IMN patients can have variable disease courses20.Some patients may suffer from rapid deterioration of renal function, while others may experience spontaneous proteinuria remission or a relatively good response to treatment21–23. Previous studies have shown that increased proteinuria, decreased eGFR, increased serum anti-PLA2R levels, or severe tubulointerstitial lesions are associated with iMN progression5,24,25. In this study, we found that increased serum BAFF causes severe clinical phenotypes and a worse prognosis in iMN patients.
BAFF and APRIL levels are increased in many autoimmune kidney diseases26–29. In this study, we first showed that the baseline levels of serum BAFF and APRIL in iMN patients were significantly higher than those in healthy controls. In addition, we also found that the serum BAFF level was significantly correlated with the serum anti-PLA2R antibody level, serum APRIL level, 24-h proteinuria and albumin level. These results suggest that BAFF and APRIL may be involved in the pathogenesis of iMN and cause peripheral B lymphocytes to produce more anti-PLA2R antibodies. According to the results of the multivariate Cox proportional hazard ratio analysis, the serum BAFF level, but not the serum APRIL level, is an independent risk factor for iMN prognosis. A lower serum BAFF level was significantly correlated with complete or partial remission during the follow-up period. Moreover, a lower serum APRIL level was significantly related to partial remission.
BAFF (also known as BLyS) is a member of the TNF superfamily that promotes B-cell survival and differentiation30. BAFF is produced by activated radiation-resistant stromal cells, B cells, activated T cells, and most myelogenous cell lines, including monocytes, macrophages, stimulated neutrophils, TLR9‐activated plasmacytoid dendritic cells (DCs) and IL2‐activated natural killer cells31–36. BAFF can maintain the activation of B cells and enhance the occurrence and development of autoimmune diseases. Overexpression of BAFF leads to polyclonal B cells and hyperglobulinemia, and an increase in serum BAFF level can be detected in patients with several autoimmune diseases, such as systemic lupus erythematosus (SLE), IgA nephropathy, membranous nephropathy and SS17,29,37,38.Studies have shown that BAFF is also related to increased tumor growth and invasion and inflammatory overreaction39–41.BAFF expression was found in cultured rat and human renal tubular epithelial cells (TECs) and was related to the disease activity and histopathological activity index of SLE42.Compared with those in the biopsy tissues of living donors before transplantation, the expression level of BAFF mRNA in the glomeruli and renal tubules of patients with proliferative lupus nephritis was significantly greater43. Several studies have shown that the level of serum BAFF in patients with IgA nephropathy is increased 29, which may be related to the overexpression of serum IgA1 and may also play a role in the development of IgAN. In addition, the plasma BAFF concentration in patients with renal tubular atrophy/interstitial fibrosis and global glomerulosclerosis is significantly greater than that in healthy individuals, suggesting that the plasma BAFF level in patients with IgAN is related to renal function and disease activity44.Several studies have shown that the serum BAFF level is greater in patients with primary membranous nephropathy than in healthy controls16,17,45.Similarly, our study revealed that the serum BAFF level was significantly greater in the iMN group than in the healthy control group. In addition, the expression profile of BAFF in iMN is similar to that in other autoimmune diseases, which affects renal prognosis16. Giuseppe Stefano Netti and other scholars reported that among primary MN patients, compared with those with negative anti-PLA2R, those with anti-PLA2Rhad significantly greater baseline BAFF levels. Moreover, after 6 months of immunosuppression therapy, among the anti-PLA2R-positive patients, the baseline serum level of BAFF in the patients who cleared the circulating anti-PLA2R antibody was significantly lower than that in other patients with persistent anti-PLA2R antibody, suggesting that there may be a pathogenic relationship between anti-PLA2R-positive primary MN and BAFF17.Although all the above studies revealed that the serum BAFF level is increased in membranous nephropathy, there is a lack of research on its correlation with patient prognosis and the anti-PLA2R antibody. Many investigators have shown that the serum BAFF level is correlated with the titer of autoimmune antibodies in patients with conditions such as SLE, rheumatoid arthritis, Sjögrensyndrome46and chronic hepatitis C virus infection47.In this study, we found that the serum BAFF level but not the APRIL level in iMN patients was related to the anti-PLA2R antibody titer. In addition, the serum BAFF level was positively correlated with the serum APRIL concentration and 24-h proteinuria and negatively correlated with the serum albumin level. It is suggested that the serum BAFF level can be used as a biomarker of the severity of renal function damage in iMN patients.
A proliferation-inducing ligand (APRIL) is produced as a homotrimer and contains protease cleavage sites in the proximal part of its extracellular domain48. Like BAFF, APRIL belongs to the TNF family, and its main physiological function is to induce immunoglobulin conversion and plasma cell survival. It is expressed on monocytes, macrophages, DCs, B cells, activated T cells and several types of tumor cells49. Like that of BAFF, the level of serum APRIL is increased in several autoimmune diseases50.Matthias et al. reported that the level of APRIL mRNA in the glomeruli of patients with proliferative lupus nephritis increased significantly, as did the tubulointerstitial expression of APRIL, BCMA and TACI43. Previous studies have shown that the serum APRIL level in SLE patients is higher than that in healthy controls and is positively correlated with disease activity and organ damage in SLE patients51,52. A recent study showed that the expression of the APRIL gene in the tonsil reproductive center of IgAN patients increased, which was related to the serum Gd-IgA1 level and the severity of the disease53. Makita et al. studied the relationship between APRIL and TLR9 activation and reported that TLR9 activation increased APRIL gene expression and serum levels, which further suggested that APRIL plays an important role in the overproduction of IgA and in the formation of IgG-IgA ICs induced by TLR9-induced nephritis54.In addition, it has been reported that the serum APRIL level is increased in patients with anti-GBM disease, which may be related to disease activity and renal damage27.Our findings in this study are consistent with those of previous reports. Compared with that in healthy controls, the serum APRIL level in iMN patients was significantly greater17.However, Seung et al. reported that the plasma APRIL level in iMN patients was comparable to that in healthy controls, which was inconsistent with our observation16.A reasonable explanation is that our sample size was limited. At present, there is also a lack of research on the correlation between serum APRIL levels and the prognosis of iMN and anti-PLA2Rantibodies.In this study, we found that the serum APRIL level was not significantly correlated with clinical indicators, such as the serum anti-PLA2R antibody level, 24-hour proteinuria, the serum albumin level or the eGFR.
In this study, we also found that lower baseline serum BAFF level was easier to achieve partial and complete remission than higher baseline BAFF level, and lower baseline serum APRIL level was easier to achieve partial remission than higher baseline APRIL level, which was consistent with Giuseppe Stefano Netti and others17.However, there was no significant difference between patients with lower baseline serum APRIL levels and those with higher baseline APRIL levels in achieving complete remission. Possible explanations for these differences may include the inherent heterogeneity of iMNs or differences in disease stage when patients were enrolled in this study. In addition, in our study, we also found that the serum BAFF level, rather than the serum APRIL level, is an independent predictor of iMN prognosis. The relationships between BAFF and APRIL and renal outcome differ, which indicates that these two cytokines perform different functions in the immune microenvironment of iMN. It is known that BAFF plays a crucial role in B-cell development, survival, immunoglobulin production and T-cell stimulation55,56.Previous studies have shown that transgenic mice overexpressing BAFF have a phenotype similar to that of autoimmune lupus-like diseases and are characterized by the deposition of autoantibodies and immune complexes against nuclear antigens in the kidney57. In addition, transgenic mice that overexpress BAFF also exhibit spontaneous germinal center reactions and secrete autoantibodies, increasing the number of plasma cells in secondary lymphoid organs, increasing the number of effector T cells and increasing the deposition of immunoglobulin in kidneys10. Despite likely not being critical for B-cell development 58, APRIL is involved in several B-cell functions, particularly antigen presentation, Ig class switching and plasma cell survival50,59.We speculate that the pathogenesis of BAFF and APRIL may differ in different types of nephritis and that BAFF may play a dominant role in the pathogenesis of iMN.
One limitation of this study is that our clinical sample size was limited, and the follow-up time was relatively short. A large clinical sample size is needed to confirm these results in future studies. In addition, the underlying mechanism through which BAFF or APRIL influence the prognosis of iMN needs to be further clarified.
In summary, this is the first study to explore the correlation between BAFF and APRIL and between clinical manifestations and outcomes in iMN patients. We found that patients with low serum BAFF levels had relatively mild clinical manifestations and were more likely to achieve PR and CR than patients with high serum BAFF levels. However, further studies are needed to determine whether BAFF or APRIL levels change during the course of disease or in response to specific treatment regimens, and the pathogenic roles of BAFF and APRIL are worthy of further exploration.