Yaşlı Bireylerde İmmun Sistem
Özet
İlerleyen yaşla birlikte bağışıklık sisteminde meydana gelen ve "immünosenesens" olarak adlandırılan yeniden modelleme süreci, organizmanın enfeksiyonlara, tümör hücrelerine ve hastalıklara karşı direncini azaltmaktadır. Yaşlanma sürecinde kemik iliğindeki doku kaybı ve telomer kısalması nedeniyle hematopoetik kök hücrelerin yenilenme kapasitesi düşmekte, pro-B hücre üretimi ve perifere çıkan B hücresi sayısı azalmaktadır. En belirgin değişimlerden biri olan timus bezinin involüsyonu (atrofiye uğraması), naif T hücre üretiminde ve T hücresi reseptör repertuarında ciddi bir daralmaya yol açmaktadır. Doğal bağışıklık mekanizmaları edinsel bağışıklığa göre daha iyi korunsa da, makrofaj ve nötrofillerin fagositoz yeteneği azalmakta, plazmasitoid dendritik hücrelerde fonksiyonel kayıplar görülmektedir. "İnflammaging" olarak tanımlanan kronik, düşük dereceli inflamasyon artışı ile birleşen bu hücresel gerilemeler; yaşlı bireylerde pnömoni, influenza ve COVID-19 gibi enfeksiyonlara duyarlılığı artırmakta, aşı yanıtlarını zayıflatmaktadır. Ayrıca, azalan düzenleyici T hücre fonksiyonu ve temizlenemeyen apoptotik hücreler sebebiyle otoantikor üretimi artmakta, bu durum yaşlı popülasyonda malignite ve atipik seyirli otoimmün hastalıkların (SLE, RA) insidansını belirgin şekilde yükseltmektedir.
The progressive restructuring of the immune system during aging, termed "immunosenescence," significantly impairs the body's ability to combat infections, malignancies, and autoimmune disorders. With advancing age, bone marrow degeneration and sequential telomere shortening lead to a sharp decline in the proliferative capacity of hematopoietic stem cells, substantially reducing pro-B cell production and peripheral B cells. Concurrently, the involution of the thymus gland drastically limits the generation of naive T cells and constricts the diversity of the T-cell receptor repertoire, hindering the host's capacity to mount responses against novel antigens. Although innate immunity remains relatively better preserved than adaptive immunity, critical cellular functions display age-related deficits; the phagocytic capacity of macrophages and neutrophils declines, and plasmacytoid dendritic cells undergo numerical and functional attrition. Coupled with "inflammaging"—a state of chronic, low-grade systemic inflammation—these combined alterations render elderly individuals highly susceptible to severe infections like pneumonia and COVID-19 while blunting vaccine efficacy. Furthermore, diminished regulatory T-cell function and impaired clearance of apoptotic cells drive an uptick in autoantibody production, culminating in elevated rates of malignancies and atypically presenting autoimmune diseases.
Referanslar
Cunha LL, dos Santos Valsecchi VA, Ward LS. Investigating population-level immunosenescence: From bench to bedside. Frontiers in Immunology. 2022. 13. https://doi.org/10.3389/fimmu.2022.949928
St Sauver JL, Boyd CM, Grossardt BR, et al. Risk of developing multimorbidity across all ages in an historical cohort study: differences by sex and ethnicity. BMJ Open. 2015;5(2). https://doi.org/10.1136/bmjopen-2014-006413
Franceschi C, Garagnani P, Parini P, et al. (2018). Inflammaging: a new immune–metabolic viewpoint for age-related diseases. Nature Reviews Endocrinology. 2018. 14(10), 576-590. https://doi.org/10.1038/s41574-018-0059-4
Geiger H, Rudolph KL. Aging in the lympho-hematopoietic stem cell compartment. Trends in immunology.2009. 30(7), 360-365. https://doi.org/10.1016/j.it.2009.03.010
Vaziri H, Dragowska W, Allsopp RC, et al. Evidence for a mitotic clock in human hematopoietic stem cells: loss of telomeric DNA with age. Proceedings of the National Academy of Sciences. 1994. 91(21), 9857-9860.https://doi.org/10.1073/pnas.91.21.9857.
Cancro MP, Hao Y, Scholz JL, Riley RL, et al. B cells and aging: molecules and mechanisms. Trends in immunology. 2009. 30(7), 313-318. https://doi.org/10.1016/j.it.2009.04.005
Chambers SM, Goodell MA. Hematopoietic stem cell aging: wrinkles in stem cell potential. Stem cell reviews. 2007. 3(3), 201-211. https://doi.org/10.1007/s12015-007-0027-1
Weiskopf D, Weinberger B, Grubeck-Loebenstein B. The aging of the immune system. Transpl Int. 2009;22:1041-50. https://doi.org/10.1111/j.1432-2277.2009.00927.x
Shaw AC, Joshi S, Greenwood H, et al. Aging of the innate immune system. Current opinion in immunology. 2010. 22(4), 507-513. https://doi.org/10.1016/j.coi.2010.05.003
Tizazu AM, Mengist HM, Demeke G. Aging, inflammaging and immunosenescence as risk factors of severe COVID-19. Immunity & Ageing, 2022. 19(1), 1-18. https://doi.org/10.1186/s12979-022-00309-5
Ogawa T, Kitagawa M, Hirokawa, K. Age-related changes of human bone marrow: a histometric estimation of proliferative cells, apoptotic cells, T cells, B cells and macrophages. Mechanisms of ageing and development, 2000.117(1-3), 57-68. https://doi.org/10.1016/s0047-6374(00)00137-8
Plowden, J, Renshaw‐Hoelscher , Engleman C, et al. Innate immunity in aging: impact on macrophage function. Aging cell, 2004;3(4), 161-167. https://doi.org/10.1111/j.1474-9728.2004.00102.
Panda A, Arjona A, Sapey E, et al. Human innate immunosenescence: causes and consequences for immunity in old age. Trends in immunology.2009; 30(7), 325-333. https://doi.org/10.1016/j.it.2009.05.004
Borrego F, Alonso MC, Galiani MD, et al. NK phenotypic markers and IL2 response in NK cells from elderly people. Experimental gerontology, 1999;34(2), 253-265. https://doi.org/10.1016/s0531-5565(98)00076
Przemska-Kosicka A, Childs CE, Maidens C, et al. Age-related changes in the natural killer cell response to seasonal influenza vaccination are not influenced by a synbiotic: A randomised controlled trial. Frontiers in immunology. 2018; 9, 591. https://doi.org/10.3389/fimmu.2018.00591
Le Garff‐Tavernier M, Béziat V, Decocq J, et al. Human NK cells display major phenotypic and functional changes over the life span. Aging cell. 2010;9(4), 527-535. https://doi.org/10.1111/j.1474-9726.2010.00584.
Ogata K, An E, Shioi Y, et al. Association between natural killer cell activity and infection in immunologically normal elderly people. Clinical & Experimental Immunology. 2001; 124(3), 392-397. https://doi.org/10.1046/j.1365-2249.2001.01571.
Sansoni P, Cossarizza A, Brianti V, et al. Lymphocyte subsets and natural killer cell activity in healthy old people and centenarians. Blood 1993; 82:2767.
Agrawal A, Agrawal S, Gupta S. et al. Dendritic cells in human aging. Experimental gerontology.2007; 42(5), 421-426. https://doi.org/10.1016/j.exger.2006.11.007
Jing Y, Shaheen E, Drake RR, et al. Aging is associated with a numerical and functional decline in plasmacytoid dendritic cells, whereas myeloid dendritic cells are relatively unaltered in human peripheral blood. Human immunology.2009;70(10), 777-784. https://doi.org/10.1016/j.humimm.2009.07.005
Panda A, Qian F, Mohanty S, et al. Age-associated decrease in TLR function in primary human dendritic cells predicts influenza vaccine response. The Journal of Immunology. 2010;184(5), 2518-2527. https://doi.org/10.4049/jimmunol.0901022
Flores KG, Li J, Sempowski GD, et al. Analysis of the human thymic perivascular space during aging. J Clin Invest.1999; 104:103. 1039. https://doi.org/10.1172/JCI7558
Naylor K, Li G, Vallejo AN, et al. The influence of age on T cell generation and TCR diversity. The Journal of Immunology.2005;174(11), 7446-7452. https://doi.org/10.4049/jimmunol.174.11.7446
Nasi M, Troiano L, Lugli E, et al.Thymic output and functionality of the IL‐7/IL‐7 receptor system in centenarians: implications for the neolymphogenesis at the limit of human life. Aging cell.2006;5(2), 167-175. https://doi.org/10.1111/j.1474-9726.2006.00204.
Kaltoft K. Cytokine-Driven Immortalization of in vitro Activated Human T Lymphocytes. Experimental and clinical immunogenetics.1998;15(2), 84-89. https://doi.org/10.1159/000019058
Haynes L, Maue AC.Effects of aging on T cell function. Current opinion in immunology.2009;21(4), 414-417. https://doi.org/10.1016/j.coi.2009.05.009
Uciechowski P, Kahmann L, Plümäkers B,et al. TH1 and TH2 cell polarization increases with aging and is modulated by zinc supplementation. Experimental gerontology.2008; 43(5), 493-498. https://doi.org/10.1016/j.exger.2007.11.006
Cakman I, Rohwer J, Schütz RM, et al. Dysregulation between TH1 and TH2 T cell subpopulations in the elderly. Mechanisms of ageing and development.1996; 87(3), 197-209. https://doi.org/10.1016/0047-6374(96)01708-3
Mansfield AS, Nevala WK, Dronca R.S, et al.Normal ageing is associated with an increase in Th2 cells, MCP-1 (CCL1) and RANTES (CCL5), with differences in sCD40L and PDGF-AA between sexes. Clinical & Experimental Immunology.2012; 170(2), 186-193. https://doi.org/10.1111/j.1365-2249.2012.04644.
Sakata-Kaneko S, Wakatsuki Y, Matsunaga Y, et al. Altered Th1/Th2 commitment in human CD4+ T cells with ageing. Clinical & Experimental Immunology.2000;120(2), 267-273. https://doi.org/10.1046/j.1365-2249.2000.01224.
Frasca D, Blomberg BB. Effects of aging on B cell function. Current opinion in immunology.2009;21(4), 425-430. https://doi.org/10.1016/j.coi.2009.06.001
Blomberg BB, Ryan JG, Schwartz R, et al. Aging Down-Regulates the Transcription. J Immunol.2008;180, 5283-5290. https://doi.org/10.4049/jimmunol.180.8.5283
Lazuardi L, Jenewein B, Wolf AM, et al. Age‐related loss of naive T cells and dysregulation of T‐cell/B‐cell interactions in human lymph nodes. Immunology.2005;114(1), 37-43. https://doi.org/10.1111/j.1365-2567.2004.02006.
Marcos-Pérez D, Sánchez-Flores M, Maseda A, et al. Frailty in older adults is associated with plasma concentrations of inflammatory mediators but not with lymphocyte subpopulations. Frontiers in immunology.2018; 9, 1056. https://doi.org/10.3389/fimmu.2018.01056
Henson SM, Akbar AN. Memory T-cell homeostasis and senescence during aging. In Memory T Cells.2010 (pp. 189-197). https://doi.org/10.1007/978-1-4419-6451-9_15
Hancock K, Veguilla V, Lu X, et al. Cross-reactive antibody responses to the 2009 pandemic H1N1 influenza virus. New England journal of medicine.2009; 361(20), 1945-1952. https://doi.org/10.1056/NEJMoa0906453
Monsalvo AC, Batalle JP, Lopez MF, et al. Severe pandemic 2009 H1N1 influenza disease due to pathogenic immune complexes. Nature medicine.2011;17(2), 195-199. https://doi.org/10.1038/nm.2262
Wagner A, Garner-Spitzer E, Jasinska J, et al. Age-related differences in humoral and cellular immune responses after primary immunisation: indications for stratified vaccination schedules. Scientific reports.2018; 8(1), 1-12. https://doi.org/10.1038/s41598-018-28111-8
Weinberger B, Haks MC, De Paus RA, et al. Impaired immune response to primary but not to booster vaccination against hepatitis B in older adults. Frontiers in immunology.2018; 9, 1035. https://doi.org/10.3389/fimmu.2018.01035
Gavazzi G, Krause KH. Ageing and infection. The Lancet infectious diseases.2002; 2(11), 659-666. https://doi.org/10.1016/s1473-3099(02)00437-1
Aprahamian T, Takemura Y, Goukassian D, et al. Ageing is associated with diminished apoptotic cell clearance in vivo. Clinical & Experimental Immunology.2008;152(3), 448-455. https://doi.org/10.1111/j.1365-2249.2008.03658.x
Ramos-Casals M, Brito-Zerón P, López-Soto A, et al. Systemic autoimmune diseases in elderly patients: Atypical presentation and association with neoplasia. Autoimmunity reviews.2004; 3(5), 376-382. https://doi.org/10.1016/j.autrev.2003.12.002
Deal CL, Meenan RF, Goldenberg DL, et al. The clinical features of elderly‐onset rheumatoid arthritis. A comparison with younger‐onset disease of similar duration. Arthritis & Rheumatism: Official Journal of the American College of Rheumatology.1985; 28(9), 987-994. https://doi.org/10.1002/art.1780280905
