Regulation of Type I Interferon Production in Plasmacytoid Dendritic Cells Effect of Genetic Factors and Interactions with NK Cells and B Cells

• The type I interferon (IFN) system plays a central role in the etiopathogenesis of many autoimmune diseases, e.g. systemic lupus erythematosus (SLE). Activation of the type I IFN system in SLE is promoted by endogenous nucleic acid-containing immune complexes (ICs) which stimulate plasmacytoid dendritic cells (pDCs). This thesis focuses on the regulation of IFN-α production in pDCs, by interactions with B cells and natural killer (NK) cells, and by genetic factors. In Study I , RNA-IC-stimulated CD56 dim NK cells were found to be activated via FcγRIIIa and enhanced the IFN-α production by pDCs. The enhancing effect of the NK cells was mediated via both soluble factors, such as the cytokine MIP-1β, and in a cell-cell contact mediated manner via the adhesion molecule LFA-1. In Study II , B cells enhanced the IFN-α production by pDCs via cell-cell contact or soluble factors, depending on the stimuli. The cell-cell contact-mediated enhancement, when the cells were stimulated with RNA-IC, was abolished by blocking the cell adhesion molecule CD31. B cells stimulated with the oligonucleotide ODN2216 enhanced the IFN-α production via soluble factors. In Study III , gene variants related to autoimmune or inflammatory diseases were analyzed for the association to the IFN-α production by pDCs, alone or in coculture with NK or B cells. Depending on cell combination, 18-86 SNPs (p < 0.001) were associated with the IFN-α production. Several of the SNPs showed novel associations to the type I IFN system, while some loci have been described earlier for their association with SLE, e.g. IL10 and PXK . In Study IV , several B cell populations were affected by cocultivation with pDCs and stimulation with RNA-IC. The frequency of CD24 hi CD38 hi B cells of regulatory character was increased in the pDC-B cell cocultures. However, RNA-IC-stimulation only induced modest levels of IL-10. A remarkably increased frequency of double negative CD27 - IgD - B cells was found in the RNA-IC-stimulated cocultures of pDCs and B cells. In conclusion, the findings in the present thesis reveal novel mechanisms behind the regulation of the type I IFN system which could be important targets in autoimmune diseases with constantly activated pDCs.

Ämnesord

Medical and Health Sciences  (hsv)

Clinical Medicine  (hsv)

Rheumatology and Autoimmunity  (hsv)

Medicin och hälsovetenskap  (hsv)

Klinisk medicin  (hsv)

Reumatologi och inflammation  (hsv)

Medicinsk vetenskap  (uu)

Medical Science  (uu)

Nyckelord

Systemic lupus erythemtosus

IFN-alpha

autoimmunity

immune complex

single nuclear polymorphisms