THU0168 Serum progranulin levels are elevated in patients with systemic lupus erythematosus, reflecting disease activity
Authors: A. Tanaka, H. Tsukamoto, H. Mitoma, N. Ueda, M. Ayano, S.-I. Ohta, Y. Inoue, Y. Arinobu, H. Niiro, T. Horiuchi, K. Akashi
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Granulin (GRN) is a soluble cofactor for TLR9 signaling and enhances the interaction between TLR9 and CpG-DNA. TLR9 is involved in the pathogenesis of systemic lupus erythematosus (SLE) via this DNA-containing immune complex. The roles of progranulin (PGRN) and GRN in SLE are still unknown. <h3>Objectives</h3> To determine if serum PGRN levels are elevated in patients with SLE and are correlated with disease activity and to investigate the role of PGRN in the pathogenesis of SLE. <h3>Methods</h3> The serum levels of PGRN and IL-6 were measured by ELISA in patients with SLE (n=68; active (SLEDAI score ≥6): n=46, inactive: n=22; female: n=58, male: n=10, median age=37 years), age- and sex-matched rheumatoid arthritis (RA, n=20) and normal healthy controls (NHCs, n=32). We assessed the correlation between the serum PGRN levels and an established disease activity index. The sera from the patients with high PGRN titers (&gt;80 ng/ml) at the initial evaluation were reevaluated after the disease was ameliorated by treatment (n=15). We also measured the IL-6 secreted by peripheral blood mononuclear cells (PBMCs) from healthy donors stimulated with 1) CpG-B in the presence or absence of recombinant human PGRN (rhPGRN) 2) lupus serum in the presence or absence of an anti-PGRN antibody. <h3>Results</h3> The serum PGRN levels were significantly higher in the SLE patients (median: 87.6 ng/ml) than in the RA patients (54.2 ng/ml, P=0.0082) and NHCs (44.5 ng/ml, P&lt;0.0001). The levels significantly correlated with the presence of malar rash/discoid rash (P=0.0021), alopecia (P=0.026), serositis (P=0.0038), arthritis (P=0.0003), thrombocytopenia (P=0.026), leucopenia (P=0.0004), anemia (P=0.0071), anti-Sm (P=0.03), or anti-nRNP (P=0.0028) antibody. They also correlated significantly with SLEDAI (r=0.53, P=0.0003) and anti-double stranded DNA antibody titers (r=0.45, P=0.0023) and were inversely associated with CH50 (r=-0.47, P=0.01), C3 (r=-0.41, P=0.002), and C4 (r=-0.37, P=0.0035) levels. Moreover, serum PGRN levels significantly decreased following successful treatment of SLE (P&lt;0.0001). The rhPGRN significantly upregulated the production of IL-6 by PBMCs stimulated with CpG-B and neutralizing PGRN in the lupus serum significantly attenuated the production of IL-6 by PBMCs <i>in vitro</i> (respectively, P&lt;0.05). The serum PGRN levels significantly correlated with the serum IL-6 levels (r=0.47, P&lt;0.0001). <h3>Conclusions</h3> These findings indicate that PGRN is associated with global activities of lupus. PGRN may play a role in the pathogenesis of SLE by affecting the TLR9 signaling elicited by immune complexes and could therefore be a therapeutic target for SLE. <h3>References</h3> Park B, Buti L, Lee S, et al. Granulin is a soluble cofactor for toll-like receptor 9 signaling. Immunity 2011;34:505-513. <h3>Disclosure of Interest</h3> None Declared