The Role of Soluble Costimulatory Molecules as the Biomarkers for Aging Predictors

Authors

  • Kusworini Handono Department of Clinical Pathology Faculty of Medicine Universitas Brawijaya Malang
  • Mirza Zaka Pratama Rheumatology Division Department of Internal Medicine Faculty of Medicine Universitas Brawijaya Malang
  • Hani Susianti Department of Clinical Pathology Faculty of Medicine Universitas Brawijaya Malang
  • Cesarius Singgih Wahono Rheumatology Division Department of Internal Medicine Faculty of Medicine Universitas Brawijaya Malang
  • Nimas Eka Firdaningrum Medical Study Program Faculty of Medicine Universitas Brawijaya Malang
  • Siti Roziah Ria Famuji Medical Study Program Faculty of Medicine Universitas Brawijaya Malang
  • Norma Hanifah Sumarta Medical Study Program Faculty of Medicine Universitas Brawijaya Malang
  • Ade Wildan Rizky Fachry Medical Study Program Faculty of Medicine Universitas Brawijaya Malang
  • Levrita Nindya Poetri Rheumatology Division Department of Internal Medicine Faculty of Medicine Universitas Brawijaya Malang
  • Handono Kalim Rheumatology Division Department of Internal Medicine Faculty of Medicine Universitas Brawijaya Malang

DOI:

https://doi.org/10.21776/ub.jkb.2022.032.03.4

Keywords:

Comorbidities, elderly, immune aging, soluble costimulatory molecules

Abstract

This study aimed to determine the role of the soluble costimulatory molecules in aging and the association with the presence of comorbid in aged individuals. Thirty-two elderly and twenty healthy subjects were included in this study. The soluble costimulatory molecules sCD28, sCD80, sCD86, sCD163, and sCTLA4 were measured using ELISA. The presence of comorbid was documented from medical records. Charlson Comorbidity Index (CCI) was measured to evaluate the survival/mortality risk for the subjects. The levels of the majority of soluble costimulatory molecules significantly increased in the elderly participants, while the level of sCD86 was comparable. There were weak positive correlations between the subject's age and levels of sCD28 (R=0.214, p=0.048), sCTLA4 (R=0.238, p=0.041), and sCD80 (R=0.317, p=0.012). sCD80 were discovered to be the best to predict immune aging in the elderly with AUC 0.71 [0.57-0.86], sensitivity 53,1%, specificity 80.0%, and cut off 129ng/ml. Most of the elderly participants had at least one comorbid, in which approximately 25.0% and 3.1% of the subjects were classified as mild and moderate CCI. Multivariate analysis showed that comorbidities in elderly individuals have been associated with levels of sCTLA4 ≥26.5ng/ml and sCD80 ≥129.0ng/ml. Furthermore, subjects with comorbid (CCI ≥1) were associated with sCD80 ≥129.0ng/ml (OR 12.44 [95% CI 1.32–117.03], p=0.027). Considering these results, sCD28, sCTLA4, and sCD80 can be developed as biomarkers for predicting immune aging and elderly comorbidities, respectively.

Downloads

Download data is not yet available.

References

El-Naseery NI, Mousa HSE, Noreldin AE, El-Far AH, and Elewa YHA. Aging-Associated Immunosenescence via Alterations in Splenic Immune Cell Populations in Rat. Life Sciences. 2020; 241: 1-46.

Weyh C, Krüger K, Strasser B. Physical Activity and Diet Shape the Immune System during Aging. Nutrients. 2020; 12(3): 1-17.

Fulop T, Larbi A, Dupuis G, et al. Immunosenescence and Inflamm-Aging as Two Sides of the Same Coin: Friends or Foes? Frontiers in Immunology. 2018; 8: 1-13.

Weyand CM and Goronzy JJ. Aging of the Immune System. Mechanisms and Therapeutic Targets. Annals of the American Thoracic Society. 2018; 13(5): 422–428.

Pawelec G. Age and Immunity: What is "immunosenescence"? Experimental Gerontology. 2018; 105: 4–9.

Kalim H, Pratama MZ, Mahardini E, Winoto ES, Krisna PA, and Handono K. Accelerated Immune Aging Was Correlated With Lupus‐Associated Brain Fog In Reproductive‐Age Systemic Lupus Erythematosus Patients. International Journal of Rheumatic Diseases. 2020; 23(5): 620–626.

Muller GC, Gottlieb MGV, Correa BL, Filho IG, Moresco RN, and Bauer ME. The Inverted CD4:CD8 Ratio is Associated with Gender-Related Changes in Oxidative Stress during Aging. Cellular Immunology. 2015; 296(2): 149–154.

Wang D, Du Q, Luo G, et al. Aberrant Production of Soluble Inducible T Cell Co-stimulator and Soluble Programmed Cell Death Protein 1 in Patients with Chronic Hepatitis B. Molecular Medicine Reports. 2017; 16(6): 8556–8562.

García‐Chagollán M., Ledezma‐Lozano IY, Hernández‐Bello J, Sánchez‐Hernández PE, Gutiérrez‐Ureña SR, Muñoz‐Valle JF. Expression Patterns of CD28 and CTLA‐4 in Early, Chronic, and Untreated Rheumatoid Arthritis. J Clin Lab Anal. 2020; 34(5): 1-7.

Montoya-Ortiz G. Immunosenescence, Aging, and Systemic Lupus Erythematous. Autoimmune Diseases. 2013; 2013: 1–15.

Cao J, Zou L, Luo P, Chen P, and Zhang L. Increased Production of Circulating Soluble Co-Stimulatory Molecules CTLA-4, CD28, and CD80 in Patients with Rheumatoid Arthritis. International Immunopharmacology. 2012; 14(4): 585–592.

Gu D, Ao X, Yang Y, Chen Z, and Xu X. Soluble Immune Checkpoints In Cancer: Production, Function And Biological Significance. Journal for ImmunoTherapy of Cancer. 2018; 6: 1-14.

Thurman M, Johnson S, Acharya A, Pallikkuth S, Mahesh M, and Byrareddy SN. Biomarkers of Activation and Inflammation to Track Disparity in Chronological and Physiological Age of People Living With HIV on Combination Antiretroviral Therapy. Front. Immunol. 2020; 11: 1-11.

Pistillo MP, Fontana V, Morabito A, et al. Soluble CTLA-4 as a Favorable Predictive Biomarker in Metastatic Melanoma Patients Treated with Ipilimumab: An Italian Melanoma Intergroup Study. Cancer Immunology Immunotherapy. 2019; 68(1): 97–107.

Fukushima Y, Minato N, and Hattori M. The Impact of Senescence-Associated T Cells on Immunosenescence and Age-Related Disorders. Inflammation and Regeneration. 2018; 38: 1-6.

Pera A, Campos C, López N, et al. Immunosenescence: Implications for Response to Infection and Vaccination in Older People. Maturitas. 2015; 82: 50–55.

Gofur NRP, Nurdiana, Handono K, and Kalim H. Immune Aging Marker Associated with Periodontitis in Systemic Lupus Erythematosus Patients. Proceeding at the International Conference on Bioinformatics and Nano-Medicine from Natural Resources for Biomedical Research: 3rd Annual Scientific Meeting for Biomedical Sciences. Malang, Indonesia, 21-23 November 2019; p. 020003.

Nikolich-Žugich J. Author Correction: The Twilight of Immunity: Emerging Concepts in Aging of the Immune System. Nature Immunology. 2018; 19: 1146–1146.

Etzerodt A and Moestrup SK. CD163 and Inflammation: Biological, Diagnostic, and Therapeutic Aspects. Antioxidants & Redox Signaling. 2013; 18(17): 2352–2363.

Qin XY, Lu J, Li GX, et al. CTLA-4 Polymorphisms are Associated with Treatment Outcomes of Patients with Multiple Myeloma Receiving Bortezomib-Based Regimens. Annals of Hematology. 2018; 97(3): 485–495.

Bottazzi B, Riboli E, and Mantovani A. Aging, Inflammation, and Cancer. Seminars in Immunology. 2018; 40: 74–82.

Bektas A, Schurman SH, Sen R, and Ferrucci L. Human T Cell Immunosenescence and Inflammation in Aging. Journal of Leukocyte Biology. 2017; 102(4): 977–988.

Sakthivel P. Co-Stimulatory Molecules: Genes to Protein in Autoimmune and Inflammatory Disorders. [Thesis]. Karolinska Institutet, Stockholm. 2007.

Jubel JM, Randau TM, Becker-Gotot J, et al. sCD28, sCD80, sCTLA-4, and sBTLA are Promising Markers in Diagnostic and Therapeutic Approaches for Aseptic Loosening and Periprosthetic Joint Infection. Frontiers in Immunology. 2021; 12: 1-10.

Ward FJ, Dahal LN, Wijesekera SK, et al. The Soluble Isoform of CTLA-4 as a Regulator of T-Cell Responses. European Journal of Immunology. 2013; 43: 1274–1285.

Liu Q, Hu P, Deng G, et al. Soluble Cytotoxic T-Lymphocyte Antigen 4: A Favorable Predictor in Malignant Tumors after Therapy. Onco Targets and Therapy. 2017; 10: 2147–2154.

Kakoulidou M, Wang X, Zhao X, Pirskanen R, and Lefvert AK. Soluble Costimulatory Factors sCD28, sCD80, sCD86 and sCD152 in Relation to Other Markers of Immune Activation in Patients with Myasthenia Gravis. Journal of Neuroimmunology. 2007; 185(1-2): 150–161.

van Onna M and Boonen A. The Challenging Interplay between Rheumatoid Arthritis, Ageing and Comorbidities. BMC Musculoskeletal Disorder. 2016; 17(1): 1-9.

Xu-Dong P, Ling W, Jin-Fang S, Guang-Bo Z, and Xue-Guang Z. Expression and Its Clinical Significance of the Membrane CD28 and The Serum Level of Soluble CD28 in Elderly Patients with Primary Non-Small Cell Lung Cancer. Chinese Journal of Geriatrics. 2009; 6: 445-448.

.Hamzaoui K, Hamzaoui A, Bouajina L, and Houman H. Circulating Soluble CD28 in Patients with Behçet's Disease: Relationship to Clinical Manifestations. Clinical and Experimental Rheumatology. 2005; 23(4): 49-52.

Newcombe EA, Camats-Perna J, Silva ML, Valmas N, Huat TJ, and Medeiros R. Inflammation: The Link between Comorbidities, Genetics, and Alzheimer's Disease. Journal of Neuroinflammation. 2018; 15: 1-26.

Hong H, Wang Q, Li J, Liu H, Meng X, and Zhang H. Aging, Cancer, and Immunity. Journal of Cancer. 2019; 10(13): 3021–3027.

Simone R, Pesce G, Antola P, Rumbullaku M, Bagnasco M, Bizzaro N, and Saverino D. The Soluble Form of CTLA-4 from Serum of Patients with Autoimmune Diseases Regulates T-Cell Responses. BioMed Research International. 2014; 2014: 1–9.

Wong CK, Ho AWY, Tong PCY, et al. Aberrant Expression of Soluble Co-stimulatory Molecules and Adhesion Molecules in Type 2 Diabetic Patients with Nephropathy. Journal of Clinical Immunology. 2008; 28(1): 36–43.

Downloads

Published

2023-02-27 — Updated on 2023-05-08

Versions

Issue

Vol. 32 No. 3 (2023)

Section

Research Article

License

Authors who publish with this journal agree to the following terms:

  1. Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
  2. Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.
  3. Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work (See The Effect of Open Access).

Most read articles by the same author(s)