Session Type: Poster Session D
Session Time: 1:00PM-3:00PM
Background/Purpose: Self-renewal ability, which is important for the adaptive immunity and adequate T cell function, is severely impaired in rheumatoid arthritis (RA). This leads to a disbalance between the increased frequency of common lymphoid progenitors and the low numbers of recent thymic emigrants. 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: Blood CD4+T cells of 167 RA patients (87 patients with low, and 78 patients with high disease activity) were subjected to transcriptional analysis by RNAseq (Illumina). Treatment outcomes in PBX1hi and PBX1lo groups were compared. The genes differentially expressed (DEG, nominal p< 0.05) between PBX1hi and PBX1lo groups were identified (Bioconductor, DESeq2 package, Benjamini-Hochberg correction). PBX1-associated phenotype and biological processes were analyzed by covariance clustering of DEGs. PBX1hi 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: PBX1hiCD4+ cells had imprinted features of pluripotency and lacked cytokine production. In active RA, PBX1hi cells were enriched with CD34+ pre-thymic lymphocyte progenitors. PBX1hi patients had better reduction of DAS28 on anti-TNF treatment and low frequency of non-responders compared to PBX1lo (both, p=0.026). In inactive RA, PBX1hi cells were enriched with post-thymic naïve T cells expressing CD62L/SELL and CD31/PECAM1. Here, PBX1hi patients required less treatment to reach remission compared to PBX1lo patients (p=0.011). Pathway analysis of the DEGs identified strong enrichment for regulation of transcription (cor.p=10-23), RNA metabolic processes (cor.p=10-18) and differentiation (cor.p=10-7) in PBX1hi CD4+ cells, which corresponds to the known biological properties of PBX1. In thymus, CD34 and PECAM1 were annotated within PBX1hi 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 PBX1-enriched CD4+T cells are favorable for treatment success of RA. PBX1 denotes pre-thymic lymphoid progenitors and recent thymic emigrants. T cell maturation genes were transcriptionally dependent on PBX1, which makes PBX1 a regulator of thymic passage by pluripotent CD4+ T cells.
To cite this abstract in AMA style:Andersson K, Malmhäll-Bah E, Oparina N, Weiyang T, Erlandsson M, Chandrasekaran V, Pandit A, Töyrä Silfverswärd S, Bokarewa M, pullerits R. Pluripotency Marker PBX1 Predicts Treatment Effect in Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2022; 74 (suppl 9). https://acrabstracts.org/abstract/pluripotency-marker-pbx1-predicts-treatment-effect-in-rheumatoid-arthritis/. Accessed .
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/pluripotency-marker-pbx1-predicts-treatment-effect-in-rheumatoid-arthritis/