Change of Serum B-Cell Activating Factor Level in Patients with Positive Antiphospholipid Antibodies and Previous Adverse Pregnancy Outcomes and Its Significance
B-cell activating factor (BAFF), also known as B-lymphocyte stimulator (BLyS), is a crucial growth factor for B cells. It plays a significant role in the survival, homeostasis, and plasma cell differentiation of B cells. BAFF is produced by various cells, including antigen-presenting cells, neutrophils, epithelial cells, and activated T lymphocytes. Elevated levels of BAFF have been detected in patients with systemic lupus erythematosus (SLE) and correlate with disease activity. However, the role of BAFF in antiphospholipid syndrome (APS), particularly in obstetric antiphospholipid syndrome (OAPS), remains poorly understood.
Obstetric antiphospholipid syndrome is an autoimmune disease characterized by the presence of antiphospholipid antibodies (aPLs) and adverse pregnancy outcomes (APOs). The pathogenic mechanisms of OAPS are not fully elucidated, but it is known that aPLs can disrupt various cellular functions through the activation of endothelial cells and placental tissue, leading to obstetric complications. Given the role of BAFF in B-cell survival and differentiation, it is plausible that BAFF may be involved in the pathogenesis of OAPS.
This study aimed to analyze serum BAFF concentrations in patients with positive aPLs and previous APOs, along with different pregnancy outcomes. The study enrolled 36 pregnant patients positive for aPLs and previous APOs (patient group), 25 healthy pregnant females (HP group), and 35 healthy non-pregnant females (HNP group) from the Peking University Third Hospital between October 2018 and March 2019. Serum samples from the HNP group and serum samples from patients and HP group in the first gestational trimester were collected. Enzyme-linked immunosorbent assay (ELISA) kits were used to measure serum BAFF and interferon-alpha (IFN-α) concentrations. Cytometric bead array analysis was used to measure serum concentrations of cytokines, including interleukin (IL)-2, IL-4, IL-6, IL-10, IL-17A, and tumor necrosis factor-alpha (TNF-α). The patient group was further divided into APOs and non-APOs (NAPOs) groups, fetal loss, and live birth groups based on pregnancy outcomes. The Mann-Whitney U-test was used to assess significance between and within groups, and Spearman rank-order was used to evaluate correlation coefficients between BAFF and related cytokines.
The results showed that serum BAFF levels in the HP group were significantly lower than in the HNP group (245.24 [218.80, 265.90] vs. 326.94 [267.31, 414.80] pg/mL, Z = -3.966, P < 0.001). The BAFF level was significantly elevated in the patient group compared to the HP group (307.77 [219.86, 415.65] vs. 245.24 [218.80, 265.90] pg/mL, Z = -2.464, P = 0.013). BAFF levels in the APOs group tended to be higher than in the NAPOs group (416.52 [307.07, 511.12] vs. 259.37 [203.59, 375.81] pg/mL, Z = -2.718, P = 0.006). Compared to the HP group, concentrations of IFN-α, IL-6, and TNF-α were higher in the patient group (33.37 [18.85, 48.12] vs. 13.10 [6.85, 25.47] pg/mL, Z = -2.023, P = 0.043; 39.16 [4.41, 195.87] vs. 3.37 [2.92, 3.90] pg/mL, Z = -3.650, P < 0.001; 8.23 [2.27, 64.46] vs. 1.53 [1.25, 2.31] pg/mL, Z = -3.604, P < 0.001, respectively). Serum BAFF levels had a positive correlation with the concentrations of both IL-6 and IL-10 (IL-6: r = 0.525, P = 0.002; IL-10: r = 0.438, P = 0.012).
The findings of this study suggest that serum BAFF levels are increased in patients with positive aPLs and previous APOs compared to healthy pregnant females and tend to be higher in individuals with current APOs. The BAFF levels have a positive correlation with serum IL-6 and IL-10, indicating a potential role of BAFF in the pathogenesis of OAPS.
BAFF is essential for B-cell survival, homeostasis, and plasma cell differentiation. The reduction in BAFF levels during pregnancy, along with B-cell lymphopenia, may represent an acquired protective mechanism related to maternal-fetal immune tolerance. However, in patients with positive aPLs and previous APOs, elevated BAFF levels may promote B-cell survival and differentiation, leading to the production of aPLs and the generation of immune complexes. This could result in aPL-mediated pathological changes, including inflammation, complement activation, and vascular thrombosis in trophoblastic and decidua cells.
The elevated serum BAFF concentrations in current APOs patients further support the idea that BAFF may be involved in the pathogenesis of OAPS. Increased BAFF levels can activate monocytes and other antigen-presenting cells to release pro-inflammatory cytokines such as IL-6, IL-17, and IL-23, which are predominant in APS. These cytokines can further activate neutrophils, sustaining the inflammation status. In OAPS, the production of pro-inflammatory factors is one of the pathogenic mechanisms. Endothelial cells treated with IgG-aPL can increase the expression of tissue factors, IL-6, IL-8, and TNF-α, leading to thrombosis and placental tissue injury. Therefore, higher serum BAFF levels may indicate an intensive inflammatory status in OAPS patients.
IFN-α is important in the production and pathological function of BAFF. Previous studies have shown that IFN-α is the most efficient trigger of BAFF production in monocytes and up-regulates BAFF expression in human dendritic cell (DC) cultures. In systemic autoimmune diseases, a defect in the clearance of apoptotic materials or an excess of apoptosis leads to the accumulation of nuclear autoantigens and immune complexes, which are phagocytized by DCs through Fcγ receptor (FcγR) IIa. This triggers the activation of Toll-like receptor (TLR) 7 and TLR9, culminating in the production of IFN-α. High levels of IFN-α promote the activation and induction of BAFF in B cells, monocytes, mature DCs, and neutrophils. In this study, elevated levels of IFN-α were found in patients positive for aPLs with APOs compared to the control group, although a positive correlation was not found between the levels of serum BAFF and IFN-α.
The imbalance of cytokines is another critical feature in OAPS. Th2 cells secrete IL-4, IL-6, and IL-10, which can promote the activation of B-lymphocytes and induce the production of IgG1. The decreased function of Th1 and the hyperfunction of Th2 lead to excessive activation of B cells, generation of autoantibodies, and tissue injury. Increased serum levels of pro-inflammatory cytokines, such as IL-6 and TNF-α, have been observed in APS patients. This study revealed similar serum cytokine trends in OAPS patients, with positive correlations between BAFF and the cytokines IL-6 and IL-10, indicating an interacting pathogenic relationship between OAPS, cytokines, and BAFF.
In conclusion, this study provides valuable insights into the role of BAFF in patients with positive aPLs and previous APOs. Increased serum levels of BAFF in these patients, particularly in those with current APOs, support the idea that BAFF may be a potential biomarker to predict pregnancy outcomes and a promising therapeutic target for OAPS patients in the future. Further research is needed to dynamically assess the concentrations of serum BAFF and IFN-α, as well as cytokine levels, during different gestational periods to better understand the role of BAFF in the pathogenesis of OAPS.
doi.org/10.1097/CM9.0000000000000948
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