Circulating mature granzyme B+ T cells distinguish Crohn's disease-associated axial spondyloarthritis from axial spondyloarthritis and Crohn's disease

Arthritis Res Ther. 2021 May 22;23(1):147. doi: 10.1186/s13075-021-02531-w.

Adam R Lefferts # 1, Emilie H Regner # 2 3, Andrew Stahly 1, Becky O'Rourke 4, Mark E Gerich 2, Blair P Fennimore 2, Frank I Scott 2, Alison E Freeman 2 5, Ken Jones 4 6, Kristine A Kuhn 7


Author information

  • 1Division of Rheumatology, Department of Medicine, Anschutz Medical Campus, Aurora, CO, USA.
  • 2Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA.
  • 3Present Address: Division of Gastroenterology, Department of Medicine, Oregon Health Sciences University, Portland, OR, USA.
  • 4Section of Pediatric Hematology/Oncology/Bone Marrow Transplant, Department of Pediatrics, University of Colorado, Anschutz Medical Campus, Aurora, CO, USA.
  • 5Present Address: Cascade Gastroenterology, Bend, OR, USA.
  • 6Present Address: Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
  • 7Division of Rheumatology, Department of Medicine, Anschutz Medical Campus, Aurora, CO, USA. kristine.kuhn@cuanschutz.edu.

#Contributed equally.


Background: Axial spondyloarthritis (axSpA) has strong connections with intestinal inflammation as occurs in Crohn's disease (CD). However, the immunologic mechanisms that distinguish axSpA, CD, and those with features of both diseases (CD-axSpA) are unknown. This study aimed to address this question by initial unbiased single cell RNA-sequencing (scRNAseq) on a pilot cohort followed by validating findings using flow cytometry and ELISA in a larger cohort.

Methods: Two individuals each with CD, axSpA, CD-axSpA, and healthy controls (HC) were recruited for a pilot discovery scRNAseq cohort, and the validation cohort consisted of 18 axSpA, 24 CD, 13 CD-axSpA, and 17 HC that was evaluated by flow cytometry on PBMCs and ELISAs for plasma cytokines.

Results: Uniquely, PBMCs from subjects with CD-axSpA demonstrated a significant increase in granzyme B+ T cells of both CD4+ and CD8+ lineages by both scRNAseq and flow cytometry. T cell maturation was also greater in those with CD-axSpA, particularly the CD4+ granzyme B+ population. Pathway analysis suggested increased interferon response genes in all immune cell populations within CD-axSpA. Although IFN-γ was elevated in the plasma of a subset of subjects with CD-axSpA, IL-6 was also significantly elevated.

Conclusions: Our findings support the presence of a chronic interferonopathy in subjects with CD-axSpA characterized by interferon signaling by pathway analysis and an expansion of mature, cytotoxic T cells. These data indicate fundamental immunological differences between CD-axSpA and both of the putative "parent" conditions, suggesting that it is a distinct disease with unique natural history and treatment needs.


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