Date: Sunday, October 21, 2018
Session Type: ACR Poster Session A
Session Time: 9:00AM-11:00AM
Background/Purpose: The etiology and pathogenesis of SSc are poorly understood; however, an increasing body of evidence supports an early inflammatory phase that precedes, and may precipitate, fibrosis. Circulating monocytes are likely to play a role in the progression of SSc because they produce inflammatory cytokines, including interferon, that have previously been identified in SSc patients. Moreover, monocytes are precursors of macrophages that can reorganize the extracellular matrix (ECM), resulting in end-organ fibrosis.
Methods: We sequenced RNA from classical and nonclassical monocytes obtained from whole blood of patients enrolled in the Prospective Registry of Early Systemic Sclerosis (PRESS) cohort at one of 11 United States Scleroderma Centers and compared them with age-, sex-, and ethnicity-matched controls. The PRESS cohort includes patients with early (< 2 years’ duration since first non-Raynaud symptom attributed to SSc) diffuse cutaneous SSc (swollen hands or sclerodactyly and at least one of the following: anti-topoisomerase I or anti-RNA polymerase III serum autoantibodies; proximal skin involvement; tendon friction rubs). Patients were 73% women, 67% white, and mean (SD) age was 51y (12); healthy controls were 73% women, 67% white, and mean (SD) age was 52y (13). Skin biopsies collected through the Northwestern Scleroderma Patient Registry were used to examine gene expression in dermal myeloid cells.
Results: Based on RNA sequencing data from classical monocytes, we define three sub-groups of patients who are robustly delineated by upregulation of distinct functional pathways. Group 1 was defined by an interferon signature, group 2 exhibited marked increase in pro-inflammatory chemokines including CCL2 and proliferation markers, and group 3 samples upregulated genes associated with TGFß signaling and ECM remodeling. These sub-groups were recapitulated in nonclassical monocytes, although not all the same genes were up-regulated. Additionally, we found that expression of genes associated with monocyte maturation from classical to nonclassical phenotype differed in these three patient groups. Finally, we examined gene expression in myeloid cells isolated from the fibrotic skin of SSc patients and healthy control participants. Genes associated with patient groups 1 and 3 were generally more upregulated in patients than genes from group 2. This result bolsters previous findings regarding the importance of interferon and TGFß signaling in SSc skin disease and illustrates a relationship between disease-specific gene expression during maturation from blood-borne monocytes to tissue-resident myeloid cells.
Conclusion: Our study confirms the role of monocytes in SSc pathogenesis through the dysregulation of genes that have been previously reported in SSc patients. Future studies will integrate longitudinal data in order to determine whether the gene expression that defined patient groups in our study is stable over time and whether it predicts patient response to specific therapies.
To cite this abstract in AMA style:Dunn JLM, Homan PJ, Dominguez S, Cuda CM, Aren K, Carns MA, Frech TM, Khanna D, Assassi S, Perlman H, Hinchcliff M, Winter DR. Monocyte Transcriptome Delineates SSc Patients with Functionally Distinct Patterns of Gene Dysregulation That Persist through Differentiation [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/monocyte-transcriptome-delineates-ssc-patients-with-functionally-distinct-patterns-of-gene-dysregulation-that-persist-through-differentiation/. Accessed December 7, 2019.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/monocyte-transcriptome-delineates-ssc-patients-with-functionally-distinct-patterns-of-gene-dysregulation-that-persist-through-differentiation/