Short communicationThe expression of BAFF in the muscles of patients with dermatomyositis
Introduction
A B-cell activating factor of the tumor necrosis factor (TNF) family (BAFF, also known as BLys, TALL-1, THANK or zTNF4) plays an important role in B cell biology. BAFF is expressed by monocytes, macrophages, dendritic cells, neutrophils, T cells, B cells, and even cancer cells (Kimberley et al., 2009, Mackay and Schneider, 2009). BAFF can bind to 3 different cell surface receptors: BAFF-receptor (BAFF-R) (also known as BR3), B-cell maturation antigen (BCMA), and transmembrane activator and calcium modulator and cyclophilin ligand (TACI) (Thangarajh et al., 2004, Thangarajh et al., 2006, Dalakas, 2008). BCMA and TACI also bind to a proliferation-inducing ligand (APRIL), a counterpart of BAFF, whereas BAFF-R binds specifically to BAFF. BAFF-R is expressed in mature B cells and subset of activated T cells (Xu and Lam, 2001, Ng et al., 2004, O'Connor et al., 2004, Zhang et al., 2005).
BAFF plays a crucial role in B-cell survival and maturation. Either the transgenic overexpression of BAFF or the injection of BAFF in mice increases the level of immunoglobulins in blood (Moore et al., 1999, Khare et al., 2000). The injection of BAFF into mice enhanced both T-cell-dependent and T-cell-independent B cell responses (Do et al., 2000). BAFF transgenic mice have a high number of peripheral B cells, and overexpression of BAFF results in systemic lupus erythematosus (SLE)-like condition in mice (Gross et al., 2000, Khare et al., 2000, Ju et al., 2007). BAFF also plays a role in T-cell activation and differentiation as well as in B-cell maturation and survival (Tangye et al., 2006). APRIL is also important for B-cell development and function (Mackay et al., 2003).
Elevated serum levels of BAFF and APRIL have been linked to several autoimmune diseases, such as Sjögren syndrome, SLE and rheumatoid arthritis (Cheema et al., 2001, Zhang et al., 2001, Mariette et al., 2003, Mackay et al., 2007). In myasthenia gravis (MG), serum BAFF expression is elevated (Kim et al., 2008), and the number of CD19+ BAFF-R+ B cells are also increased (Li et al., 2008).
DM is a chronic inflammatory disorder of the skin and muscle (Mantegazza et al., 1997). DM, one of autoimmune inflammatory myopathies, is characterized by muscle weakness and inflammatory cell infiltration (CD4+ T cells and B cells) in skeletal muscle (Greenberg and Amato, 2004, Page et al., 2004, Greenberg et al., 2005). In patients with idiopathic inflammatory myopathy, serum BAFF level was significantly higher than in normal controls. Particularly, patients with anti-Jo-1 autoantibodies had higher serum BAFF levels, and patients with DM had higher BAFF levels compared to polymyositis (PM) (Krystufková et al., 2009).
This study was aimed to investigate the role of BAFF in the immunopathogenesis of DM.
Section snippets
Subjects
We studied frozen sections of muscle biopsy specimens from nine well-characterized patients with DM and four normal subjects. All tissues were obtained with an informed consent at Gangnam Severance Hospital (Seoul, Republic of Korea). This study was approved by Gangnam Severance Hospital Institutional Review Board.
RT-PCR analysis
Total RNAs were extracted with the Trizol reagent according to the manufacturer's protocol (Invitrogen, Carlsbad, CA, USA). Three microgram of total RNA was reverse-transcribed using
Increase in the expression of BAFF mRNA in DM patients compared with normal controls
To examine whether BAFF is expressed or not in skeletal muscle, BAFF mRNA level was analyzed by RT-PCR. RT-PCR analysis was performed on muscle biopsy specimens from 4 controls and 9 patients with DM. BAFF mRNA level was increased in DM patients compared with normal controls (Fig. 1A). However the mRNA expression of APRIL in patients with DM was not different from normal controls (Fig. 1B). BAFF-R and TACI mRNA expression (BCMA mRNA level was not detected.) also did not show a significant
Discussion
BAFF is essential for B-cell survival and maturation and plays a role in T-cell activation and differentiation (Thangarajh et al., 2004, Tangye et al., 2006). Injection of BAFF in normal mice leads to the disruption of the splenic B and T cell structures and results in elevated levels of IgM in the serum (Moore et al., 1999). BAFF transgenic (Tg) mice have a high number of B lymphocytes in the periphery, secreting various autoantibodies. BAFF Tg mice also have an SLE-like condition (Mackay et
References (32)
Serum BAFF expression in patients with myasthenia gravis
J. Neuroimmunol.
(2008)Decrease of CD4+CD25highFoxp3+ regulatory T cells and elevation of CD19+BAFF-R+ B cells and soluble ICAM-1 in myasthenia gravis
Clin. Immunol.
(2008)B cells and the BAFF/APRIL axis: fast-forward on autoimmunity and signaling
Curr. Opin. Immunol.
(2007)BAFF, APRIL and human B cell disorders
Semin. Immunol.
(2006)Expression of B-cell-activating factor of the TNF family (BAFF) and its receptors in multiple sclerosis
J. Neuroimmunol.
(2004)The thymus is a source of B-cell-survival factors-APRIL and BAFF-in myasthenia gravis
J. Neuroimmunol.
(2006)Elevated serum B lymphocyte stimulator levels in patients with systemic immune-based rheumatic diseases
Arthritis Rheum.
(2001)B cells as therapeutic targets in autoimmune neurological disorders
Nat. Clin. Pract. Neurol.
(2008)Attenuation of apoptosis underlies B-lymphocyte stimulator enhancement of humoral immune response
J. Exp. Med.
(2000)- et al.
Uncertainties in the pathogenesis of adult dermatomyositis
Curr. Opin. Neurol.
(2004)
Interferon-α/β-mediated innate immune mechanisms in dermatomyositis
Ann. Neurol.
TACI and BCMA are receptors for a TNF homologue implicated in B-cell autoimmune disease
Nature
Unexpected development of autoimmunity in BAFF-R-mutant MRL-lpr mice
Immunology
The biochemistry and biology of BAFF, APRIL and their receptors
Curr. Dir. Autoimmun.
Severe B-cell hyperplasia and autoimmune disease in TALL-1 transgenic mice
Proc. Natl. Acad. Sci.
APRIL in B-cell malignancies and autoimmunity
Results Probl. Cell Differ.
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2021, Autoimmunity ReviewsCitation Excerpt :In biopsies of dermatomyositis (DM) patients BAFF was detected in skeletal muscles, expression could be located more precisely in the perifascicular area of muscle fibers. Additionally BAFF-R expression was detected on regenerative and necrotic muscle fibers [52]. Studies concerning BAFF expression in conjunction with viral infections indicate the link between innate immunity and autoimmunity.
Role of B cells in immune-mediated dermatoses
2020, Molecular ImmunologyPolymyositis and dermatomyositis – challenges in diagnosis and management
2019, Journal of Translational AutoimmunityCitation Excerpt :B cells and plasma cells that infiltrate into the perivasculature of DM patients are also found in all subtypes of IIMs [75,76]. Upregulated BAFF signaling and Toll like receptor (TLR) expression [77–82], decreased Breg subset [83], and notably, multiple autoantibody production, demonstrate a highly activated humoral immune state in DM and PM. Researchers analyzed the molecular characteristics of the antigen (Ag) receptor on B cells from muscle and found that BCR affinity maturation and oligoclonal expansion occurred, suggesting a B cell Ag-specific response in the muscle tissue of patients with DM and PM [84,85].
Immune checkpoint failures in inflammatory myopathies: An overview
2018, Autoimmunity ReviewsCitation Excerpt :Serum levels of BAFF are increased in IM [84–87], in muscle fibers in the perifascicular area [84], as well as on peripheral blood mononuclear cells. BAFFR is increased in inflammatory cells in IM muscle tissue [86, 88]. The major mechanisms by which peripheral B cell tolerance is achieved consists of anergy by downregulation of IgM and ignorance.
Interferons as components of the complex web of reactions sustaining inflammation in idiopathic inflammatory myopathies
2015, CytokineCitation Excerpt :BAFF can be induced by type 1 IFN stimulation of myeloid DCs [55] and has been shown induced in epithelial cells treated with IFN-γ [56]. Increased levels of BAFF mRNA were detected in DM muscle compared to normal controls, and expression of BAFF protein localised to the perifascicular muscle fibres [57]. The expression of chemoattractant cytokines termed α – (CXCL) and β – (CCL) chemokines can either be induced or inhibited by IFNs.