Inflammatory and T Helper 17/ Regulatory T Cells Related Cytokines Balance in Cutaneous Lupus Erythematosus (CLE)
Abstract
The cutaneous lupus erythematosus (CLE) is a common manifestation among systemic lupus erythematosus (SLE) patients. Malar rash and discoid lupus (DLE) are in the category of acute and chronic CLE, respectively. The pathogenesis of CLE is multifactorial, and cytokine imbalances contribute to immune dysfunction and the induction of organ damage. Many aspects of cytokine dysregulation are still unclear in SLE and in particular CLE. Therefore, we concurrently measured the inflammatory [Tumor necrosis factor-alpha (TNF-α) and Interleukin (IL)-6)], T helper (Th)-17 (IL-17 and IL-23) and regulatory T cells [Transforming growth factor-beta (TGFβ) and IL-10)]-related cytokines in patients with CLE (patients with malar rash and/or DLE) and compared them with SLE patients and healthy individuals (n=25 in each group, a total of 75 patients). The serum levels of cytokines were assessed by Enzyme-Linked Immunosorbent Assay (ELISA) method. IL-6 cytokine was significantly higher in SLE, DLE, and malar rash patients compared to those in healthy controls (p=0.025) and in patients with arthralgia (p=0.038), and gastrointestinal involvement (p=0.048). IL-17 was significantly higher in malar rash patients compared to normal individuals (p=0.023), SLE (p=0.008) and DLE patients (p=0.019) and in patients with oropharyngeal ulcer (p=0.05) but, IL-23 was significantly higher only in DLE patients than healthy controls (p=0.019). In conclusion, inflammatory cytokines such as IL-6 involved in inflammation and differentiation of Th17 cells are probably responsible in part for Th17 activity in CLE. IL-17, IL-23, and IL-6/IL-6R (IL-6 receptor) inhibitors may be good treatments for CLE patients. So targeting these cytokines activity pathways can improve the CLE treatment strategy and may open a novel guideline for SLE and CLE treatment.
1. Jarrett P, Werth VP. A review of cutaneous lupus erythematosus: improving outcomes with a multidisciplinary approach. J Multidiscip Healthc 2019; 12:419-28.
2. Mendez-Flores S, Hernandez-Molina G, Enriquez AB, Faz-Munoz D, et al. Cytokines and Effector/Regulatory Cells Characterization in the Physiopathology of Cutaneous Lupus Erythematous: A Cross-Sectional Study. Mediators Inflamm 2016; 2016:7074829.
3. Kole AK, Ghosh A. Cutaneous manifestations of systemic lupus erythematosus in a tertiary referral center. Indian J Dermatol 2009; 54(2):132-6.
4. Stannard JN, Kahlenberg JM. Cutaneous lupus erythematosus: updates on pathogenesis and associations with systemic lupus. Curr Opin Rheumatol 2016; 28(5):453-9.
5. Das NK, Dutta RN, Sengupta SR. Skin lesions in lupus erythematosus: a marker of systemic involvement. Indian J Dermatol 2011; 56(5):537-40.
6. Okon LG, Werth VP. Cutaneous lupus erythematosus: diagnosis and treatment. Best Pract Res Clin Rheumatol 2013;27(3):391-404.
7. Thorpe RB, Gray A, Kumar KR, Susa JS, Chong BF. Site-specific analysis of inflammatory markers in discoid lupus erythematosus skin. Scientific World Journal 2014; 2014:925805.
8. Pacheco Y, Barahona-Correa J, Monsalve DM, Acosta-Ampudia Y, Rojas M, Rodriguez Y, et al. Cytokine and autoantibody clusters interaction in systemic lupus erythematosus. J Transl Med 2017; 15(1):239.
9. Robinson ES, Werth VP. The role of cytokines in the pathogenesis of cutaneous lupus erythematosus. Cytokine 2015; 73(2):326-34.
10. Werth VP, Zhang W, Dortzbach K, Sullivan K. Association of a promoter polymorphism of tumor necrosis factor-alpha with subacute cutaneous lupus erythematosus and distinct photoregulation of transcription. J Invest Dermatol 2000; 115(4):726-30.
11. Korn T, Bettelli E, Gao W, Awasthi A, Jager A, Strom TB, et al. IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature 2007; 448(7152):484-7.
12. Kuhn A, Landmann A, Wenzel J. Advances in the treatment of cutaneous lupus erythematosus. Lupus 2016; 25(8):830-7.
13. Wallace DJ, Strand V, Merrill JT, Popa S, Spindler AJ, Eimon A, et al. Efficacy and safety of an interleukin 6 monoclonal antibody for the treatment of systemic lupus erythematosus: a phase II dose-ranging randomised controlled trial. Ann Rheum Dis 2017; 76(3):534-42.
14. Chang SH, Dong C. Signaling of interleukin-17 family cytokines in immunity and inflammation. Cell Signal 2011; 23(7):1069-75.
15. Wong CK, Lit LC, Tam LS, Li EK, Wong PT, Lam CW. Hyperproduction of IL-23 and IL-17 in patients with systemic lupus erythematosus: implications for Th17-mediated inflammation in auto-immunity. Clin Immunol 2008; 127(3):385-93.
16. De Souza A, Ali-Shaw T, Strober BE, Franks AG, Jr. Successful treatment of subacute lupus erythematosus with ustekinumab. Arch Dermatol 2011; 147(8):896-8.
17. Winchester D, Duffin KC, Hansen C. Response to ustekinumab in a patient with both severe psoriasis and hypertrophic cutaneous lupus. Lupus 2012; 21(9):1007-10.
18. Dahl C, Johansen C, Kragballe K, Olesen AB. Ustekinumab in the treatment of refractory chronic cutaneous lupus erythematosus: a case report. Acta Derm Venereol 2013; 93(3):368-9.
19. Franz B, Fritzsching B, Riehl A, Oberle N, Klemke CD, Sykora J, et al. Low number of regulatory T cells in skin lesions of patients with cutaneous lupus erythematosus. Arthritis Rheum 2007; 56(6):1910-20.
20. Szmyrka-Kaczmarek M, Kosmaczewska A, Ciszak L, Szteblich A, Wiland P. Peripheral blood Th17/Treg imbalance in patients with low-active systemic lupus erythematosus. Postep hig med dosw 2014; 68:893-8.
21. Alunno A, Bartoloni E, Bistoni O, Nocentini G, Ronchetti S, Caterbi S, et al. Balance between regulatory T and Th17 cells in systemic lupus erythematosus: the old and the new. Clin Dev Immunol 2012; 2012:823085.
22. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997; 40(9):1725.
23. Stannard, Jasmine N., Tamra J. Reed, Emily Myers, Lori Lowe, Mrinal K. Sarkar, Xianying Xing, et al. Lupus skin is primed for IL-6 inflammatory responses through a keratinocyte-mediated autocrine type I interferon loop. J. Investig. Dermatol 2017; 137(1): 115-122.
24. Svensson, Camilla I. Interleukin-6: a local pain trigger? Arthritis Res Ther 2010; 12(5):145.
25. Berti A, Cavalli G, Campochiaro C, Guglielmi B, Baldissera E, Cappio S, et al.Interleukin-6 in ANCA-associated vasculitis: Rationale for successful treatment with tocilizumab.Semin Arthritis Rheum 2015; 45(1):48-54.
26. Eilertsen GO, Nikolaisen C, Becker-Merok A, Nossent JC. Interleukin-6 promotes arthritis and joint deformation in patients with systemic lupus erythematosus. Lupus 2011; 20(6):607-13.
27. Fasching P, Stradner M, Graninger W, Dejaco C, Fessler J. Therapeutic Potential of Targeting the Th17/Treg Axis in Autoimmune Disorders. Molecules 2017; 22(1).
28. Talaat RM, Mohamed SF, Bassyouni IH, Raouf AA. Th1/Th2/Th17/Treg cytokine imbalance in systemic lupus erythematosus (SLE) patients: Correlation with disease activity. Cytokine 2015; 72(2):146-53.
29. Tanasescu C, Balanescu E, Balanescu P, Olteanu R, Badea C, Grancea C, et al. IL-17 in cutaneous lupus erythematosus. Eur J Intern Med 2010; 21(3):202-7.
30. Sud V, Abboud A, Tohme S, Vodovotz Y, Simmons RL, Tsung A. IL-17A - A regulator in acute inflammation: Insights from in vitro, in vivo and in silico studies. Cytokine 2018; (18)30-S1043-4666:116-9.
31. Pisitkun P, Ha HL, Wang H, Claudio E, Tivy CC, Zhou H, et al. Interleukin-17 cytokines are critical in development of fatal lupus glomerulonephritis.Immunity 2012;14; 37(6):1104-15.
32. Miletic M, Stojanovic R, Pajic O, Bugarski D, Mojsilovic S, Cokic V, et al. Serum interleukin-17 & nitric oxide levels in patients with primary Sjogren's syndrome. Indian J Med Res 2012; 135(4):513-9.
33. Larosa M, Zen M, Gatto M, Jesus D, Zanatta E, Iaccarino L, et al. IL-12 and IL-23/Th17 axis in systemic lupus erythematosus. Exp Biol Med 2019; 244(1):42-51.
34. Antiga E, Del Bianco E, Difonzo E, Fabbri P, Caproni M. Serum levels of the regulatory cytokines transforming growth factor-beta and interleukin-10 are reduced in patients with discoid lupus erythematosus. Lupus 2011; 20(6):556-60.
35. Menyawi ME, Fawzy M, Habib M, Shaker O. Serum Transforming Growth Factor-Beta 1 Level in Egyptian Systemic Lupus Erythematosus Patients. Arch Rheumatol 2018; 33(3):358-66.
36. Saxena A, Khosraviani S, Noel S, Mohan D, Donner T, Hamad AR. Interleukin-10 paradox: A potent immunoregulatory cytokine that has been difficult to harness for immunotherapy. Cytokine 2015; 74(1):27-34.
37. Mikita N, Ikeda T, Ishiguro M, Furukawa F. Recent advances in cytokines in cutaneous and systemic lupus erythematosus. J Dermatol 2011; 38(9):839-49.
38. van Vollenhoven RF, Hahn BH, Tsokos GC, Wagner CL, Lipsky P, Touma Z, et al. Efficacy and safety of ustekinumab, an IL-12 and IL-23 inhibitor, in patients with active systemic lupus erythematosus: results of a multicentre, double-blind, phase 2, randomised, controlled study. Lancet 2018; 392(10155):1330-9.
2. Mendez-Flores S, Hernandez-Molina G, Enriquez AB, Faz-Munoz D, et al. Cytokines and Effector/Regulatory Cells Characterization in the Physiopathology of Cutaneous Lupus Erythematous: A Cross-Sectional Study. Mediators Inflamm 2016; 2016:7074829.
3. Kole AK, Ghosh A. Cutaneous manifestations of systemic lupus erythematosus in a tertiary referral center. Indian J Dermatol 2009; 54(2):132-6.
4. Stannard JN, Kahlenberg JM. Cutaneous lupus erythematosus: updates on pathogenesis and associations with systemic lupus. Curr Opin Rheumatol 2016; 28(5):453-9.
5. Das NK, Dutta RN, Sengupta SR. Skin lesions in lupus erythematosus: a marker of systemic involvement. Indian J Dermatol 2011; 56(5):537-40.
6. Okon LG, Werth VP. Cutaneous lupus erythematosus: diagnosis and treatment. Best Pract Res Clin Rheumatol 2013;27(3):391-404.
7. Thorpe RB, Gray A, Kumar KR, Susa JS, Chong BF. Site-specific analysis of inflammatory markers in discoid lupus erythematosus skin. Scientific World Journal 2014; 2014:925805.
8. Pacheco Y, Barahona-Correa J, Monsalve DM, Acosta-Ampudia Y, Rojas M, Rodriguez Y, et al. Cytokine and autoantibody clusters interaction in systemic lupus erythematosus. J Transl Med 2017; 15(1):239.
9. Robinson ES, Werth VP. The role of cytokines in the pathogenesis of cutaneous lupus erythematosus. Cytokine 2015; 73(2):326-34.
10. Werth VP, Zhang W, Dortzbach K, Sullivan K. Association of a promoter polymorphism of tumor necrosis factor-alpha with subacute cutaneous lupus erythematosus and distinct photoregulation of transcription. J Invest Dermatol 2000; 115(4):726-30.
11. Korn T, Bettelli E, Gao W, Awasthi A, Jager A, Strom TB, et al. IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature 2007; 448(7152):484-7.
12. Kuhn A, Landmann A, Wenzel J. Advances in the treatment of cutaneous lupus erythematosus. Lupus 2016; 25(8):830-7.
13. Wallace DJ, Strand V, Merrill JT, Popa S, Spindler AJ, Eimon A, et al. Efficacy and safety of an interleukin 6 monoclonal antibody for the treatment of systemic lupus erythematosus: a phase II dose-ranging randomised controlled trial. Ann Rheum Dis 2017; 76(3):534-42.
14. Chang SH, Dong C. Signaling of interleukin-17 family cytokines in immunity and inflammation. Cell Signal 2011; 23(7):1069-75.
15. Wong CK, Lit LC, Tam LS, Li EK, Wong PT, Lam CW. Hyperproduction of IL-23 and IL-17 in patients with systemic lupus erythematosus: implications for Th17-mediated inflammation in auto-immunity. Clin Immunol 2008; 127(3):385-93.
16. De Souza A, Ali-Shaw T, Strober BE, Franks AG, Jr. Successful treatment of subacute lupus erythematosus with ustekinumab. Arch Dermatol 2011; 147(8):896-8.
17. Winchester D, Duffin KC, Hansen C. Response to ustekinumab in a patient with both severe psoriasis and hypertrophic cutaneous lupus. Lupus 2012; 21(9):1007-10.
18. Dahl C, Johansen C, Kragballe K, Olesen AB. Ustekinumab in the treatment of refractory chronic cutaneous lupus erythematosus: a case report. Acta Derm Venereol 2013; 93(3):368-9.
19. Franz B, Fritzsching B, Riehl A, Oberle N, Klemke CD, Sykora J, et al. Low number of regulatory T cells in skin lesions of patients with cutaneous lupus erythematosus. Arthritis Rheum 2007; 56(6):1910-20.
20. Szmyrka-Kaczmarek M, Kosmaczewska A, Ciszak L, Szteblich A, Wiland P. Peripheral blood Th17/Treg imbalance in patients with low-active systemic lupus erythematosus. Postep hig med dosw 2014; 68:893-8.
21. Alunno A, Bartoloni E, Bistoni O, Nocentini G, Ronchetti S, Caterbi S, et al. Balance between regulatory T and Th17 cells in systemic lupus erythematosus: the old and the new. Clin Dev Immunol 2012; 2012:823085.
22. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997; 40(9):1725.
23. Stannard, Jasmine N., Tamra J. Reed, Emily Myers, Lori Lowe, Mrinal K. Sarkar, Xianying Xing, et al. Lupus skin is primed for IL-6 inflammatory responses through a keratinocyte-mediated autocrine type I interferon loop. J. Investig. Dermatol 2017; 137(1): 115-122.
24. Svensson, Camilla I. Interleukin-6: a local pain trigger? Arthritis Res Ther 2010; 12(5):145.
25. Berti A, Cavalli G, Campochiaro C, Guglielmi B, Baldissera E, Cappio S, et al.Interleukin-6 in ANCA-associated vasculitis: Rationale for successful treatment with tocilizumab.Semin Arthritis Rheum 2015; 45(1):48-54.
26. Eilertsen GO, Nikolaisen C, Becker-Merok A, Nossent JC. Interleukin-6 promotes arthritis and joint deformation in patients with systemic lupus erythematosus. Lupus 2011; 20(6):607-13.
27. Fasching P, Stradner M, Graninger W, Dejaco C, Fessler J. Therapeutic Potential of Targeting the Th17/Treg Axis in Autoimmune Disorders. Molecules 2017; 22(1).
28. Talaat RM, Mohamed SF, Bassyouni IH, Raouf AA. Th1/Th2/Th17/Treg cytokine imbalance in systemic lupus erythematosus (SLE) patients: Correlation with disease activity. Cytokine 2015; 72(2):146-53.
29. Tanasescu C, Balanescu E, Balanescu P, Olteanu R, Badea C, Grancea C, et al. IL-17 in cutaneous lupus erythematosus. Eur J Intern Med 2010; 21(3):202-7.
30. Sud V, Abboud A, Tohme S, Vodovotz Y, Simmons RL, Tsung A. IL-17A - A regulator in acute inflammation: Insights from in vitro, in vivo and in silico studies. Cytokine 2018; (18)30-S1043-4666:116-9.
31. Pisitkun P, Ha HL, Wang H, Claudio E, Tivy CC, Zhou H, et al. Interleukin-17 cytokines are critical in development of fatal lupus glomerulonephritis.Immunity 2012;14; 37(6):1104-15.
32. Miletic M, Stojanovic R, Pajic O, Bugarski D, Mojsilovic S, Cokic V, et al. Serum interleukin-17 & nitric oxide levels in patients with primary Sjogren's syndrome. Indian J Med Res 2012; 135(4):513-9.
33. Larosa M, Zen M, Gatto M, Jesus D, Zanatta E, Iaccarino L, et al. IL-12 and IL-23/Th17 axis in systemic lupus erythematosus. Exp Biol Med 2019; 244(1):42-51.
34. Antiga E, Del Bianco E, Difonzo E, Fabbri P, Caproni M. Serum levels of the regulatory cytokines transforming growth factor-beta and interleukin-10 are reduced in patients with discoid lupus erythematosus. Lupus 2011; 20(6):556-60.
35. Menyawi ME, Fawzy M, Habib M, Shaker O. Serum Transforming Growth Factor-Beta 1 Level in Egyptian Systemic Lupus Erythematosus Patients. Arch Rheumatol 2018; 33(3):358-66.
36. Saxena A, Khosraviani S, Noel S, Mohan D, Donner T, Hamad AR. Interleukin-10 paradox: A potent immunoregulatory cytokine that has been difficult to harness for immunotherapy. Cytokine 2015; 74(1):27-34.
37. Mikita N, Ikeda T, Ishiguro M, Furukawa F. Recent advances in cytokines in cutaneous and systemic lupus erythematosus. J Dermatol 2011; 38(9):839-49.
38. van Vollenhoven RF, Hahn BH, Tsokos GC, Wagner CL, Lipsky P, Touma Z, et al. Efficacy and safety of ustekinumab, an IL-12 and IL-23 inhibitor, in patients with active systemic lupus erythematosus: results of a multicentre, double-blind, phase 2, randomised, controlled study. Lancet 2018; 392(10155):1330-9.
| Files | ||
| Issue | Vol 19, No 1 (2020) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijaai.v19i1.2411 | |
| PMID | 32245325 | |
| Keywords | ||
| Cutaneous lupus erythematosus Inflammatory cytokines Regulatory T cells T helper 17 | ||
| Rights and permissions | |
|
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Yazdani M-R, Aflaki E, Gholijani N. Inflammatory and T Helper 17/ Regulatory T Cells Related Cytokines Balance in Cutaneous Lupus Erythematosus (CLE). Iran J Allergy Asthma Immunol. 2020;19(1):9-17.
