Raised serum level of APRIL in patients with systemic lupus erythematosus: Correlations with disease activity indices

Abstract

The aim of the present study is to assess serum APRIL levels in SLE patients versus rheumatoid arthritis (RA) patients and normal control and to correlate serum APRIL levels in SLE patients with disease activity indices. Serum APRIL levels was measured in 40 SLE patients, 20 patients with RA and 20 healthy volunteers who served as control group. Disease activity in SLE patients was assessed by the British Isles Lupus Assessment Group (BILAG) index and SLE disease activity index (SLEDAI), and results were correlated with serum APRIL levels. Significantly higher serum APRIL levels was observed in SLE patients compared to RA patients and normal controls (p = 0.003 and p ≤ 0.001, respectively). Positive correlations were found between serum APRIL levels and total BILAG index (r = 0.486 and p = 0.001), BILAG musculoskeletal score (r = 0.848 and p ≤ 0.001) and BILAG cardiorespiratory score (r = 0.326 and 0.04). Serum APRIL was higher in SLE patients compared to RA patients and normal control subjects and positively correlates with BILAG index and higher levels may be associated with musculoskeletal manifestations of the disease. APRIL antagonism could be a potential therapeutic target in SLE.

Introduction

Systemic lupus erythematosus (SLE) is prototypical systemic autoimmune diseases characterized by the production of autoantibodies against a spectrum of nuclear antigens. Multiple autoantibodies induce tissue damage by either binding directly to self antigens or inducing inflammation following the tissue deposition of immune complexes. These autoantibodies are produced by autoreactive B lymphocytes in the presence or absence of autoreactive T lymphocytes and induce tissue damage by either binding directly to self antigens or inducing inflammation following the tissue deposition of immune complexes [1].

Several members of the tumor necrosis factor (TNF) ligand superfamily have emerged as candidate targets of biological agents for the management of patients with SLE. One such TNF ligand superfamily member is B lymphocyte stimulator (BlyS), also known as (BAFF, TALL-1, THANK, TNFSF13B and zTNF4) a potent B cell survival factor [2], [3], [4].

Most members of the TNF ligand family are type II transmembrane proteins with the receptor-binding motif located at their C terminus. TNF family members are expressed as cell surface proteins acting in a juxtacrine and autocrine manner. Proteolytic processing of some of the ligands generates their corresponding soluble forms, whereas the majority of proteins of the TNF receptor family are composed of type I transmembrane molecules and many of these receptors also exist in soluble forms generated by proteolytic cleavage of the cell surface protein or transcribed by alternative splicing mechanisms from the genes encoding the full-length receptors [5]. Like most other TNF family members, soluble BLyS is created by cleavage of a transmembrane cell surface protein [6]. In contrast, soluble APRIL is produced in the Golgi apparatus within the cell by a furin convertase [7]. Furthermore, the transmembrane form of APRIL (named TWEPRIL) is an unusual fusion product of two alternatively spliced RNAs, composed of exons encoding intracellular and transmembrane domains from the neighboring family member TWEAK also called Apo3L or TNFSF12 [8] and exons from APRIL encoding the extracellular part of the molecule [9].

BLyS transgenic mice have an elevated number of circulating B cells, harbor elevated serum titers of autoantibodies and develop a systemic lupus erythematosus (SLE)-like syndrome [10]. In humans, elevated serum BLyS levels have been found in SLE, rheumatoid arthritis (RA) and Sjögren's syndrome patients [[11], [12], [13]], suggesting that abnormal B cell activity seen in these conditions may, at least in part, be due to BLyS.

Another member of the TNF ligand superfamily related to, but distinct from, BLyS is APRIL (a proliferation-inducing ligand, also known as TNFSF13A). It is formed of a 250 amino acid protein that binds to two of the three BLyS receptors BCMA (B cell maturation antigen) and TACI (transmembrane activator) [14], [15], [16], but not to the third BLyS receptor, BAFF-R [17], [18].

Recently, it has been reported that APRIL can affect T cell response [19] and that dendritic cells induce CD40-independent immunoglobulin class switching through APRIL. Moreover APRIL and BLyS can each independently promote T-cell-independent class switching of IgD B cells in vitro [20], and surface expression of B cell maturation antigen (BCMA) by in vitro generated plasma blasts renders them sensitive to agonist effects of both APRIL and BLyS as indicated by their survival and immunoglobulin secretion. Accordingly, APRIL could potentiate and/or supplement BLyS activity. On the other hand, TACI (which is bound by both BLyS and APRIL) can transmit to the B cell a negative signal that is vital for the prevention of B cell based autoimmunity. Accordingly, APRIL could serve as a homoeostatic down modulator of B cell hyperactivity; these lines of evidence suggest that APRIL may be involved in the pathogenesis of SLE [21].

The aim of this case controlled study is to investigate serum APRIL levels in patients with SLE and to correlate it with SLE disease activity indices.