When MS Risk DNA Flips the Script: A Gene Switch in Human Dendritic Cells
A Frontiers in Immunology study shows that multiple-sclerosis (MS)–linked variants near ANKRD55 and IL6ST don’t behave the same in every immune cell: in immature monocyte-derived dendritic cells (moDCs) they lower ANKRD55/IL6ST expression, while in CD4⁺ T cells the same risk alleles tend to raise it. That cell-type flip hints that MS genetics may act through monocyte→dendritic-cell differentiation and IL-6 signaling balance.
Why this matters
Most MS risk variants sit in non-coding DNA, so their effects are usually regulatory and often cell-type specific. The ANKRD55 locus on chromosome 5q11.2 is one of the strongest MS hits (lead SNP rs7731626), and it sits next to IL6ST (which encodes gp130, the common signal-transducer for IL-6 family cytokines). Prior work in blood and CD4⁺ T cells tied the risk alleles to higher ANKRD55 (and sometimes IL6ST) expression, but what happens in myeloid cells was unclear.
What the authors did
Built human dendritic cells in a dish. They purified CD14⁺ monocytes from healthy donors and differentiated them for 6 days with IL-4 + GM-CSF to make immature moDCs (quality-checked by strong CD209/DC-SIGN staining in >95% of cells).
Pushed and pulled the cells. They tested a panel of “tolerizing” agents; the retinoic-acid receptor-α agonist AM580 stood out. They also matured the moDCs with IFN-γ + LPS, poly(I:C)+LPS, or CpG.
Measured RNAs precisely by qPCR and droplet digital PCR (ddPCR), profiled three ANKRD55 splice variants, and localized ANKRD55 by immunofluorescence microscopy.
Genotyped key SNPs (rs7731626, rs6859219, and the monocyte-trait SNP rs13186299) and related genotype to gene expression in healthy donors and untreated MS patients.
The headline findings
1) ANKRD55 “turns on” during monocyte→DC differentiation, then “dims” upon maturation
ANKRD55 expression was negligible in monocytes, rose by day 2, and was significantly higher by day 6 in immature moDCs; IL6ST stayed relatively steady while IL31RA fell and SLC38A9 peaked early.
Maturing moDCs with IFN-γ/LPS markedly downregulated ANKRD55 (and SLC38A9), with the deepest dip between 3–12 h; IL6ST barely moved, while IL31RA spiked.
Bonus cell biology: ANKRD55 protein localized to the nucleus of immature moDCs in speckle-like foci, co-staining with ALYREF and HNRNPC; maturation reduced nuclear ANKRD55 intensity.
AM580 effect: The RARα agonist AM580 boosted ANKRD55 (≈2–3× across isoforms) and massively upregulated IL31RA; ALDH1A2 induction confirmed retinoid activity.
2) The genetics do a cell-type flip
In healthy donors’ moDCs, the protective alleles were linked to higher ANKRD55/IL6ST mRNA, whereas the risk alleles were linked to lower levels—the opposite of the pattern in CD4⁺ T cells reported previously.
A nearby intronic variant tied to monocyte traits, rs13186299, explained this best: rs13186299-GG carriers had lowest ANKRD55 and IL6ST in moDCs, and this SNP is the top IL6ST eQTL in whole blood in GTEx. Notably, rs13186299-G rides the same European haplotype as the MS-risk rs7731626-G.
3) In MS patients, the picture shifts again
In CD4⁺ T cells from MS patients, rs7731626 still tracked with ANKRD55 expression. In patients’ moDCs, however, genotype-expression associations largely disappeared—hinting that disease context (or pre-conditioning of monocytes) may override the genetic effect.
Clinical stratification added nuance: ANKRD55 was higher in moDCs from primary-progressive (PP) MS than in controls, while IL6ST was lower in both PP and RR/SP MS.
4) A tie-in to IL-6 trans-signaling
Because IL6ST encodes gp130, the team looked at soluble gp130 (sgp130)—a natural brake on IL-6 trans-signaling. Serum sgp130 was higher in patients homozygous for the protective rs7731626 allele, consistent with a model where more sgp130 dampens pro-inflammatory IL-6 signals (even though CD4⁺ T-cell sgp130 mRNA doesn’t mirror serum levels one-to-one).
How to read the biology
A differentiation window that exposes genetic risk. The data place monocyte→DC differentiation as a stage where the ANKRD55–IL6ST locus is dynamically regulated—and where MS-risk haplotypes bias expression down, not up. That’s important, because inflammatory DC subsets can drive Th17 responses implicated in MS.
Opposite directions across lineages are… the point. A single non-coding haplotype can push expression up in T cells yet down in moDCs, plausibly via different enhancer wiring; the rs13186299 eQTL and its link to monocyte counts strengthen that idea.
IL-6 pathway rheostat. Changes in IL6ST/gp130 (and serum sgp130) align with altered IL-6 trans-signaling, a pathway known to shape Treg/Th17 balance in neuroinflammation.
Caveats worth flagging
MoDCs ≠ all DCs in vivo. Monocyte-derived DCs are a robust model, but they’re not the only human DC lineage; results need confirmation in primary DC subsets in tissues.
Not a formal eQTL map in purified myeloid subsets. The genetic analyses are strong but will benefit from larger, single-cell eQTL datasets across differentiation/maturation states.
Disease context matters. Loss of genotype-expression coupling in patients’ moDCs suggests environment/therapy/epigenetics can override baseline genetic effects.
Take-home
This paper reframes the ANKRD55–IL6ST risk region as a cell-state-specific dial: in the T-cell compartment, risk pushes expression up; in immature dendritic cells, risk pulls it down. That duality could be exactly how a single locus nudges immune networks toward MS—by perturbing both antigen presentation/innate-to-adaptive crosstalk and IL-6 signaling balance across lineages.
Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.
References:
Mena, J., Alloza, I., Tulloch Navarro, R., Aldekoa, A., Díez García, J., Villanueva Etxebarria, A., ... & Vandenbroeck, K. (2022). Genomic multiple sclerosis risk variants modulate the expression of the ANKRD55–IL6ST gene region in immature dendritic cells. Frontiers in immunology, 12, 816930.
