The expression of BAFF in the muscles of patients with dermatomyositis

doi:10.1016/j.jneuroim.2012.04.006

Journal of Neuroimmunology

Volume 249, Issues 1–2, 15 August 2012, Pages 96-100

https://doi.org/10.1016/j.jneuroim.2012.04.006 Get rights and content

Abstract

A B-cell activating factor of the tumor necrosis factor (TNF) family (BAFF) plays a crucial role in B-cell survival and maturation. An elevated serum BAFF level has been linked to several autoimmune diseases such as Sjögren syndrome, systemic lupus erythematosus and rheumatoid arthritis. Dermatomyositis (DM), one of autoimmune inflammatory myopathies, is characterized by inflammatory cell infiltration (CD4⁺ T cells and B cells) in skeletal muscle. Serum BAFF level was significantly high in DM, but the role of BAFF is not well understood. We investigated the role of BAFF in the immunopathogenesis of DM. To examine the transcriptional increase of BAFF gene expression, we performed RT-PCR analysis with skeletal muscle tissue that contained 4 controls and 9 patients with DM. Next, in order to detect BAFF expression and cellular localization in DM, we executed immunostaining in cryosection of biopsied muscle tissue with 4 controls and 8 patients and we adopted to double immunostaining to find which inflammatory cells expressed BAFF-receptor (BAFF-R). BAFF mRNA level was increased in DM patients compared with normal controls. BAFF expression was markedly increased at muscle fibers in the perifascicular area but not blood vessels. BAFF-R was expressed in inflammatory cells in skeletal muscle tissues of DM patients. We found that BAFF expression in muscle tissue may be associated with an increased number of CD4⁺ T cells and CD19⁺ B cells in DM. Our study results suggest that BAFF might play an important role in the pathogenesis of DM.

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

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The autoimmune inflammatory myopathies constitute a heterogeneous group of acquired myopathies that have in common the presence of endomysial inflammation and moderate to severe muscle weakness. Based on currently evolved distinct clinical, histologic, immunopathologic, and autoantibody features, these disorders can be best classified as dermatomyositis, necrotizing autoimmune myositis, antisynthetase syndrome-overlap myositis, and inclusion body myositis. Although polymyositis is no longer considered a distinct subset but rather an extinct entity, it is herein described because its clinicopathologic information has provided over many years fundamental information on T-cell-mediated myocytotoxicity, especially in reference to inclusion body myositis. Each inflammatory myopathy subset has distinct immunopathogenesis, prognosis, and response to immunotherapies, necessitating the need to correctly diagnose each subtype from the outset and avoid disease mimics. The paper describes the main clinical characteristics that aid in the diagnosis of each myositis subtype, highlights the distinct features on muscle morphology and immunopathology, elaborates on the potential role of autoantibodies in pathogenesis or diagnosis , and clarifies common uncertainties in reference to putative triggering factors such as statins and viruses including the 2019-coronavirus-2 pandemic. It extensively describes the main autoimmune markers related to autoinvasive myocytotoxic T-cells, activated B-cells, complement, cytokines, and the possible role of innate immunity. The concomitant myodegenerative features seen in inclusion body myositis along with their interrelationship between inflammation and degeneration are specifically emphasized. Finally, practical guidelines on the best therapeutic approaches are summarized based on up-to-date knowledge and controlled studies, highlighting the prospects of future immunotherapies and ongoing controversies.
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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.
The B cell activating factor (BAFF), or B lymphocyte stimulator (BLyS), is a B cell survival factor which supports autoreactive B cells and prevents their deletion. BAFF expression is closely linked with autoimmunity and is enhanced by genetic alterations and viral infections. Furthermore, BAFF seems to be involved in adipogenesis, atherosclerosis, neuro-inflammatory processes and ischemia reperfusion (I/R) injury. BAFF is commonly overexpressed in Systemic Lupus Erythematosus (SLE) and strongly involved in the pathogenesis of the disease. The relationship between BAFF levels, disease activity and damage accrual in SLE is controversial, but growing evidence is emerging on its role in renal involvement. Belimumab, a biologic BAFF inhibitor, has been the first biologic agent licensed for SLE therapy so far. As Rituximab (RTX) has been shown to increase BAFF levels following B cell depletion, the combination therapy of RTX plus belimumab (being evaluated in two RCT) seems to be a valuable option for several clinical scenarios.
In this review we will highlight the growing body of evidence of immune and non-immune related BAFF expression in experimental and clinical settings.
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Although T cells are considered as the central component in immune-mediated diseases, supportive evidence has demonstrated that B cells also contribute to the progression of these diseases. B cells are divided into various subsets according to their secreted cytokines. Different B cell subsets play diverse roles in immune-mediated dermatoses. Regulatory B cells (Bregs) are defined functionally by their ability to secrete IL-10, which has been revealed to contribute to immunological tolerance. Drugs that deplete B cells, such as rituximab, are now used for the treatment of several immune-mediated dermatoses. In this review, we present and discuss the current knowledge on the roles of B cells in several immune-mediate dermatoses including psoriasis, pemphigus, bullous pemphigoid, and dermatomyositis, atopic dermatitis.
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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].
Polymyositis (PM) and dermatomyositis (DM) are different disease subtypes of idiopathic inflammatory myopathies (IIMs). The main clinical features of PM and DM include progressive symmetric, predominantly proximal muscle weakness. Laboratory findings include elevated creatine kinase (CK), autoantibodies in serum, and inflammatory infiltrates in muscle biopsy. Dermatomyositis can also involve a characteristic skin rash. Both polymyositis and dermatomyositis can present with extramuscular involvement. The causative factor is agnogenic activation of immune system, leading to immunologic attacks on muscle fibers and endomysial capillaries. The treatment of choice is immunosuppression. PM and DM can be distinguished from other IIMs and myopathies by thorough history, physical examinations and laboratory evaluation and adherence to specific and up-to-date diagnosis criteria and classification standards. Treatment is based on correct diagnosis of these conditions.
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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.
Dermatomyositis (DM), polymyositis (PM), inclusion body myositis (IBM), immune mediated necrotizing myopathy (IMNM) and overlap myositis (OM) are classified as inflammatory myopathies (IM) with involvement of autoimmune features such as autoreactive lymphocytes and autoantibodies. Autoimmunity can be defined as a loss in self-tolerance and attack of autoantigens by the immune system. Self-tolerance is achieved by a group of immune mechanisms occurring in central and periphal lymphoid organs and tissues, called immune checkpoints, that work in synergy to protect the body from harmful immune reactions. Autoimmune disorders appear when immune checkpoints fail. In this review, the different immune checkpoint failures are discussed in DM, PM, IBM and IMNM. Exploring research contribution in each of these immune checkpoints might help to highlight research perspectives in the field and obtain a more complete picture of IM disease pathology.
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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.
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Short communicationThe expression of BAFF in the muscles of patients with dermatomyositis

Abstract

Introduction

Section snippets

Subjects

RT-PCR analysis

Increase in the expression of BAFF mRNA in DM patients compared with normal controls

Discussion

J. Neuroimmunol.

Clin. Immunol.

Curr. Opin. Immunol.

Semin. Immunol.

J. Neuroimmunol.

J. Neuroimmunol.

Elevated serum B lymphocyte stimulator levels in patients with systemic immune-based rheumatic diseases

Arthritis Rheum.

B cells as therapeutic targets in autoimmune neurological disorders

Nat. Clin. Pract. Neurol.

Attenuation of apoptosis underlies B-lymphocyte stimulator enhancement of humoral immune response

J. Exp. Med.

Uncertainties in the pathogenesis of adult dermatomyositis

Curr. Opin. Neurol.

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.

Short communication
The expression of BAFF in the muscles of patients with dermatomyositis