Dissertation: The activation and regulation of plasmacytoid dendritic cells in SLE: and possible therapeutic interventions
- Location: Akademiska sjukhuset H:son Holmdahlsalen, Akademiska sjukhuset Entrance 100-101, Dag Hammarskjölds väg 8
- Doctoral student: Karin Hjorton
- Contact person: Lars Rönnblom
Karin Hjorton defends her thesis "The activation and regulation of plasmacytoid dendritic cells in SLE: and possible therapeutic interventions".
It is possible to join the public defense via link at: https://uu-se.zoom.us/j/69170423158
Systemic Lupus Erythematosus (SLE) is an autoimmune disease, characterized by the presence of anti-nuclear antibodies and the formation of nucleic acid containing immune complexes (ICs), which can cause organ damage by deposition in tissues. ICs strongly trigger the plasmacytoid dendritic cells (pDCs) to produce interferon (IFN)-α, which potently activates the immune system. An activated type I IFN system is seen in a majority of SLE patients. Natural killer (NK) cells enhance the IC triggered response of pDCs. Other NK cell alterations are described in SLE. Standard SLE treatment, hydroxychloroquine (HCQ), reduces flare risks, and HCQ concentration measurement can optimize its dosing. However, new treatments are needed.
In paper I, we screened for autoantibodies to lectin-like NK cell receptors. In 3.4% of SLE patient sera, autoantibodies to CD94/NKG2A and CD94/NKG2C were found, which interfered with HLA-E mediated regulation of NK cell cytotoxicity, and facilitated elimination of target cells expressing expressing these receptors. Autoantibody levels correlated with SLE disease activity and with a more severe disease phenotype.
In paper II, we found that RNA-IC triggered proinflammatory cytokine production in immune cells from healthy blood donors and SLE patients. After RNA-IC stimulation of pDCs, RNA sequencing detected 975 differentially expressed genes, connected to cytokine pathways, cell regulation and apoptosis. An IRAK4i had a broader inhibitory effect on RNA-IC triggered cytokine production and pro-inflammatory pathways than HCQ.
In paper III we showed that RNA-IC induced type III IFN production in a subset of pDCs (3%) which also produced type I IFN. Type III IFN production by pDCs was enhanced by NK and B cells, as well as by IFN-λ2, IFN-α2b, interleukin (IL)-3, IL-6 and GM-CSF. Type III IFN production by RNA-IC stimulated immune cells of SLE patients was detected in a minority. IFN-α2b and GM-CSF increased the proportion of responders to RNA-IC from 11 to 33%.
In paper IV a LC-HRMS method, was evaluated for HCQ concentration measurement in whole blood (WB), serum and plasma from 26 SLE patients. The levels in WB were approximately 2-fold compared to serum and plasma, and correlated with weekly HCQ-dose. Large inter-individual variations were observed, despite equal doses. The WB matrix showed superior reproducibility in patient samples (CV<5%).
These findings add to the knowledge of how cytokine production by pDCs in SLE is regulated, and support a role for NK cells in the pathogenesis of SLE. Moreover WB was the superior matrix for HCQ measurement in SLE patients.