Increased serum concentration of BAFF/APRIL and IgA2 subclass in patients with mixed connective tissue disease complicated by interstitial lung disease

Abstract

B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) are known to be crucial for B cell maturation and survival, and increased expression of these factors in various autoimmune diseases has been reported. Human B cells produce two IgA subclasses: IgA1 and IgA2, the latter being abundant in the distal intestine, saliva, colostrum and bronchial fluid. We investigated these parameters in patients with mixed connective tissue disease (MCTD) complicated by interstitial lung disease (ILD+), and compared them with those in MCTD patients without ILD (ILD-). Sixty-three MCTD patients were divided into two groups: 21 ILD+ patients and 42 ILD- patients. In each patient group we analyzed soluble BAFF/APRIL using ELISA, and IgA1 and IgA2 using double immunodiffusion. Furthermore, we analyzed BAFF-APRIL receptors, BCMA, BAFF-R and TACI, using flow cytometry. The ILD+ patients had significantly higher levels of BAFF/APRIL than the ILD- patients. There were significant correlations between BAFF/APRIL, BAFF/KL-6 and APRIL/KL-6. Although there was no significant inter-group difference in the serum IgA1 level, ILD+ patients had a significantly elevated IgA2 level in comparison with ILD- patients. Moreover, although there were no significant inter-group differences in the expression of BCMA, BAFF-R and TACI on B cells, the expression of BAFF-R was significantly decreased in the ILD+ patients. In recent years, relationships between BAFF/APRIL and IgA subclass have been reported. Our results suggest that an elevated level of BAFF/APRIL drives the maturation of B cells, subsequently leading to IgA2 class switching, and possibly to the development of ILD in patients with MCTD.

IL-2, IL-4, IFN-γ or TNF-α enhances BAFF-stimulated cell viability and survival by activating Erk1/2 and S6K1 pathways in neoplastic B-lymphoid cells

“…A series of data have uncovered that BAFF acts as a crucial factor in aggressive B-cell malignancies and various autoimmune diseases, such as SLE, RA and SS [13, 21, 41, 46, 47]. For example, lupus serum contains elevated levels of BAFF [48].…”

“…High levels of BAFF evoke prolonged lifespan B-cell disorders [49, 50]. The SLE patients suffer from numerous pathogenic autoantibodies released from aggressive B cells, due to excessive BAFF [17, 21, 46]. However, abnormal release or effects of diverse other cytokines have been also documented in SLE patients and animal models both in vitro and in vivo , pointing to association of the autoimmune disease with the dysregulation of complex cytokine networks [47, 51].…”

Serum B cell–activating factor (BAFF) level in connective tissue disease associated interstitial lung disease

“…Serum BAFF levels are associated with disease activity for these clinical entities. Furthermore, it has been shown the myositis and mixed CTD (MCTD) patients with ILDs have significantly higher BAFF levels than those without ILDs [ 16 , 17 ]. A recent study showed plasma BAFF concentrations are significantly higher in IPF patients than in either COPD patients or control subjects [ 18 ].…”

Rapamycin inhibits BAFF-stimulated cell proliferation and survival by suppressing mTOR-mediated PP2A-Erk1/2 signaling pathway in normal and neoplastic B-lymphoid cells

“…B-cell activating factor of the TNF family is known to be crucial for B cell maturation and survival, and especially increased expression of BAFF in various autoimmune diseases, such as RA, SS and SLE, has recently received more attention [5,12,51]. For example, high levels of BAFF contribute to aggressive or neoplastic B cell disorders [16,17].…”

“…For example, high levels of BAFF contribute to aggressive or neoplastic B cell disorders [16,17]. Patients suffer from a great quantity of autoantibodies secreted from aggressive B cells, whose root is excess BAFF [8,12,51]. However, the signaling pathways that can be activated by BAFF are complex and controversial.…”