Session Type: Abstract Submissions (ACR)
Many autoimmune diseases, e.g. systemic lupus erythematosus (SLE), have an activated type I interferon (IFN) system and about 40 SLE susceptibility loci, many within the type I IFN pathway, have been identified. We recently showed that the IFNα production by plasmacytoid dendritic cells (pDC) is regulated by both NK and B cells, and demonstrated a large interindividual difference in IFNα producing capacity among healthy individuals. We therefore investigated whether the capacity to produce type I IFN correlates to single nucleotide polymorphisms (SNPs) associated with different autoimmune diseases.
Plasmacytoid dendritic cells (pDC) (n = 130), B cells (n = 128) and NK (n = 66) were isolated from healthy blood donor PBMC genotyped with the 200K ImmunoChip (Illumina). PDC alone or in co-cultures with NK or B cells were stimulated with U1 snRNP- and SLE-IgG-containing immune complex (RNA-IC), herpes simplex virus or a synthetic oligonucleotide (ODN2216). The IFNα levels in the cell cultures were measured with an immunoassay after 20h. The association analysis was performed with PLINK software version 1.07. A total of 67 000 SNPs with minor allele frequency ≥20% which passed quality control were included in the analysis. The 10 most associated signals per cell type and stimuli were selected for further analysis. The IFNα production was normalized by Box-Cox transformation and the association to the genotype was analyzed by multiple linear regression with a stepwise method (SPSS 20.0).
The IFNα production by the stimulated healthy donor pDC alone or in cocultures with B or NK cells varied from <1 to 100000 U/ml. We found a strong association (p < 0.001) between the level of produced IFNα and several SNPs (24 to 194) depending on the combination of cell type and IFN inducer. The 7 most significant associations between IFNα production and specific SNPs among the 9 different combinations were located in C1orf222, MYO9B, TOX, between NFYAP1 and LGMNP1, and IL5RA genes (all p ≤ 0.00003).
Further analysis on the combined effect of the 10 most significant SNPs was applied on each different IFN inducer and cell type combination. For instance, the variation in IFNα production by pDC and B cells stimulated with RNA-IC could be explained to 59% by a model including SNPs located between ID4 and MBOAT1, in BLK, in MOBKL2B, in BICC1, between FAM86A and RBFOX1, and between IRF8 and FOXF1 (p < 1 x 10-18, r2 = 0.59).
We found that the interindividual variation in IFNα production in healthy individuals upon stimulation with RNA containing IC as well as IFN inducers of microbial origin is associated to several autoimmune susceptibility genes. Our results may contribute to the identification of functional gene variants that directly affect the type I IFN production and IFN signature in patients with systemic autoimmune diseases. We envision that our approach using genetically characterized individuals can reveal crucial immunological targets for therapeutic intervention.
G. V. Alm,
A. C. Syvänen,
M. L. Eloranta,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/variation-of-interferon-alpha-production-in-healthy-individuals-and-association-with-autoimmune-susceptibility-genes/