Age, autoimmunity, and inflammation the role of immunosenescence.pptx

Age, autoimmunity, and inflammation the role of immunosenescence.The relationship between age, autoimmunity, and inflammation is deeply intertwined with the concept of immunosenescence, which refers to the gradual deterioration of the immune system associated with aging.

1. Age, Autoimmunity, and Inflammation the Role of Immunosenescence Samar Tharwat Radwan Ass. Professor of Rheumatology & Immunology (Internal Medicine Department) Musculoskeletal Ultrasound-EULAR Mansoura University

2. Agenda

3. Immunosenescence

4. Definition The increase in human life expectancy has led to a concomitant aging of the population Destruction and remodeling of immune organ structure as well as innate and adaptive immune dysfunction with aging, causing poor vaccination outcomes , and increased susceptibility to infection , age-related disease, and malignancies Thomas, R., Wang, W. & Su, D. M. Contributions of age-related thymic involution to immunosenescence and in fl ammaging . Immun. Ageing 17 , 2 (2020).

5. Inflammaging Systemic state of chronic low-grade in fl ammation characterized by upregulated blood in fl ammatory markers and is considered the central pillar of aging

6. Immunosenescence is a complex process that involves organ reorganization and numerous regulatory processes at the cellular level As a result, immune system function decreases , leading to an inadequate response to infections or vaccines in elderly individuals. Accardi , G. & Caruso, C. Immune-in fl ammatory responses in the elderly: an update. Immun. Ageing 15 , 11 (2018).

7. Although the full extent of the biological changes is unknown, several characteristic changes are typically observed such as thymic involution HSC dysfunctions disrupted naïve/ memory ratio in T and B cells inflammaging accumulation of senescent cells impaired new antigen response mitochondrial dysfunction genomic instability Liu, Z., Liang, Q., Ren, Y., Guo, C., Ge, X., Wang, L., Cheng, Q., Luo, P., Zhang, Y. and Han, X., 2023. Immunosenescence: molecular mechanisms and diseases.  Signal Transduction and Targeted Therapy ,  8 (1), p.200.

8. Agenda

9. Aging, as a universal biological phenomenon, is an inevitable trend during lifespan and shows close effect on the immune system

10. The immune system is one of the most ubiquitous systems of the organism which can protect the human body from internal or external pathogens and interacts with neural, circulatory and other systems McComb S, Thiriot A, Akache B, Krishnan L, Stark F. Introduction to the immune system. Methods Mol Biol (2019) 2024:1 – 24. doi : 10.1007/978-1-4939- 9597-4_1

11. Müller L, Di Benedetto S, Pawelec G. The immune system and its dysregulation with aging. Subcell Biochem (2019) 91:21 – 43. doi : 10.1007/978-981-13-3681-2_2

12. SASP and immunosenescence Guan Y, Zhang C, Lyu G, Huang X, Zhang X, Zhuang T, et al. Senescence activated enhancer landscape orchestrates the senescence-associated secretory phenotype in murine fi broblasts. Nucleic Acids Res (2020) 48(19):10909 – 23.

13. Tchkonia T, Zhu Y, van Deursen J, Campisi J, Kirkland JL. Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. J Clin Invest (2013) 123(3):966 – 72. doi : 10.1172/JCI64098

14. Inflammation and immunosenescence During aging, a state of chronic, low-grade, sterile in fl ammation has been known as in fl ammaging, which is essential to the aging process Zhu Y, Armstrong JL, Tchkonia T, Kirkland JL. Cellular senescence and the senescent secretory phenotype in age-related chronic diseases. Curr Opin Clin Nutr Metab Care (2014) 17(4):324 – 8.

15. Sanada , F., Taniyama , Y., Muratsu , J., Otsu, R., Shimizu, H., Rakugi , H. and Morishita , R., 2018. Source of chronic inflammation in aging.  Frontiers in cardiovascular medicine ,  5 , p.12.

16. Sanada , F., Taniyama , Y., Muratsu , J., Otsu, R., Shimizu, H., Rakugi , H. and Morishita , R., 2018. Source of chronic inflammation in aging.  Frontiers in cardiovascular medicine ,  5 , p.12.

17. C hanges in the gut microbiota of the elderly may activate macrophages to a pro-in fl ammatory state and induce multiple in fl ammatory pathways, which is an important source of in fl ammation Mangiola F, Nicoletti A, Gasbarrini A, Ponziani FR. Gut microbiota and aging. Eur Rev Med Pharmacol Sci (2018) 22(21):7404 – 13.

18. There is an imbalance between in fl ammatory and immune reactions in the process of aging, which reduces the ef fi ciency of immune responses and creates an immunosuppressive microenvironment Cisneros, B., García-Aguirre, I., Unzueta , J., Arrieta-Cruz, I., González-Morales, O., Domínguez- Larrieta , J.M., Tamez -González, A., Leyva-Gómez, G. and Magaña , J.J., 2022. Immune system modulation in aging: Molecular mechanisms and therapeutic targets.  Frontiers in Immunology ,  13 , p.1059173.

19. De Maeyer RPH, Chambers ES. The impact of ageing on monocytes and macrophages. Immunol Lett (2021) 230:1 – 10. doi : 10.1016/j.imlet.2020.12.003

20. Once the balance is broken, a persistent increase of in fl ammatory response in fl uences the activation of T/B lymphocytes, which is called immune paralysis and considered as one of the clinical features of immunosenescence Fulop T, Dupuis G, Baehl S, Le Page A, Bourgade K, Frost E, et al. From n fl amm -aging to immune-paralysis: a slippery slope during aging for immuneadaptation . Biogerontology (2016) 17(1):147 – 57. doi: 10.1007/s10522-015-9615-7

21. Telomere and immunosenescence

22. Telomere structure The telomere biology system containing telomeres (DNA – protein complexes at the ends of chromosomes) and telomerases (reverse transcriptases that add DNA repeats to the ends of telomeres), is essential to maintaining the integrity of the genes and cells Blackburn EH, Epel ES, Lin J. Human telomere biology: A contributory and interactive factor in aging, disease risks, and protection. Science (2015) 350 (6265):1193 – 8. doi : 10.1126/science.aab3389

23. The progressive telomere attrition from naive to effector memory cells shortens the telomere length, which may be resulted from mitochondrial stress. Moreover, shortened telomere could lead to DNA damage and cell cycle arrest, ultimately resulting in damaged cell function and inef fi cient pathogen clearance Zhou D, Borsa M, Simon AK. Hallmarks and detection techniques of cellular senescence and cellular ageing in immune cells. Aging Cell (2021) 20(2): e13316.

24. Metabolism and immunosenescence The interaction between immune and metabolic process is termed as immunometabolism The metabolic disorders of main nutrients (such as glucose, lipids and amino acids) in immune cells during aging lead to the dysregulation of nicotinamide adenine dinucleotide (NAD+) metabolism, activating in fl ammatory pathways and accelerating immunosenescence Li PH, Zhang R, Cheng LQ, Liu JJ, Chen HZ. Metabolic regulation of mmune cells in proin fl ammatory microenvironments and diseases during ageing. Ageing Res Rev (2020) 64:101165.

25. The NAD+ is a coenzyme which catalyzes cellular metabolic functions and converts to NADH. NAD+ decreases with age, which is resulted from reduced NAD+ biosynthesis, caused by chronic inflammation with increased oxidative stress and inflammatory cytokines, and increased NAD+ consumption, caused by DNA damage Imai S, Guarente L. NAD+ and sirtuins in aging and disease. Trends Cell Biol (2014) 24(8):464 – 71. doi : 10.1016/j.tcb.2014.04.002 The reduction of NAD+ metabolism activates NLRP3 in fl ammatory bodies during age, which may be the key to in fl ammatory diseases

26. The contribution of immune organs on immunosenescence

27. Bone marrow involution with aging HSCs are multifunctional immature cell populations that possess self-renewing capacity and give rise to all blood cells of immune system HSCs are decreased with aging with aging and the senescent HSCs acquire increased DNA damage, dysfunctional function and myeloid bias, affecting the generation of naive T cells severely Yamashita M, Iwama A. Aging and clonal behavior of hematopoietic stem cells. Int J Mol Sci (2022) 23(4):1948.

28. Thymic involution with aging The thymus is a central lymphoid organ and responsible to produce naive T cells, playing an essential role in cellular and humoral immunity. Hamazaki Y. Adult thymic epithelial cell (TEC) progenitors and TEC stem cells: Models and mechanisms for TEC development and maintenance. Eur J mmunol (2015) 45(11):2985 – 93. doi : 10.1002/eji.201545844

29. Thymic involution Thymic involution plays a vital role in the imbalance of immune cell proportions, particularly for T cells Decrease in naïve T cells Increase in peripheral late-differentiated memory T cells Diminished migration of naïve T cells to the periphery Palmer, D. B. The effect of age on thymic function. Front. Immunol. 4 , 316 (2013).

30. Thymic rejuvenation does not restore diversity Lynch, H. E. et al. Thymic involution and immune reconstitution. Trends Immunol. 30 , 366 – 373 (2009).

31. Impaired peripheral lymphoid organs with aging Thompson HL, Smithey MJ, Surh CD, Nikolich-Z ̌ ugich J. Functional and homeostatic impact of age-related changes in lymph node stroma. Front Immunol 2017) 8:706. doi: 10.3389/ fi mmu.2017.00706

32. Remarkable differences between the young and aged splenic environment Budamagunta V, Foster TC, Zhou D. Cellular senescence in lymphoid organs and immunosenescence . Aging (Albany NY) (2021) 13(15):19920 – 41. doi : 10.18632/aging.203405

33. The alterations of immune cell subsets related to immunosenescence Wang, Y., Dong, C., Han, Y., Gu, Z. and Sun, C., 2022. Immunosenescence, aging and successful aging.  Frontiers in immunology ,  13 , p.942796. Immunosenescence re fl ects the regulation of innate and acquired immune system, in which cell subsets, surface markers, quantity and function of immune cells, such as T cells, B cells, NK cells, DCs, neutrophils and macrophages, undergo a series of changes

34. Effects of immunosenescence on B cells and age-related diseases Wang, Y., Dong, C., Han, Y., Gu, Z. and Sun, C., 2022. Immunosenescence, aging and successful aging.  Frontiers in immunology ,  13 , p.942796.

35. Agenda

36. Immunosenescence and neurodegenerative diseases ( Alzheimer ’ s disease) One of the most severe neurodegenerative diseases in the elderly Neuroinflammation and brain-resident immune cells (microglia) Immunity is involved in the development of neurodegenerative diseases, but further researches are necessary to study the interaction between senescent cell subsets and AD Burgaletto , C., Munafò , A., Di Benedetto, G., De Francisci , C., Caraci , F., Di Mauro, R., Bucolo , C., Bernardini, R. and Cantarella , G., 2020. The immune system on the TRAIL of Alzheimer’s disease. Journal of Neuroinflammation, 17(1), pp.1-11.

37. Immunosenescence and cancers The declined immunity in older humans may increase the risk of cancers, which may be mediated by multiple cells In elderly people, immune function is obviously suppressed, which leads to increased tumor-in fi ltrating Treg cells, promoting tumor growth and metastasis Berben , L., Floris, G., Wildiers , H. and Hatse , S., 2021. Cancer and aging: two tightly interconnected biological processes.  Cancers ,  13 (6), p.1400.

38. Immunosenescence and cardiovascular diseases Results suggest senescent T cells may be involved in the pathophysiological process of cardiovascular diseases through inflammatory response and cytotoxicity. Wang, Y., Dong, C., Han, Y., Gu, Z. and Sun, C., 2022. Immunosenescence, aging and successful aging.  Frontiers in immunology ,  13 , p.942796.

39. Immunosenescence and autoimmune diseases Immunosenescence is also associated with autoimmune diseases, especially RA. Immunosenescence is often accompanied by increased level of inflammation High levels of the proinflammatory cytokines, such as TNF and IL-6, lead to chronic inflammatory states for long time, which cause Th17/Treg imbalance and amplified immune response in the development of RA At present, the effects of T cell senescence on the occurrence and development of RA have been widely concerned, and other immune cells (such as Treg cells on RA, T/ B cells on lupus or Sjogren Syndrome) have been reported Wang, Y., Dong, C., Han, Y., Gu, Z. and Sun, C., 2022. Immunosenescence, aging and successful aging.  Frontiers in immunology ,  13 , p.942796.

40. Patients with RA had major memory dysfunctions and alterations in certain lymphocyte subsets commonly found in healthy immunosenescence . Furthermore, expansions of activated and senescence-associated T cells were correlated with poor memory performance.

41. In conclusion, all analyses demonstrated that two senescence markers (CD4/CD8 ratio and CD8 + CD28 null ) predicted the SLE disease activity with good sensitivity and specificity.

42. Overview of the main strategies of immunomodulation Aiello, A., Farzaneh , F., Candore , G., Caruso, C., Davinelli , S., Gambino, C.M., Ligotti , M.E., Zareian , N. and Accardi , G., 2019. Immunosenescence and its hallmarks: how to oppose aging strategically? A review of potential options for therapeutic intervention.  Frontiers in immunology ,  10 , p.2247.

43. In conclusion Immunosenescence is a complex and varied process of immune system, which participates in many age-related diseases, with the alteration of immune cell subsets, cytokine secretion and the defect in cell function and quantity