The autoimmune disease-associated transcription factors EOMES and TBX21 are dysregulated in multiple sclerosis and define a molecular subtype of disease

Abstract

We have identified a marked over-representation of transcription factors controlling differentiation of T, B, myeloid and NK cells among the 110 MS genes now known to be associated with multiple sclerosis (MS). To test if the expression of these genes might define molecular subtypes of MS, we interrogated their expression in blood in three independent cohorts of untreated MS (from Sydney and Adelaide) or clinically isolated syndrome (CIS, from San Francisco) patients. Expression of the transcription factors (TF) controlling T and NK cell differentiation, EOMES, TBX21 and other TFs was significantly lower in MS/CIS compared to healthy controls in all three cohorts. Expression was tightly correlated between these TFs, with other T/NK cell TFs, and to another downregulated gene, CCL5. Expression was stable over time, but did not predict disease phenotype. Optimal response to therapy might be indicated by normalization of expression of these genes in blood.

The low EOMES/TBX21 molecular phenotype in multiple sclerosis reflects CD56+ cell dysregulation and is affected by immunomodulatory therapies

“…When assessed together with our previously published cohort, the reduction in MS was highly significant (EOMES, p < 0.0001; TBX21, p < 0.0006; CCL5, p < 0.0001; Fig 1B, D, F). As we found in our original study [11], the expression of EOMES was tightly correlated with TBX21 and CCL5 (Fig 1G, r = 0.745, p = 8.792e-13; Fig 1H, r = 0.607, p = 5.692e-9 respectively for the new cohort assessed together). Overall, the median expression of EOMES for MS patients was 33% lower than controls (22% for TBX21; 21% for CCL5), and 64% of MS were in the bottom quartile of controls (41% for TBX21; 59% for CCL5) for the new cohort.…”

“…Previously, we had shown that expression of EOMES and TBX21 were stable over time [11]. Here we have tested samples from a new cohort of patients and controls from two time points at least 6 months apart.…”

“…From mRNA studies of immune cell subsets [11,23] the molecular phenotype tagging genes are most highly expressed in natural killer (NK) cells. For ET phenotype we confirmed that Eomes and Tbet protein expression was highest in…”

“…Specifically, we have identified an overrepresentation of immune cell transcription factor genes amongst MS risk genes [11]. Interrogation of their expression in whole blood using RNAseq, microarray analysis and quantitative RTPCR has identified two sets of transcription factors whose expression is reduced in the peripheral blood of a high proportion of untreated MS patients, replicated in three cohorts (2 Australian, one Californian), and longitudinally stable [11]. These are EOMES and TBX21 (the ET phenotype), and ZMIZ1 and ZFP36L2 (the ZZ phenotype).…”

“…Here again, the main issue is safety [8]; hence it was not approved as a first line therapy. Since the current successful therapies target blood immune cells [9] the risk genes are predominantly expressed in these immune cells [10], and the mRNA levels of many of these genes are aberrant in MS [11], GWAS MS risk gene expression in blood may provide the needed clinical biomarkers.…”