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अमूर्त

Pluripotency Factor PBX1 Predicts Treatment Efficacy in Rheumatoid Arthritis

Karin M.E. Andersson1 , Eric Malmhäll-Bah1 , Nina Y.Oparina1 , Weiyang Tao1 , Aridaman Pandit2 , Malin C. Erlandsson1,3, Venkataragavan Chandrasekaran1 , Sofia T. Silfverswärd1 , Rille Pullerits1,3,4, Maria I. Bokarewa1,3*

Objective: We study molecular mechanisms behind T cell reconstitution in Rheumatoid Arthritis (RA) by asking if PBX1, a transcription factor that maintains stem cell pluripotency, predicts antirheumatic treatment response.

Methods: Whole-genome transcriptomics by RNA sequencing was done in CD4⁺T cells from 87 RA patients with low, and from 78 RA patients with high disease activity. Treatment outcomes in PBX1^hi and PBX1^lo groups were compared. PBX1-associated phenotype and biological processes were identified by clustering of the genes differentially expressed in PBX1^hiCD4⁺ cells. PBX1^hi clusters in thymus were identified by a single cell-based analysis. PBX1 transcriptional targets among DEGs were predicted by the integrative analysis of DNA motif, chromatin immunoprecipitation sequencing and open chromatin data.

Results: PBX1^hiCD4⁺ cells had imprinted features of pluripotency and lacked cytokine production. In active RA, PBX1^hi cells were enriched with CD34⁺ pre-thymic lymphocyte progenitors. PBX1^hi patients had better reduction of DAS28 on anti-TNF treatment and low frequency of non-responders compared to PBX1^lo (both, p=0.026). In inactive RA, PBX1^hi cells were enriched with post-thymic naïve T cells expressing CD62L/SELL and CD31/ PECAM1. Here, PBX1^hi patients required less treatment to reach remission compared to PBX1^lo patients (p=0.011). In thymus, CD34 and PECAM1 were annotated within PBX1^hi clusters. Integrative analysis disclosed that central T-cell maturation genes TBX21, PRDM1, BATF3 and KLF1 were transcriptionally dependent on PBX1.

Conclusion: This study shows that enrichment for PBX1 is associated with pluripotent phenotype of CD4⁺ cells, which favours treatment responses in RA.