Abstract
Apart from their role in the immune defence against pathogens evidence of a role of antimicrobial peptides (AMPs) in autoimmune diseases has accumulated in the past years. The aim of this project was to examine the functional impact of the human cathelicidin LL-37 and the mouse cathelicidin-related AMP (CRAMP) on the pathogenesis of lupus and arthritis. Serum LL-37 and anti-LL-37 levels were measured by ELISA in healthy donors and patients with Systemic Lupus Erythematosus (SLE) and Rheumatoid arthritis (RA). Pristane-induced lupus was induced in female wild type (WT) and cathelicidin-deficient (CRAMP−/−) mice. Serum levels of anti-Sm/RNP, anti-dsDNA, and anti-histone were determined via ELISA, cytokines in sera and peritoneal lavages were measured via Multiplex. Expression of Interferon I stimulated genes (ISG) was determined by real-time PCR. Collagen-induced arthritis (CIA) was induced in male WT and CRAMP−/− mice and arthritis severity was visually scored and analysed histomorphometrically by OsteoMeasure software. Serum levels of anti-LL-37 were higher in SLE-patients compared to healthy donors or patients with RA. However, no correlation to markers of disease activity or organ involvement was observed. No significant differences of autoantibody or cytokine/chemokine levels, or of expression of ISGs were observed between WT and CRAMP−/− mice after pristane-injection. Furthermore, lung and kidney pathology did not differ in the absence of CRAMP. Incidence and severity of CIA and histological parameters (inflammation, cartilage degradation, and bone erosion) were not different in WT and CRAMP−/− mice. Although cathelicidins are upregulated in mouse models of lupus and arthritis, cathelicidin-deficiency did not persistently affect the diseases. Also in patients with SLE, autoantibodies against cathelicidins did not correlate with disease manifestation. Reactivity against cathelicidins in lupus and arthritis could thus be an epiphenomenon caused by extensive overexpression in blood and affected tissues. In addition, other cationic AMPs could functionally compensate for the deficiency of cathelicidins.
Highlights
Apart from their role in anti-microbial defence, anti-microbial peptides (AMPs) such as the human cathelicidin LL-37 possess potent immunomodulatory properties and have recently been implicated in the pathogenesis of autoimmune diseases [1,2,3,4]
Patients with Systemic Lupus Erythematosus (SLE) [5, 6] and a subset of Rheumatoid arthritis (RA) patients [7] display a type I interferon (IFN) signature in their peripheral blood mononuclear cells. Given their reported role in SLE, AMPs may stimulate Tolllike receptor (TLR)-pathways in other autoimmune diseases characterized by reactivity to nucleic acids, such as arthritis
We investigated the presence of autoAbs to LL-37 in patient cohorts of SLE and RA originating from Erlangen and Linkoping, respectively (S1 Table)
Summary
Apart from their role in anti-microbial defence, anti-microbial peptides (AMPs) such as the human cathelicidin LL-37 possess potent immunomodulatory properties and have recently been implicated in the pathogenesis of autoimmune diseases [1,2,3,4]. In sera of patients with Systemic Lupus Erythematosus (SLE), immune complexes of AMPs and self-DNA derived from neutrophil extracellular traps (NETs) were reported to trigger activation of Tolllike receptor (TLR) 9. SLE-patients were found to develop autoantibodies (autoAbs) to both self-DNA and AMPs [2, 3]. Patients with SLE [5, 6] and a subset of RA patients [7] display a type I interferon (IFN) signature in their peripheral blood mononuclear cells. Given their reported role in SLE, AMPs may stimulate TLR-pathways in other autoimmune diseases characterized by reactivity to nucleic acids, such as arthritis. In rat pristane-induced arthritis, the increased expression of rCRAMP coincided with the development of anti-rCRAMP autoAbs [8]
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