Ann Rheum Dis. 2025;84(8):1401-1411.
A coding single nucleotide polymorphism in the interleukin-6 receptor enhances IL-6 signalling in CD4 T cells and predicts treatment response to tocilizumab in giant cell arteritis.
제1저자 Zorc R, Redmond C, Sylvester M · 교신저자 박진균, Gadina M, Grayson PC
소속 (7)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA.
- Unit of Immunology, Rheumatology, Allergy and Rare diseases, IRCCS San Raffaele Scientific Institute, Milan, Italy.
- National Heart, Lung, Blood Institute, National Institutes of Health, Bethesda, MD, USA.
- Department of Medicine, Vanderbilt University, Nashville, TN, USA.
- Center for Translational Immunology, Benaroya Research Institute at Virginia Mason, Seattle, WA, USA.
- National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA; Division of Rheumatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
- National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD, USA. Electronic address: peter.grayson@nih.gov.
Abstract
OBJECTIVES The study objective was to determine if a common single nucleotide polymorphism in the interleukin 6 (IL-6) receptor (rs2228145, p.Asp358Ala) predicted treatment response to tocilizumab in giant cell arteritis (GCA).
METHODS Genetic sequencing of the rs2228145 locus was performed in 2 independent cohorts of patients with GCA. Peripheral blood mononuclear cells (PBMCs) from patients and controls were evaluated for expression of the interleukin 6 receptor (IL-6R) and its coreceptor, gp130, using flow cytometry. The same PBMCs were stimulated with IL-6 and evaluated for downstream targets of IL-6: STAT3 phosphorylation (pSTAT3) and IL-17A expression.
RESULTS In total, 100 patients with GCA were included (derivation cohort n = 58; validation cohort n = 42). The rs2228145 variant predicted tocilizumab response in each cohort. In the derivation cohort, a gene dose-dependent response was observed with a 36% response rate in the homozygous patients and 95% response rate in patients without the variant (P = .003). In the validation cohort, tocilizumab response rates were 50% for homozygotes and 85% for patients without the variant (P = .04). pSTAT3 levels were significantly increased in response to IL-6 stimulation in a gene dose-dependent manner in CD4 T cells from patients with GCA but not controls. CD4 T cells from patients with GCA had significantly higher membrane expression of gp130 than healthy controls, and response to IL-6 correlated with gp130 expression. IL-17 producing CD4 T cells were increased in a gene dose-dependent response to IL-6 (P < .01).
CONCLUSIONS The rs2228145 variant is associated with decreased treatment response to tocilizumab and worse outcomes in GCA by enhancing CD4 T cell response to IL-6.
Published by Elsevier B.V.
Conflict of interest statement
Competing interests All authors declare that they have no competing interests.
그 밖의 정보
- 출판 형태
- Journal Article
- 저널
- Annals of the rheumatic diseases · eISSN 1468-2060
- 전자 출판
- 2025-02-24
- MeSH
- Humans · Antibodies, Monoclonal, Humanized* / therapeutic use · Receptors, Interleukin-6* / genetics / metabolism · Giant Cell Arteritis* / drug therapy / genetics / immunology · Polymorphism, Single Nucleotide · Male · Female · Aged · Interleukin-6* / metabolism · CD4-Positive T-Lymphocytes* / metabolism / immunology · Signal Transduction / genetics · Treatment Outcome · STAT3 Transcription Factor / metabolism · Cytokine Receptor gp130 / metabolism · Middle Aged · Interleukin-17 / metabolism · Aged, 80 and over
- Substances
- Antibodies, Monoclonal, Humanized · tocilizumab · Receptors, Interleukin-6 · Interleukin-6 · STAT3 Transcription Factor · Cytokine Receptor gp130 · IL6R protein, human · Interleukin-17 · STAT3 protein, human · IL17A protein, human
- 연구비
- Intramural NIH HHS ZIA AR041204
- 참고문헌
- 43편