Circulating dendritic cells of multiple sclerosis patients are dysregulated and their frequency is correlated with MS-associated genetic risk factors

Abstract

Purpose/Objective: Dendritic cells (DC) are widely known as professional antigen-presenting cells and provide an important link to the adaptive immune system where they regulate the balance between immunity and tolerance. Alternations in the DC compartment can ultimately lead to the induction or perpetuation of autoimmune diseases such as multiple sclerosis (MS). This study aims to identify alterations in DC phenotype and functionality in MS. Moreover, the contribution of genetic risk factors to DC alterations was determined. Materials and methods: An ex vivo analysis of myeloid (mDC) and plasmacytoid DC (pDC) was carried out on peripheral blood of MS patients(n=104) and age- and gender-matched healthy controls(HC, n=112). Frequencies and expressions of costimulatory (CD80 and CD86) and migratory molecules (CD62L, CCR5 and CCR7) were investigated. Interleukin (IL)-12p70 and interferon (IFN)-a secretion was measured following Toll-like receptor (TLR) challenge. Study subjects were genotyped for HLA-DRB1*1501 and IL-7R α. Results: A significant decrease of circulating pDC was found in peripheral blood of patients with chronic progressive MS (CPMS) compared to relapsing-remitting (RR) MS and HC. No differences in blood frequencies of mDC were found between different study groups. Both mDC and pDC of MS patients show shifts in the expression of CD86, CCR5 and CCR7 indicating that activation and migratory patterns of DC change during MS. Moreover, RRMS patients showed a reduced upregulation of CD86 on pDC and enhanced IL-12 production by mDC and pDC. HLA-DRB1*1501 carriers have reduced frequencies of circulating mDC as compared to non-HLA-DRB1*1501 carriers. Moreover, patients not carrying the protective IL-7Ra haplotype 2 have lower frequencies of pDC in the peripheral blood, indicating that genetic risk factors may impact the DC compartment of MS patients. Conclusion: Our data indicate that circulating DC subsets undergo changes in phenotype and functionality during MS disease. This studie further provides evidence that MS-associated genetic risk factors such as HLA-DRB1-1501 and absence of IL-7Ra haplotype 2 have an impact on the DC compartment and thereby may contribute to the induction and/or maintenance of autoimmune responses.

Publication appears at doi: 10.1111/imm.12002