Prognostic values of sera IL-6/IL-10 and high titration of anti-SSA/Ro and anti-SSB/La autoantibodies in female patients with connective tissue diseases

Abstract

Aim:The high levels of anti-SSA/Ro and anti-SSB/La autoantibodies are closely associated with a group of diseases related to connective tissues, also known as connective tissue diseases (CTD). The current study attested to profile the multifactorial association between interleukin IL-6 and IL-10 in sera from the study cohort to underline its putative prognostic and therapeutic characteristics for future application in CTD.

Methods:The study cohort was recruited from government hospitals and screened for autoantibody using Enzyme Immunoassay (EIA) and Immunofluorescence Assay (IFA) while cytokine levels were measured using ELISA.

Results:Our data showed the mean age of female patients is 38.1 years. Higher mean levels of both cytokines were observed in the first year of disease onset and menopause autoimmune-CTD patients. The mean levels of IL-6 and IL-10 were significantly higher in positive anti-Ro/La compared to the control group (p < 0.05). Also, the significant correlation of IL-6 and IL-10 in CTD patients as opposed to healthy control has underlined the putative role of these biologics.

Conclusions:These data suggest the putative manipulation of IL-6 and IL-10 as prognostic and therapeutics molecules in managing CTD, as an alternative to steroid-based medications to control the disease manifestations.

Keywords

IL-6 / IL-10 / anti-Ro/anti-La / interleukins / cytokine / connective tissue diseases / SLE / rheumatoid arthritis

References

[1] Abbas AK, Lichtman AH, Pillai S. Basic immunology: functions and disorders of the immune system. 4th ed. India: Elsevier; 2016.

[2] Gough SCL, Simmonds MJ. The HLA Region and Autoimmune Disease: Associations and Mechanisms of Action. Curr Genomics. 2007; 8: 453-65.

[3] National Institute of Health. National Institutes of Health Autoimmune Disease Coordinating Committee Report. 2002. Bethesda (MD): The Institutes; 2002.

[4] Wang L, Wang F, Gershwin ME. Human autoimmune diseases: a comprehensive update. J Intern Med. 2015; 278: 369-95.

[5] Crosslin KL, Wiginton KL. The impact of race and ethnicity on disease severity in systemic lupus erythematosus. Ethn Dis. 2009; 19: 301-7.

[6] Shaharir SS, Kadir WDA, Nordin F, Bakar FA, Ting MWH, Jamil A, et al. Systemic lupus erythematosus among male patients in Malaysia: how are we different from other geographical regions? Lupus. 2019; 28: 137-44.

[7] Elkon K, Casali P. Nature and functions of autoantibodies. Nat Clin Pract Rheumatol. 2008; 4: 491-8.

[8] Effa SZN, Phang SJ, Ahmad HF. Autoimmune Diseases and Gut Symbionts: The Unpopular Liaison. Mal J Med Health Sci. 2019; 15: 165-72.

[9] Gershwin ME, Meroni PL, Shoenfeld Y. Autoantibodies. Elsevier; 2002.

[10] Satoh M, Chan EKL, Ho LA, Rose KM, Parks CG, Cohn RD, et al. Prevalence and sociodemographic correlates of antinuclear antibodies in the United States. Arthritis Rheum. 2012; 64: 2319-27.

[11] Brandt JE, Priori R, Valesini G, Fairweather D. Sex differences in Sjögren’s syndrome: a comprehensive review of immune mechanisms. Biol Sex Differ. 2015; 6: 19.

[12] Gómez-Martín D, Galindo-Feria AS, Barrera-Vargas A, Merayo-Chalico J, Juárez-Vega G, Torres-Ruiz J, et al. Ro52/TRIM21-deficient expression and function in different subsets of peripheral blood mononuclear cells is associated with a proinflammatory cytokine response in patients with idiopathic inflammatory myopathies. Clin Exp Immunol. 2017; 188: 154-62.

[13] Franceschini F, Cavazzana I. Anti-Ro/SSA and La/SSB antibodies. Autoimmunity. 2005; 38: 55-63.

[14] Gottenberg J, Busson M, Loiseau P, Cohen-Solal J, Lepage V, Charron D, et al. In primary Sjögren’s syndrome, HLA class II is associated exclusively with autoantibody production and spreading of the autoimmune response. Arthritis Rheum. 2003; 48: 2240-5.

[15] Smolen JS, Aletaha D, Koeller M, Weisman MH, Emery P. New therapies for treatment of rheumatoid arthritis. Lancet. 2007; 370: 1861-74.

[16] Moudgil KD, Choubey D. Cytokines in autoimmunity: role in induction, regulation, and treatment. J Interferon Cytokine Res. 2011; 31: 695-703.

[17] Roescher N, Tak PP, Illei GG. Cytokines in Sjögren’s syndrome. Oral Dis. 2009; 15: 519-26.

[18] Lucey DR, Clerici M, Shearer GM. Type 1 and type 2 cytokine dysregulation in human infectious, neoplastic, and inflammatory diseases. Clin Microbiol Rev. 1996; 9: 532-62.

[19] Furuzawa-Carballeda J, Sánchez-Guerrero J, Betanzos JL, Enriquez AB, Avila-Casado C, Llorente L, et al. Differential cytokine expression and regulatory cells in patients with primary and secondary Sjögren’s syndrome. Scand J Immunol. 2014; 80: 432-40.

[20] Yoshimoto K, Tanaka M, Kojima M, Setoyama Y, Kameda H, Suzuki K, et al. Regulatory mechanisms for the production of BAFF and IL-6 are impaired in monocytes of patients of primary Sjögren’s syndrome. Arthritis Res Ther. 2011; 13: R170.

[21] Kishimoto T. The biology of interleukin-6. Blood. 1989; 74: 1-10.

[22] Grebenciucova E, VanHaerents S. Interleukin 6: at the interface of human health and disease. Front Immunol. 2023; 14: 1255533.

[23] Trovato M, Ruggeri RM, Sciacchitano S, Vicchio TM, Picerno I, Pellicanò G, et al. Serum interleukin-6 levels are increased in HIV-infected patients that develop autoimmune disease during long-term follow-up. Immunobiology. 2018; 223: 264-8.

[24] Taylor PC, Feist E, Pope JE, Nash P, Sibilia J, Caporali R, et al. What have we learnt from the inhibition of IL-6 in RA and what are the clinical opportunities for patient outcomes? Ther Adv Musculoskelet Dis. 2024; 16: 1759720X241283340.

[25] Bertorello R, Cordone MP, Contini P, Rossi P, Indiveri F, Puppo F, et al. Increased levels of interleukin-10 in saliva of Sjögren’s syndrome patients. Correlation with disease activity. Clin Exp Med. 2004; 4: 148-51.

[26] Willeke P, Gaubitz M, Schotte H, Becker H, Domschke W, Schlüter B. The role of interleukin-10 promoter polymorphisms in primary Sjogren’s syndrome. Scand J Rheumatol. 2008; 37: 293-9.

[27] Asadullah K, Sterry W, Volk HD. Interleukin-10 therapy——review of a new approach. Pharmacol Rev. 2003; 55: 241-69.

[28] Anaya JM, Correa PA, Herrera M, Eskdale J, Gallagher G. Interleukin 10 (IL-10) influences autoimmune response in primary Sjögren’s syndrome and is linked to IL-10 gene polymorphism. J Rheumatol. 2002; 29: 1874-6.

[29] Garcíc-Carrasco M, Font J, Filella X, Cervera R, Ramos-Casals M, Sisó A, et al. Circulating levels of Th1/Th2 cytokines in patients with primary Sjögren’s syndrome: correlation with clinical and immunological features. Clin Exp Rheumatol. 2001; 19: 411-5.

[30] McCarthy EM, Smith S, Lee RZ, Cunnane G, Doran MF, Donnelly S, et al. The association of cytokines with disease activity and damage scores in systemic lupus erythematosus patients. Rheumatology (Oxford). 2014; 53: 1586-94.

[31] Oliver JE, Silman AJ. Why are women predisposed to autoimmune rheumatic diseases? Arthritis Res Ther. 2009; 11: 252.

[32] Low LL, Rahim FIAB, Hamzah NAR, Ismail MS. Process evaluation of enhancing primary health care for non-communicable disease management in Malaysia: Uncovering the fidelity & feasibility elements. PLoS One. 2021; 16: e0245125.

[33] Park T, Jang Y, Kim W, Shin J, Toh HT, Kim C, et al. Chloroquine modulates inflammatory autoimmune responses through Nurr1 in autoimmune diseases. Sci Rep. 2019; 9: 15559.

[34] Ruiz-Irastorza G, Ramos-Casals M, Brito-Zeron P, Khamashta MA. Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review. Ann Rheum Dis. 2010; 69: 20-8.

[35] Gevers S, Kwa MSG, Wijnans E, van Nieuwkoop C. Safety considerations for chloroquine and hydroxychloroquine in the treatment of COVID-19. Clin Microbiol Infect. 2020; 26: 1276-7.

[36] Mohana A, Sulaiman T, Mahmoud N, Hassanein M, Alfaifi A, Alenazi E, et al. Hydroxychloroquine Safety Outcome within Approved Therapeutic Protocol for COVID-19 Outpatients in Saudi Arabia. Int J Infect Dis. 2021; 102: 110-4.

[37] Abdullah B, Moize B, Ismail BA, Zamri M, Nasir NFM. Prevalence of menopausal symptoms, its effect to quality of life among Malaysian women and their treatment seeking behaviour. Med J Malaysia. 2017; 72: 94-9.

[38] Endrighi R, Hamer M, Steptoe A. Post-menopausal Women Exhibit Greater Interleukin-6 Responses to Mental Stress Than Older Men. Ann Behav Med. 2016; 50: 564-71.

[39] Maselli A, Conti F, Alessandri C, Colasanti T, Barbati C, Vomero M, et al. Low expression of estrogen receptor β in T lymphocytes and high serum levels of anti-estrogen receptor α antibodies impact disease activity in female patients with systemic lupus erythematosus. Biol Sex Differ. 2016; 7: 3.

[40] Voulgari PV, Katsimbri P, Alamanos Y, Drosos AA. Gender and age differences in systemic lupus erythematosus. A study of 489 Greek patients with a review of the literature. Lupus. 2002; 11: 722-9.

[41] Mohammad I, Starskaia I, Nagy T, Guo J, Yatkin E, Väänänen K, et al. Estrogen receptor α contributes to T cell-mediated autoimmune inflammation by promoting T cell activation and proliferation. Sci Signal. 2018; 11: eaap9415.

[42] Pierdominici M, Ortona E. Estrogen impact on autoimmunity onset and progression: the paradigm of systemic lupus erythematosus. Int Trends Immun. 2013; 1: 24-34.

[43] Cunningham MA, Wirth JR, Naga O, Eudaly J, Gilkeson GS. Estrogen Receptor Alpha Binding to ERE is Required for Full Tlr7- and Tlr9-Induced Inflammation. SOJ Immunol. 2014; 2: 7.

[44] Kawaguchi Y. Contribution of interleukin-6 to the pathogenesis of systemicsclerosis. J Scleroderma Relat Disord. 2017; 2: S6-12.

[45] Dean GS, Tyrrell-Price J, Crawley E, Isenberg DA. Cytokines and systemic lupus erythematosus. Ann Rheum Dis. 2000; 59: 243-51.

[46] Torre MDL, Urra JM, Blanco J. Raised expression of cytokine receptor gp130 subunit on peripheral lymphocytes of patients with active lupus. A useful tool for monitoring the disease activity? Lupus. 2009; 18: 216-22.

[47] Mozo L, López P, Caminal-Montero L, Rodríguez-Carrio J, Suárez A. Anti-ribosomal P antibodies are associated with elevated circulating IFNα and IL-10 levels in systemic lupus erythematosus patients. Lupus. 2014; 23: 1477-85.

[48] Rousset F, Garcia E, Defrance T, Péronne C, Vezzio N, Hsu DH, et al. Interleukin 10 is a potent growth and differentiation factor for activated human B lymphocytes. Proc Natl Acad Sci U S A. 1992; 89: 1890-3.

[49] Hassan AB, Gunnarsson I, Karlsson G, Klareskog L, Forslid J, Lundberg IE. Longitudinal study of interleukin-10, tumor necrosis factor-alpha, anti-U1-snRNP antibody levels and disease activity in patients with mixed connective tissue disease. Scand J Rheumatol. 2001; 30: 282-9.

[50] Alipour S, Nouri M, Khabbazi A, Samadi N, Babaloo Z, Abolhasani S, et al. Hypermethylation of IL-10 gene is responsible for its low mRNA expression in Behçet’s disease. J Cell Biochem. 2018; 119: 6614-22.

[51] Shaheen DAH, Habib HM, Marie MA. Interleukin-6: a proinflammatory role in nephritis in patients with systemic lupus erythematosus. Int J Genet Genomics. 2015; 3: 53-8.

[52] Umare V, Pradhan V, Nadkar M, Rajadhyaksha A, Patwardhan M, Ghosh KK, et al. Effect of proinflammatory cytokines (IL-6, TNF-α, and IL-1β) on clinical manifestations in Indian SLE patients. Mediators Inflamm. 2014; 2014: 385297.

[53] Abd Elazeem MI, Mohammed RA, Abdallah NH. Correlation of serum interleukin-10 levels with disease activity and severity in systemic lupus erythematosus. Egypt Rheumatol Rehabil. 2018; 45: 25-33.

[54] He S, Xue M, Cai G. IL-6 alters migration capacity of CD4⁺Foxp3⁺regulatory T cells in systemic lupus erythematosus . Scand J Immunol. 2021; 94: e13099.