. Mechanistically, type I interferon (IFN-I), predominantly IFNβ, signals to thymic hematopoietic cells, strongly delaying T-cell development at the earliest precursor stage. Furthermore, IFN-I signaling to the nonhematopoietic compartment provides a second signal essential to favor B-cell differentiation and maturation within the thymus. Importantly, chronic infection yields changes in the B-cell population for at least 50 days following infection, long after thymic atrophy has subsided. Thus, the inflammatory milieu induced by chronic viral infection has a profound, and long-lasting, effect on thymic composition leading to the generation of a novel population of thymic B cells.