Single-Cell Transcriptomics Reveals a Pivotal Role of DOCK2 in Sjögren Disease

Overview

Journal ACR Open Rheumatol

Date 2024 Oct 9

PMID 39382155

Authors

Yiran Shen

Alexandria Voigt

Indraneel Bhattacharyya

Cuong Q Nguyen

Affiliations

Soon will be listed here.

Abstract

Objective: Sjögren disease (SjD) is an autoimmune condition characterized by the dysfunction of the salivary and lacrimal glands. The study aimed to decipher the pathogenic cell populations and their immunologic pathways in the salivary glands. We further determined the therapeutic effect of inhibiting dedicator of cytokinesis 2 (DOCK2) shared by novel clusters of CD8 T cells in an SjD mouse model.

Methods: This study employed single-cell RNA sequencing to examine the composition and dynamics of immune cells in the salivary glands of SjD mice. By analyzing the transcriptomic data and employing clustering analysis, a specific target was identified, leading to the treatment of mice with a targeted inhibitor.

Results: The results showed diverse immune cell types, including B cells, CD4 T cells, CD8 T cells, macrophages, and natural killer cells. We identified specific clusters possessing phenotypic characteristics of immune cell subpopulations, thereby showing specific genes/pathways associated with the disease. The most striking finding was the elevated expression of DOCK2 in CD8 T cells in the SjD model. This discovery is significant because subsequent treatment with a DOCK2 inhibitor 4-[3-(2-Chlorophenyl)-2-propen-1-ylidene]-1-phenyl-3,5-pyrazolidinedione (CPYPP) led to a marked amelioration of SjD signs.

Conclusion: The effectiveness of DOCK2 inhibition in alleviating SjD signs highlights the potential of DOCK2 as a therapeutic target, opening new avenues for treatment strategies that could modulate the immune response more effectively in SjD.

References

De Leon-Oliva D, Garcia-Montero C, Fraile-Martinez O, Boaru D, Garcia-Puente L, Rios-Parra A . AIF1: Function and Connection with Inflammatory Diseases. Biology (Basel). 2023; 12(5). PMC: 10215110. DOI: 10.3390/biology12050694. View

Goules A, Kapsogeorgou E, Tzioufas A . Insight into pathogenesis of Sjögren's syndrome: Dissection on autoimmune infiltrates and epithelial cells. Clin Immunol. 2017; 182:30-40. DOI: 10.1016/j.clim.2017.03.007. View

Schnell A, Littman D, Kuchroo V . T17 cell heterogeneity and its role in tissue inflammation. Nat Immunol. 2023; 24(1):19-29. PMC: 10795475. DOI: 10.1038/s41590-022-01387-9. View

Ruterbusch M, Pruner K, Shehata L, Pepper M . In Vivo CD4 T Cell Differentiation and Function: Revisiting the Th1/Th2 Paradigm. Annu Rev Immunol. 2020; 38:705-725. DOI: 10.1146/annurev-immunol-103019-085803. View

Stevenson C, de la Rosa G, Anderson C, Murphy P, Capece T, Kim M . Essential role of Elmo1 in Dock2-dependent lymphocyte migration. J Immunol. 2014; 192(12):6062-70. PMC: 4127066. DOI: 10.4049/jimmunol.1303348. View

Peck A, Nguyen C, Ambrus J . Upregulated Chemokine and Rho-GTPase Genes Define Immune Cell Emigration into Salivary Glands of Sjögren's Syndrome-Susceptible C57BL/6.NOD- Mice. Int J Mol Sci. 2021; 22(13). PMC: 8267620. DOI: 10.3390/ijms22137176. View

Cook D, Kannarkat G, Cintron A, Butkovich L, Fraser K, Chang J . LRRK2 levels in immune cells are increased in Parkinson's disease. NPJ Parkinsons Dis. 2017; 3:11. PMC: 5459798. DOI: 10.1038/s41531-017-0010-8. View

Gupta S, Witas R, Voigt A, Semenova T, Nguyen C . Single-Cell Sequencing of T cell Receptors: A Perspective on the Technological Development and Translational Application. Adv Exp Med Biol. 2020; 1255:29-50. PMC: 8845565. DOI: 10.1007/978-981-15-4494-1_3. View

Papa N, Minniti A, Lorini M, Carbonelli V, Maglione W, Pignataro F . The Role of Interferons in the Pathogenesis of Sjögren's Syndrome and Future Therapeutic Perspectives. Biomolecules. 2021; 11(2). PMC: 7916411. DOI: 10.3390/biom11020251. View

10.

Xin H, Lian Q, Jiang Y, Luo J, Wang X, Erb C . GMM-Demux: sample demultiplexing, multiplet detection, experiment planning, and novel cell-type verification in single cell sequencing. Genome Biol. 2020; 21(1):188. PMC: 7393741. DOI: 10.1186/s13059-020-02084-2. View

11.

Brayer J, Lowry J, Cha S, Robinson C, Yamachika S, Peck A . Alleles from chromosomes 1 and 3 of NOD mice combine to influence Sjögren's syndrome-like autoimmune exocrinopathy. J Rheumatol. 2000; 27(8):1896-904. View

12.

Mahajan V, Demissie E, Alsufyani F, Kumari S, Yuen G, Viswanadham V . DOCK2 Sets the Threshold for Entry into the Virtual Memory CD8 T Cell Compartment by Negatively Regulating Tonic TCR Triggering. J Immunol. 2019; 204(1):49-57. PMC: 6920543. DOI: 10.4049/jimmunol.1900440. View

13.

Spits H, Di Santo J . The expanding family of innate lymphoid cells: regulators and effectors of immunity and tissue remodeling. Nat Immunol. 2010; 12(1):21-7. DOI: 10.1038/ni.1962. View

14.

Brayer J, Cha S, Nagashima H, Yasunari U, Lindberg A, Diggs S . IL-4-dependent effector phase in autoimmune exocrinopathy as defined by the NOD.IL-4-gene knockout mouse model of Sjögren's syndrome. Scand J Immunol. 2001; 54(1-2):133-40. DOI: 10.1046/j.1365-3083.2001.00958.x. View

15.

Sarkar I, Davies R, Aarebrot A, Solberg S, Petrovic A, Joshi A . Aberrant signaling of immune cells in Sjögren's syndrome patient subgroups upon interferon stimulation. Front Immunol. 2022; 13:854183. PMC: 9441756. DOI: 10.3389/fimmu.2022.854183. View

16.

Nguyen C, Gao J, Kim H, Saban D, Cornelius J, Peck A . IL-4-STAT6 signal transduction-dependent induction of the clinical phase of Sjögren's syndrome-like disease of the nonobese diabetic mouse. J Immunol. 2007; 179(1):382-90. PMC: 2856075. DOI: 10.4049/jimmunol.179.1.382. View

17.

Nguyen C, Yin H, Lee B, Carcamo W, Chiorini J, Peck A . Pathogenic effect of interleukin-17A in induction of Sjögren's syndrome-like disease using adenovirus-mediated gene transfer. Arthritis Res Ther. 2010; 12(6):R220. PMC: 3046533. DOI: 10.1186/ar3207. View

18.

Tuzlak S, Dejean A, Iannacone M, Quintana F, Waisman A, Ginhoux F . Repositioning T cell polarization from single cytokines to complex help. Nat Immunol. 2021; 22(10):1210-1217. DOI: 10.1038/s41590-021-01009-w. View

19.

Verstappen G, Pringle S, Bootsma H, Kroese F . Epithelial-immune cell interplay in primary Sjögren syndrome salivary gland pathogenesis. Nat Rev Rheumatol. 2021; 17(6):333-348. PMC: 8081003. DOI: 10.1038/s41584-021-00605-2. View

20.

Chen W, Yang F, Xu G, Ma J, Lin J . Follicular helper T cells and follicular regulatory T cells in the immunopathology of primary Sjögren's syndrome. J Leukoc Biol. 2020; 109(2):437-447. DOI: 10.1002/JLB.5MR1020-057RR. View