Genetics on the outside-in/Inside out trail of immune activation in MS.
Evidence for the astrocyte
Ponath G, Lincoln MR, Levine-Ritterman M, Park C, Dahlawi S, Mubarak M, Sumida T, Airas L, Zhang S, Isitan C, Nguyen TD, Raine CS, Hafler DA, Pitt D. Enhanced astrocyte responses are driven by a genetic risk allele associated with multiple sclerosis.Nat Commun. 2018 Dec 17;9(1):5337
Epigenetic annotation studies of genetic risk variants for multiple sclerosis (MS) implicate dysfunctional lymphocytes in MS susceptibility; however, the role of central nervous system (CNS) cells remains unclear. We investigated the effect of the risk variant, rs7665090G, located near NFKB1, on astrocytes. We demonstrated that chromatin is accessible at the risk locus, a prerequisite for its impact on astroglial function. The risk variant was associated with increased NF-κB signaling and target gene expression, driving lymphocyte recruitment, in cultured human astrocytes and astrocytes within MS lesions, and with increased lesional lymphocytic infiltrates and lesion sizes. Thus, our study establishes a link between genetic risk for MS (rs7665090G) and dysfunctional astrocyte responses associated with increased CNS access for peripheral immune cells. MS may therefore result from variant-driven dysregulation of the peripheral immune system and of the CNS, where perturbed CNS cell function aids in establishing local autoimmune inflammation.
Genome-wide association studies (GWAS) have now identified over 200 genetic variants that confer increased risk of developing MS. Many of these variants influence immune function. The authors had not done any reading as they were unclear if any of the genes would affect any CNS cells.
They asked is a variant of Nuclear Factor Kappa B Factor B, which is a master cytokine regulator, would influence astrocyte function.
NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, oxidized LDL, and bacterial or viral antigens. NF-κB plays a key role in regulating the immune response to infection. Incorrect regulation of NF-κB has been linked to cancer, inflammatory and autoimmune diseases, septic shock, viral infection, and improper immune development. NF-κB has also been implicated in processes of synaptic plasticity and memory.
SO more on the” inside out” theory and now it is astrocytes that control the show.
They looked at a variant of NFKB which is common in the general population and adds tiny risk of MS, However a lot of MS risk geneses have functions that will affect NFKB.
They made astrocytes from people with MS, starting with their skin cells (so maybe it is time to call time on using animal astrocytes to do studies). NFKB activation was higher in the astrocytes with the MS risk variant.
TNFα, IL-1β, and IFNγ stimulation resulted in significant upregulation of 23 genes in astrocytes with the protective variant, and 28 genes in astrocytes with the risk variant compared to baseline. Transcripts that were differentially expressed by 2-fold or higher (p ≤ 0.05) in stimulated astrocytes with the risk compared to the protective variants were IL-15 (IL-2-like cytokine, which makes T cells grow), ICAM1 (Vascular adhesion molecule and co-stimulatory pathway for lymphocyte activation), CXCL10 , CCL5/RANTES (Chemokines), and complement component 3 (C3). These are involved in lymphocyte recruitment and activation and they looked at astrocytes in MS lesions and they produced these cytokines. Stimulated astrocytes contained the NFKB variants were as non-reactive astrocytes in the lesion vicinity and normal appearing white matter (NAWM), indicating low constitutive levels of NF-κB signaling in non-activated astrocytes. This suggests that upregulation of NFKB could be a effect of activation rather than perhaps a trigger. They didn’t find the NFKB variants in endothelial cells. However, they found We found that the number of CD3+ T cells around blood vessels in the active rim was significantly higher in lesions with the risk than the protective variants, but not in the gliotic lesion centre.
There was positive correlations between NF-κB signaling in astrocytes and expression of chemokines, CCL5 and CXCL10 (r = 0.88; r = 0.84) and astroglial expression of cytosolic p50 (r = 0.80) and CXCL10 (r = 0.67), and between lesion sizes and astroglial expression of C3d (r = 0.81) and IL-15 (r = 0.88).
So the implication is there that these astrocytes are controlling lesion formation because of the NFKB so so do people with this genetic variant have more lesions…do a massive MRI study and supplementary data here we come because there was no influence. They found that the risk variant was not associated with a significant increase in lesion load in pwMS.
It is suggested that multiple factors in addition to effects on astrocytes are important in lesion development and despite increase in NF-KB activation this molecule has minor influence on MS risk and so this genetic effect has a minor part in overall susceptibility and so it is not surprising that they did not find a correlation with lesion load by MRI.
It is inconceivable that the genetic variant would not impinge on adaptive immune function within the lymphoid tissue and whilst an influence on astrocyte function is one possibility, another would be on microglial activity. Indeed NFKB signalling was also upregulated in microglia/macrophages in lesions and in lymphocytes also. The authors also suggest others too.
Is the evidence “compeling” that the risk gene occurs via astrocyte function, they didn’t really attempt to show it didn’t.
There was a suggestion that laquinimod may act by blocking NFKB in astrocytes
Reduced astrocytic NF-κB activation by laquinimod protects from cuprizone-induced demyelination.
, Pförtner R
, Pham T
, Zhang J
, Hayardeny L
, Piryatinsky V
, Hanisch UK
, Regen T
, van Rossum D
, Brakelmann L
, Hagemeier K
, Kuhlmann T
, Stadelmann C
, John GR
, Kramann N
, Wegner C
You know what happened with laquinimod (rather useless as a DMT for relapsing MS and did nothong of note in progressive MS trial), so perhaps do not hold your breathe whilst waiting for a therapey to come out of this