Genome wide association studies (GWAS) have identified many genetic loci which are associated with SLE;however, we still need to understand the contribution of each to disease initiation or pathogenesis. Specifically, GWAS identified that B lymphocyte induced maturation protein-1 (Blimp-1) has a susceptibility polymorphism for systemic lupus erythematosus (SLE) rs548234 but neither the significance of the polymorphism for Blimp-1 expression and function, nor its significance for SLE pathogenesis has been identified. We have generated a novel mouse model of SLE in which Blimp-1 is deleted in a dendritic cell (DC) specific manner (DCBlimp-1ko mice). Compared to the other established models, DCBlimp-1ko mice show a more pronounced gender dependent disease development, similar to the human disease. Moreover, the lupus-like phenotype in DCBlimp-1ko mice depends on the presence of estrogen. Blimp-1 deficient DCs show an activated phenotype and increased expression of proinflammatory cytokines following toll-like receptor (TLR) stimulation. We determined that Blimp-1 directly regulates expression of microRNA Let-7c in DCs, thus Blimp-1 induction leads to an aberrant increase of Let-7c and a decrease in the Let-7c target molecule, suppressor of cytokine signaling-1 (SOCS-1). We investigated the function of DCs from healthy individuals with the SLE risk allele of Blimp-1. Our preliminary studies demonstrate that there is a decrease in the level of Blimp-1 and increase in Let-7c in DCs of risk allele carriers. The differential expression of Blimp-1 and Let-7c is DC specific since there is no significant difference in Blimp-1 expression between B cells of risk allele and non-risk allele carriers. DCs of risk allele carriers also secrete an increased level of IL-6 following TLR stimulation. Finally, these phenotypic and functional changes depend on gender, since male risk allele carriers exhibit a much milder phenotype. We hypothesize that Blimp-1 has a critical immune tolerogenic function in DCs. In this proposal, we will identify how the risk allele affects the expression of Blimp-1 in DCs. We will identify target molecules of Blimp-1 which regulate the proinflammatory phenotype in DCs. We will also investigate the role of estrogen in Blimp-1 expression or function. Where limitations to human studies are great, we will employ the DCBlimp-1ko mouse model. There are strong similarities between human Blimp-1 risk allele carriers and DCBlimp-1ko mice and these similarities give us a unique opportunity to understand its contribution to human disease pathogenesis.

Public Health Relevance

We have evidence that expression of the transcriptional repressor B lymphocyte induced maturation protein -1 (Blimp-1) in dendritic cells has a critical role in immune tolerance. We identified its importance in both a mouse model and in human cells. We will investigate how a Blimp-1 variant associated with systemic lupus regulates the function of dendritic cells and promotes lupus pathogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
1R01AR065209-01A1
Application #
8664181
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Wang, Yan Z
Project Start
2014-09-01
Project End
2018-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Feinstein Institute for Medical Research
Department
Type
DUNS #
City
Manhasset
State
NY
Country
United States
Zip Code
11030
Kim, Sun Jung; Schätzle, Sebastian; Ahmed, S Sohail et al. (2017) Increased cathepsin S in Prdm1-/- dendritic cells alters the TFH cell repertoire and contributes to lupus. Nat Immunol 18:1016-1024
Jang, Su Hwa; Chen, Helen; Gregersen, Peter K et al. (2017) Kruppel-like factor4 regulates PRDM1 expression through binding to an autoimmune risk allele. JCI Insight 2:e89569
Son, Myoungsun; Kim, Sun Jung; Diamond, Betty (2016) SLE-associated risk factors affect DC function. Immunol Rev 269:100-17
Kim, Sun Jung (2015) Immunological function of Blimp-1 in dendritic cells and relevance to autoimmune diseases. Immunol Res 63:113-20