title: No evidence of pathogenic involvement of cathelicidins in patient cohorts and mouse models of lupus and arthritis.
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.
authors.affiliation: Department of Internal Medicine 3, Universitätsklinikum Erlangen, Erlangen, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Kienhöfer
authors.affiliation: Department of Internal Medicine 3, Universitätsklinikum Erlangen, Erlangen, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Hahn
authors.affiliation: Department of Internal Medicine 3, Universitätsklinikum Erlangen, Erlangen, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Schubert
authors.affiliation: Department of Internal Medicine 3, Universitätsklinikum Erlangen, Erlangen, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Reinwald
authors.affiliation: Department of Internal Medicine 3, Universitätsklinikum Erlangen, Erlangen, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Ipseiz
authors.affiliation: Department of Internal Medicine 3, Universitätsklinikum Erlangen, Erlangen, Germany.
authors.forename: S C
authors.initials: SC
authors.lastname: Lang
authors.affiliation: Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: È Bosch
authors.initials: ÈB
authors.lastname: Borràs
authors.affiliation: Department of Nephropathology, Universitätsklinikum Erlangen, Erlangen, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Amann
authors.affiliation: Rheumatology/AIR, Department of Clinical and Experimental medicine, Linköping university, Linköping, Sweden.
authors.forename: C
authors.initials: C
authors.lastname: Sjöwall
authors.affiliation: Department of Bioengineering, Stanford University, Stanford, CA, United States of America.
authors.forename: A E
authors.initials: AE
authors.lastname: Barron
authors.affiliation: Department of Internal Medicine 3, Universitätsklinikum Erlangen, Erlangen, Germany.
authors.forename: A J
authors.initials: AJ
authors.lastname: Hueber
authors.affiliation: Division of Clinical Microbiology, F68, Department of Laboratory Medicine, Karolinska University, Huddinge, Stockholm, Sweden.
authors.forename: B
authors.initials: B
authors.lastname: Agerberth
authors.affiliation: Department of Internal Medicine 3, Universitätsklinikum Erlangen, Erlangen, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Schett
authors.affiliation: Department of Internal Medicine 3, Universitätsklinikum Erlangen, Erlangen, Germany.
authors.forename: M H
authors.initials: MH
authors.lastname: Hoffmann
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D023181:Antimicrobial Cationic Peptides; D001169:Arthritis, Experimental / Q000276:immunology* / Q000473:pathology; D001323:Autoantibodies / Q000276:immunology; D001773:Blood Cells / Q000473:pathology; D054804:Cathelicidins / Q000097:blood / Q000172:deficiency / Q000276:immunology / Q000378:metabolism*; D018925:Chemokines / Q000378:metabolism; D015331:Cohort Studies; D004247:DNA / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005500:Follow-Up Studies; D006470:Hemorrhage / Q000473:pathology; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism; D008137:Longitudinal Studies; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000276:immunology*; D008297:Male; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D010533:Peritoneal Lavage; D012313:RNA / Q000378:metabolism; D013729:Terpenes; D055815:Young Adult
chemical_list: D023181:Antimicrobial Cationic Peptides; D001323:Autoantibodies; D054804:Cathelicidins; D018925:Chemokines; D016898:Interferon-alpha; D013729:Terpenes; C009042:pristane; D012313:RNA; D004247:DNA