9^th European Immunology Conference associated with Antibody Engineering Meeting

Background: Infl amed lupus skin/kidney over-express LL37, an antimicrobial peptide (AMP) with immuno-modulatory functions. By binding to nucleic acids, LL37 triggers plasmacytoid dendritic cells (pDCs) activation and Type I interferon (IFN-I), a master factor in lupus, via TLR7/9. In silico/experimental data indicate that LL37 sequence harbors T-cell promiscuous epitopes behaving as T-cell autoantigens in psoriasis, an autoimmune disease characterized by high skin LL37 levels. In Systemic lupus erythematosus (SLE), LL37 is released during NETosis and becomes target of anti-LL37 antibodies that correlate with serum IFN-I and lupus disease activity (SLEDAI).

 

Objectives: We addressed LL37 capacity to act as T-cells autoantigen in SLE patients.

 

Methods: We assessed circulating SLE T-cell proliferation and cytokine production to LL37 and control AMPs by BrdUincorporation- assay and ELISA/intracellular staining, respectively. We characterized SLE LL37-specifi c T-cell lines/clones and detected LL37-specifi c T-cells in blood by peptide-HLA-ClassII-tetramers; we addressed antibody reactivity to LL37 and DNA

in SLE patients’ sera and in in vitro-PBMC-cultures stimulated with LL37 or control AMPs by ELISA. We addressed presence of LL37 in lupus tissues by confocal microscopy.

 

Results: T-helper-17(Th 17)/T-follicular-helper(Tfh )-like LL37-specifi c T-cells were present in 45% of SLE patients, correlated with SLEDAI and declined during stable remissions. LL37-specifi c T-cells correlated with (and help production of) NETinducing anti-LL37 and anti-DNA antibodies.

 

Conclusions: LL37 is target of T-cells and autoantibodies with pathogenic functions in SLE. Th e data suggest that T-cell and anti-LL37-antibody reactivity can represent novel SLE disease markers and highlights the role of NETosis in inducing autoreactive T-cells in SLE and, possibly, in other autoimmune diseases.