Increased CD69+CCR7+ circulating activated T cells and STAT3 expression in cutaneous lupus erythematosus patients recalcitrant to antimalarials

Abstract

Background

Antimalarials are first-line systemic therapy for cutaneous lupus erythematosus (CLE). While some patients unresponsive to hydroxychloroquine (HCQ) alone benefit from the addition of quinacrine (QC), a subset of patients is refractory to both antimalarials.

Methods

We classified CLE patients as HCQ-responders, HCQ+QC-responders, or HCQ+QC-nonresponders to compare immune profiles. Immunohistochemistry, immunofluorescence, and qRT-PCR were used to characterize inflammatory cells and cytokines in lesional skin.

Results

Immunohistochemistry showed that CD69⁺ T cells were higher in HCQ+QC-nonresponders compared to HCQ- and HCQ+QC-responders (p < 0.05). Immunofluorescence further identified these cells as CD69+CCR7+ circulating activated T cells. Myeloid dendritic cells were significantly higher in HCQ+QC-responders compared to both HCQ-responders and HCQ+QC-nonresponders. Plasmacytoid dendritic cells were significantly increased in HCQ-responders compared to HCQ- and HCQ+QC-nonresponders. No differences were found in the number of autoreactive T cells, MAC387+ cells, and neutrophils among the groups. CLASI scores of the HCQ+QC-nonresponder group positively correlated with CD69+CCR7+ circulating activated T cells (r = 0.6335, p < 0.05) and MAC387+ cells (r = 0.5726, p < 0.05). IL-17 protein expression was higher in HCQ+QC-responders compared to HCQ-responders or HCQ+QC-nonresponders, while IL-22 protein expression did not differ. mRNA expression demonstrated increased STAT3 expression in a subset of HCQ+QC-nonresponders.

Conclusion

An increased number of CD69+CCR7+ circulating activated T cells and a strong correlation with CLASI scores in the HCQ+QC-nonresponders suggest these cells are involved in antimalarial-refractory skin disease. STAT3 is also increased in HCQ+QC-nonresponders and may also be a potential target for antimalarial-refractory skin disease.

Keywords

Cutaneous lupus erythematosus antimalarials refractory skin disease myeloid dendritic cells CD69 cells

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References

Fabbri

Cardinali

Giomi

, et al. Cutaneous lupus erythematosus: diagnosis and management. Am J Clin Dermatol 2003; 4: 449–465.

Chang

Piette

Foering

, et al. Response to antimalarial agents in cutaneous lupus erythematosus: a prospective analysis. Arch Dermatol 2011; 147: 1261–1267.

Chasset

Arnaud

Jachiet

, et al. Changing antimalarial agents after inefficacy or intolerance in patients with cutaneous lupus erythematosus: a multicenter observational study. J Am Acad Dermatol 2018; 78: 107–114.

Chang

Ghazi

Okawa

, et al. Quality of life differences between responders and nonresponders in the treatment of cutaneous lupus erythematosus. JAMA Dermatol 2013; 149: 104–106.

Klein

Moghadam-Kia

Taylor

, et al. Quality of life in cutaneous lupus erythematosus. J Am Acad Dermatol 2011; 64: 849–858.

Robinson

Werth

. The role of cytokines in the pathogenesis of cutaneous lupus erythematosus. Cytokine 2015; 73: 326–334.

Sarkar

Hile

Tsoi

, et al. Photosensitivity and type I IFN response in cutaneous lupus are driven by epidermal-derived interferon kappa. Ann Rheum Dis 2018; 77: 1653–1664.

Stannard

Reed

Myers

, et al. Lupus skin is primed for IL-6 inflammatory responses through a keratinocyte-mediated autocrine type 1 interferon loop. J Invest Dermatol 2017; 137: 115–122.

Ding

Cai

Marroquin

, et al. Plasmacytoid dendritic cells regulate autoreactive B cell activation via soluble factors and in a cell-to-cell contact manner. J Immunol 2009; 183: 7140–7149.

10.

Eriksen

Lovato

Skov

, et al. Increased sensitivity to interferon-alpha in psoriatic T cells. J Invest Dermatol 2005; 125: 936–944.

11.

Le Bon

Durand

Kamphuis

, et al. Direct stimulation of T cells by type I IFN enhances the CD8+ T cell response during cross-priming. J Immunol 2006; 176: 4682–4689.

12.

Mikita

Ikeda

Ishiguro

, et al. Recent advances in cytokines in cutaneous and systemic lupus erythematosus. J Dermatol 2011; 38: 839–849.

13.

Nabatian

Bashir

Wysocka

, et al. Tumor necrosis factor α release in peripheral blood mononuclear cells of cutaneous lupus and dermatomyositis patients. Arthritis Res Ther 2012; 14(1): R1.

14.

Levine

Switlyk

Gottlieb

. Cutaneous lupus erythematosus and anti-TNF-alpha therapy: a case report with review of the literature. J Drugs Dermatol 2010; 9: 1283–1287.

15.

Palucka

Blanck

Bennett

, et al. Cross-regulation of TNF and IFN-alpha in autoimmune diseases. Proc Natl Acad Sci USA 2005; 102: 3372–3377.

16.

Pisetski

. Tumor necrosis factor alpha blockers and the induction of anti-DNA antibodies. Arthritis Rheum 2000; 43: 2381–2382.

17.

Kalia

Dutz

. New concepts in antimalarial use and mode of action in dermatology. Dermatol Ther 2007; 20: 160–174.

18.

Wozniaka

Carter

McCaullife

. Antimalarials in cutaneous lupus erythematosus: mechanisms of therapeutic benefit. Lupus 2002; 11: 71–81.

19.

Zeidi

Kim

Werth

. Increased myeloid dendritic cells and TNF-alpha expression predicts poor response to hydroxychloroquine in cutaneous lupus erythematosus. J Invest Dermatol 2019; 139: 324–332.

20.

Yan

Borucki

Sontheimer

, et al. Candidate drug replacements for quinacrine in cutaneous lupus erythematosus. Lupus Sci Med 2020; 7: e000430.

21.

Livak

Schmittgen

. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 2001; 25: 402–408.

22.

Wahie

Daly

Cordell

, et al. Clinical and pharmacogenetic influences on response to hydroxy- chloroquine in discoid lupus erythematosus: a retrospective cohort study. J Invest Dermatol 2011; 131: 1981e6.

23.

Spann

Callen

Klein

, et al. Clinical, serologic and immuno- genetic studies in patients with chronic cutaneous (discoid) lupus erythe- matosus who have verrucous and/or hypertrophic skin lesions. J Rheumatol 1988; 15: 256e61.

24.

Cibrián

Sánchez-Madrid

. CD69: from activation marker to metabolic gatekeeper. Euro J Immunol 2017; 47: 946–953.

25.

de la Fuente

Cruz‐Adalia

Martinez Del Hoyo

, et al. The leukocyte activation receptor CD69 controls T cell differentiation through its interaction with galectin‐1. Mol Cel Biol 2014; 34: 2479–2487.

26.

Lin

Wei

Tsai

, et al. Glycosylation‐dependent interaction between CD69 and S100A8/S100A9 complex is required for regulatory T‐cell differentiation. FASEB J 2015; 29: 5006–5017.

27.

Martin

Gomez

Lamana

, et al. CD69 association with Jak3/Stat5 proteins regulates Th17 cell differentiation. Mol Cel Biol 2010; 30: 4877–4889.

28.

Toscano

Bianco

Ilarregui

, et al. Differential glycosylation of TH1, TH2 and TH‐17 effector cells selectively regulates susceptibility to cell death. Nat Immunol 2007; 8: 825–834.

29.

Turk

Molodtsov

. Tissue resident CD8 memory T cell responses in cancer and autoimmunity. Front Immunol 2018; 9: 2810.

30.

Mami-Chouaib

Tartour

. Editorial: tissue resident memory T cells. Front Immunol 2019; 10: 1018.

31.

Ometto

Friso

Astorri

, et al. Calprotectin in rheumatic diseases. Exp Biol Med 2017; 242: 859–873.

32.

Alves

Bashir

Wysocka

, et al. Quinacrine suppresses tumor necrosis factor-α and IFN-α in dermatomyositis and cutaneous lupus erythematosus. J Invest Dermatol Symp Proc 2017; 18: S57–S63.

33.

Ivashkiv

Donlin

. Regulation of type I interferon responses. Nat Rev Immunol 2014; 14: 36–49.

34.

Levy

Darnell

Jr . Stats: transcriptional control and biological impact. Nat Rev Mol Cel Biol 2002; 3: 651–662.

35.

Ivashkiv

. Role of STAT3 in type I interferon responses. Negative regulation of STAT1-dependent inflammatory gene activation. J Biol Chem 2006; 281: 14111–14118.

36.

Slight-Webb

Guthridge

Chakravarty

, et al. Mycophenolate mofetil reduces STAT3 phosphorylation in systemic lupus erythematosus patients. JCI Insight 2019; 4(2): e124575.

37.

Gammon

Hansen

Costner

. Efficacy of mycophenolate mofetil in antimalarial-resistant cutaneous lupus erythematosus. J Am Acad Dermatol 2011; 65: 717–721.

38.

Roh

Kwon

, et al. Expression of interleukin‐17 is correlated with interferon‐α expression in cutaneous lesions of lupus erythematosus. Clin Exp Dermatol 2011; 36: 512–520.

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