Differences in IDO1 Dendritic Cells and Soluble CTLA-4 Are Associated with Differential Clinical Responses to Methotrexate Treatment in Rheumatoid Arthritis

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2024 Jun 6

PMID 38840915

Authors

Aniko E Malik

Drew Slauenwhite

Sarah M McAlpine

John G Hanly

Jean S Marshall

Thomas B Issekutz

Affiliations

Soon will be listed here.

Abstract

Objective: Antigen-presenting dendritic cells (DCs) and monocytes play an essential role in rheumatoid arthritis (RA) pathogenesis, however, their tolerogenic potential remains unclear. Herein, the tolerogenic profiles of DCs are characterized in treatment-naïve RA patients to determine their role to inflammatory arthritis management.

Methods: Thirty-six treatment-naïve RA patients were enrolled, of which 62% were non-responders to methotrexate (MTX) monotherapy based on disease activity score (DAS) after 6-months of therapy. DC and monocyte subset frequencies, activation (CD40, CD86, CD209 expression), and tolerogenic profile (intracellular indoleamine-2,3-dioxygenase [IDO1] and cytotoxic T lymphocyte antigen 4 [CTLA-4] expression) were examined in the baseline peripheral blood by multicolor flow-cytometry. Soluble CTLA-4 (sCTLA-4) levels in plasma were measured.

Results: DC subsets were decreased in RA compared to healthy controls (HC), and the frequency of conventional DCs (cDC) inversely correlated with inflammatory markers and improvement in disease activity. CD141 cDC1s were the major IDO1-expressing cells. IDO1cDC1s were reduced in RA patients compared to HC. The baseline frequency of IDO1cDC1s inversely correlated with improvement in disease activity. CTLA-4 expression in CD1c cDC2s and monocytes was lower in RA patients compared to HC. Moreover, MTX-responders had a significantly lower frequency of IDO1cDC1 cells and higher level of sCTLA-4 in the plasma compared to MTX non-responders. There was a strong predictive association of low IDO1cDC1 cells, low sCTLA-4 and non-response to MTX.

Conclusions: Our findings reveal altered DC and monocytes immunophenotypes that are associated with RA pathology and treatment response. The frequencies of tolerogenic IDO1cDC1s and the low level of sCTLA-4 are strongly associated with MTX non-responsiveness and therapeutic outcome. These results suggest that investigation of the association IDO1cDC1 and sCTLA-4 with response to treatment may be more generalizable to other autoimmune diseases.

References

Cooles F, Anderson A, Skelton A, Pratt A, Kurowska-Stolarska M, McInnes I . Phenotypic and Transcriptomic Analysis of Peripheral Blood Plasmacytoid and Conventional Dendritic Cells in Early Drug Naïve Rheumatoid Arthritis. Front Immunol. 2018; 9:755. PMC: 5968398. DOI: 10.3389/fimmu.2018.00755. View

Coutant F, Miossec P . Altered dendritic cell functions in autoimmune diseases: distinct and overlapping profiles. Nat Rev Rheumatol. 2016; 12(12):703-715. DOI: 10.1038/nrrheum.2016.147. View

Merah-Mourah F, Cohen S, Charron D, Mooney N, Haziot A . Identification of Novel Human Monocyte Subsets and Evidence for Phenotypic Groups Defined by Interindividual Variations of Expression of Adhesion Molecules. Sci Rep. 2020; 10(1):4397. PMC: 7064612. DOI: 10.1038/s41598-020-61022-1. View

Salazar F, Awuah D, Negm O, Shakib F, Ghaemmaghami A . The role of indoleamine 2,3-dioxygenase-aryl hydrocarbon receptor pathway in the TLR4-induced tolerogenic phenotype in human DCs. Sci Rep. 2017; 7:43337. PMC: 5335671. DOI: 10.1038/srep43337. View

Garcia-Chagollan M, Ledezma-Lozano I, Hernandez-Bello J, Sanchez-Hernandez P, Gutierrez-Urena S, Munoz-Valle J . Expression patterns of CD28 and CTLA-4 in early, chronic, and untreated rheumatoid arthritis. J Clin Lab Anal. 2020; 34(5):e23188. PMC: 7246387. DOI: 10.1002/jcla.23188. View

Plant D, Maciejewski M, Smith S, Nair N, Hyrich K, Ziemek D . Profiling of Gene Expression Biomarkers as a Classifier of Methotrexate Nonresponse in Patients With Rheumatoid Arthritis. Arthritis Rheumatol. 2019; 71(5):678-684. PMC: 9328381. DOI: 10.1002/art.40810. View

Halpert M, Konduri V, Liang D, Chen Y, Wing J, Paust S . Dendritic Cell-Secreted Cytotoxic T-Lymphocyte-Associated Protein-4 Regulates the T-cell Response by Downmodulating Bystander Surface B7. Stem Cells Dev. 2016; 25(10):774-87. PMC: 4870609. DOI: 10.1089/scd.2016.0009. View

Geijtenbeek T, Krooshoop D, Bleijs D, van Vliet S, van Duijnhoven G, Grabovsky V . DC-SIGN-ICAM-2 interaction mediates dendritic cell trafficking. Nat Immunol. 2001; 1(4):353-7. DOI: 10.1038/79815. View

Zhao J, Guo S, Schrodi S, He D . Molecular and Cellular Heterogeneity in Rheumatoid Arthritis: Mechanisms and Clinical Implications. Front Immunol. 2021; 12:790122. PMC: 8660630. DOI: 10.3389/fimmu.2021.790122. View

10.

Oyewole-Said D, Konduri V, Vazquez-Perez J, Weldon S, Levitt J, Decker W . Beyond T-Cells: Functional Characterization of CTLA-4 Expression in Immune and Non-Immune Cell Types. Front Immunol. 2021; 11:608024. PMC: 7770141. DOI: 10.3389/fimmu.2020.608024. View

11.

Criado G, Simelyte E, Inglis J, Essex D, Williams R . Indoleamine 2,3 dioxygenase-mediated tryptophan catabolism regulates accumulation of Th1/Th17 cells in the joint in collagen-induced arthritis. Arthritis Rheum. 2009; 60(5):1342-51. DOI: 10.1002/art.24446. View

12.

Maxwell L, Singh J . Abatacept for rheumatoid arthritis: a Cochrane systematic review. J Rheumatol. 2010; 37(2):234-45. DOI: 10.3899/jrheum.091066. View

13.

Mazzone R, Zwergel C, Artico M, Taurone S, Ralli M, Greco A . The emerging role of epigenetics in human autoimmune disorders. Clin Epigenetics. 2019; 11(1):34. PMC: 6390373. DOI: 10.1186/s13148-019-0632-2. View

14.

Segura E . Human dendritic cell subsets: An updated view of their ontogeny and functional specialization. Eur J Immunol. 2022; 52(11):1759-1767. PMC: 9790408. DOI: 10.1002/eji.202149632. View

15.

Szanto S, Koreny T, Mikecz K, Glant T, Szekanecz Z, Varga J . Inhibition of indoleamine 2,3-dioxygenase-mediated tryptophan catabolism accelerates collagen-induced arthritis in mice. Arthritis Res Ther. 2007; 9(3):R50. PMC: 2206348. DOI: 10.1186/ar2205. View

16.

Wang Z, Zhang J, An F, Zhang J, Meng X, Liu S . The mechanism of dendritic cell-T cell crosstalk in rheumatoid arthritis. Arthritis Res Ther. 2023; 25(1):193. PMC: 10552435. DOI: 10.1186/s13075-023-03159-8. View

17.

Geijtenbeek T, Torensma R, van Vliet S, van Duijnhoven G, Adema G, van Kooyk Y . Identification of DC-SIGN, a novel dendritic cell-specific ICAM-3 receptor that supports primary immune responses. Cell. 2000; 100(5):575-85. DOI: 10.1016/s0092-8674(00)80693-5. View

18.

Steinman R . DC-SIGN: a guide to some mysteries of dendritic cells. Cell. 2000; 100(5):491-4. DOI: 10.1016/s0092-8674(00)80684-4. View

19.

Tykocinski L, Lauffer A, Bohnen A, Kaul N, Krienke S, Tretter T . Synovial Fibroblasts Selectively Suppress Th1 Cell Responses through IDO1-Mediated Tryptophan Catabolism. J Immunol. 2017; 198(8):3109-3117. DOI: 10.4049/jimmunol.1600600. View

20.

Markovics A, Rosenthal K, Mikecz K, Carambula R, Ciemielewski J, Zimmerman D . Restoring the Balance between Pro-Inflammatory and Anti-Inflammatory Cytokines in the Treatment of Rheumatoid Arthritis: New Insights from Animal Models. Biomedicines. 2022; 10(1). PMC: 8772713. DOI: 10.3390/biomedicines10010044. View