Background 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.

Objectives 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.

Methods 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 (>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.

Results 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<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<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 in vitro (respectively, P<0.05). The serum PGRN levels significantly correlated with the serum IL-6 levels (r=0.47, P<0.0001).

Conclusions 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.

1. Park B, Buti L, Lee S, et al. Granulin is a soluble cofactor for toll-like receptor 9 signaling. Immunity 2011;34:505-513.

Disclosure of Interest None Declared