Hyperferritinemia Correlated with Activated Population of Natural Killer Cells in Pediatric Major β-Thalassemia Patients
Abstract
Natural killer (NK) cells act both as cytotoxic and cytokine producers in the innate immune response. Hyperferritinemia resulting from a routine blood transfusion as a specific treatment in major β-thalassemia patients may disturb the cellular immune system’s harmony. This study aims to investigate the correlation between hyperferritinemia and the NK cell subsets in major β-thalassemia settings. Pediatric major β-thalassemia patients who routinely received a blood transfusion at Dr. Hasan Sadikin General Hospital in 2016 were included in this cross-sectional study. Blood samples were treated with the monoclonal antibody of CD3, CD56, and CD16 to count the NK cells subsets as CD56bright, CD56dim, and CD16+ using flowcytometry. CD69+ used as an activation marker. The median fluorescence intensity (MFI) of CD56, CD16, and CD69 was measured. Total iron-binding capacity (TiBC), ferritin, and serum iron level examined as iron status. A Spearman correlation test was used for statistical analysis. Fifty-five blood samples were obtained for analysis. This study reveals that the percentage of CD3− lymphocyte population was correlated with the ferritin levels (r=−0.45, p=0.0009). Positive correlation was revealed between activated population (CD69+) of CD56bright and CD56dim NK cell subsets and hyperferritinemia [(r=0.353, p=0.008) and (r=0.355, p=0.008)]. The activated CD56bright cells was associated with ferritin level (r=0.353, p=0.008) and TiBC (r=0.334, p=0.018). Hyperferritinemia in pediatric major β-thalassemia patients may influence NK cell subsets' balance population, particularly the CD56bright and CD56dim NK cell subsets, then alter their immune response to pathogens.
KORELASI ANTARA HIPERFERITINEMIA DAN SEL NATURAL KILLER TERAKTIVASI PADA ANAK DENGAN TALASEMIA BETA MAYOR
Sel-sel natural killer (NK) telah diketahui memiliki peran sitotoksik dan dalam produksi sitokin pada respons imun bawaan. Hiperferitinemia merupakan hasil dari transfusi darah rutin yang dijalani sebagai terapi utama pada talasemia mayor. Penelitian ini bertujuan mempelajari hubungan hiperferitinemia dan sel NK pada talasemia beta mayor. Penelitian potong lintang ini melibatkan anak dengan talasemia beta mayor yang secara rutin menerima transfusi darah di RSUP Dr. Hasan Sadikin selama tahun 2016. Sampel darah diberi marker CD3, CD56, dan CD16 untuk menghitung subset sel NK sebagai CD56bright, CD56dim, dan CD16+ menggunakan flowcytometry. CD69+ digunakan sebagai penanda aktivasi. Median fluorescence intensity (MFI) CD56, CD16, dan CD69 diukur. Kadar TiBC, ferritin, dan Fe serum diperiksa sebagai status besi. Uji korelasi Spearman digunakan pada analisis statistik. Analisis dilakukan terhadap 55 sampel darah anak dengan talasemia. Penelitian ini mendapatkan populasi limfosit CD3 berkorelasi dengan kadar feritin (r=−0,45; p=0,0009). Korelasi positif didapatkan pada populasi teraktivasi (CD69+) dari subset sel CD56bright dan CD56dim NK serta hiperferitinemia [(r=0,353; p=0,008) dan (r=0,355; p=0,008)]. Sel CD56bright teraktivasi berkorelasi dengan kadar feritin (r=0,353; p=0,008) dan TiBC (r=0,334; p=0,018). Hiperferitinemia pada anak dengan talasemia mayor dapat memengaruhi populasi sel NK, khususnya pada subset CD56bright dan CD56dim sehingga berpengaruh pada respons imun terhadap patogen.
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Mishra AK, Tiwari A. Iron overload in beta thalassaemia major and intermedia patients. Mædica. 2013;8(4):328–32.
de Dreuzy E, Bhukhai K, Leboulch P, Payen E. Current and future alternative therapies for beta-thalassemia major. Biomed J. 2016;39(1):24–38.
Leecharoenkiat K, Lithanatudom P, Sornjai W, Smith DR. Iron dysregulation in beta-thalassemia. Asian Pac J Trop Med. 2016;9(11):1035–43.
Ribeil JA, Arlet JB, Dussiot M, Moura IC, Courtois G, Hermine O. Ineffective erythropoiesis in beta-thalassemia. Sci World J. 2013;2013:394295.
Wang L, Cherayil BJ. Ironing out the wrinkles in host defense: interactions between iron homeostasis. J Innate Immun. 2009;1(5):455–64.
Kao JK, Wang SC, Ho LW, Huang SW, Chang SH, Yang RC, et al. Chronic iron overload results in impaired bacterial killing of THP-1 derived macrophage through the inhibition of lysosomal acidification. PLoS One. 2016;11(5):e0156713.
Porto G, De Sousa M. Iron overload and immunity. World J Gastroenterol. 2007;13(35):4707–15.
Sari TT, Gatot D, Akib AAP, Bardosono S, Hadinegoro SRS, Harahap AR, et al. Immune response of thalassemia major patients in Indonesia with and without splenectomy. Acta Med Indones. 2014;46(3):217–25.
Akbar AN, Fitzgerald-Bocarsly PA, de Sousa M, Giardina PJ, Hilgartner MW, Grady RW. Decreased natural killer activity in thalassemia major: a possible consequence of iron overload. J Immunol. 1986;136(5):1635–40.
Atasever Arslan B, Erdem-Kuruca S, Karakas Z, Erman B, Ergen A. Effects of micro environmental factors on natural killer activity (NK) of beta thalassemia major patients. Cell Immunol. 2013;282(2):93–9.
Cooper MA, Fehniger TA, Turner SC, Chen KS, Ghaheri BA, Ghayur T, et al. Human natural killer cells: a unique innate immunoregulatory role for the CD56bright subset. Blood. 2013;97(10):3146–51.
Miller JS. The biology of natural killer cells in cancer, infection, and pregnancy. Exp Hematol. 2001;29(10):1157–68.
Lugli E, Marcenaro E, Mavilio D. NK cell subset redistribution during the course of viral infections. Front Immunol. 2014;5:390.
Wang D, Ma Y, Wang J, Liu X, Fang M. Natural killer cells in innate defense against infective pathogens. J Clin Cell Immunol. 2013;S13:006.
Bekaroğlu MG, Arslan BA. Natural killer (NK) cells in β-thalassemia major patients. JSM Biotechnol Bioeng. 2014;2(2):1040.
Yokoyama WM, Riley JK. NK cells and their receptors. Reprod Biomed Online. 2008;16(2):173–91.
Orr MT, Lanier LL. Natural Killer cell education and tolerance. Cell. 2010;142(6):847–56.
Cristiani CM, Palella E, Sottile R, Tallerico R, Garofalo C, Carbone E. Human NK cell subsets in pregnancy and disease: toward a new biological complexity. Front Immunol. 2016;7:656.
Björkström NK, Ljunggren HG, Michaëlsson J. Emerging insights into natural killer cells in human peripheral tissues. Nat Rev Immunol. 2016;16(5):310–20.
Vossen MTM, Matmati M, Hertoghs KML, Baars PA, Gent MR, Leclercq G, et al. CD27 defines phenotypically and functionally different human NK cell subsets. J Immunol. 2008;180(6):3739–45.
Luetke-Eversloh M, Killig M, Romagnani C. Signatures of human NK cell development and terminal differentiation. Front Immunol. 2013;4:499.
Sunwoo JB, Kim S, Yang L, Naik T, Higuchi DA, Rubenstein JL, et al. Distal-less homeobox transcription factors regulate development and maturation of natural killer cells. Proc Natl Acad Sci USA. 2008;105(31):10877–82.
Poli A, Michel T, Thérésine M, Andrès E, Hentges F, Zimmer J. CD56bright natural killer (NK) cells: an important NK cell subset. Immunology. 2009;126(4):458–65.
Mavilio D, Lombardo G, Benjamin J, Kim D, Follman D, Marcenaro E, et al. Characterization of CD56−/CD16+ natural killer (NK) cells: a highly dysfunctional NK subset expanded in HIV-infected viremic individuals. Proc Natl Acad Sci USA. 2005;102(8):2886–91.
Milush JM, López-Vergès S, York VA, Deeks SG, Martin JN, Hecht FM, et al. CD56negCD16+ NK cells are activated mature NK cells with impaired effector function during HIV-1 infection. Retrovirology. 2013;10:158.
Gonzalez VD, Falconer K, Björkström NK, Blom KG, Weiland O, Ljunggren HG, et al. Expansion of functionally skewed CD56-negative NK cells in chronic hepatitis C virus infection: correlation with outcome of pegylated IFN-α and ribavirin treatment. J Immunol. 2009;183(10):6612–8.
Benlahrech A, Donaghy H, Rozis G, Goodier M, Klavinskis L, Gotch F, et al. Human NK cell up-regulation of CD69, HLA-DR, interferon γ secretion and cytotoxic activity by plasmacytoid dendritic cells is regulated through overlapping but different pathways. Sensors. 2009;9(1):386–403.
de la Fuente H, Cruz-Adalia A, Martinez Del Hoyo G, Cibrián-Vera D, Bonay P, Pérez-Hernández D, et al. The leukocyte activation receptor CD69 controls T cell differentiation through its interaction with galectin-1. Mol Cell Biol. 2014;34(13):2479–87.
Sancho D, Gómez M, Sánchez-Madrid F. CD69 is an immunoregulatory molecule induced following activation. Trends Immunol. 2005;26(3):136–40.
Borrego F, Robertson MJ, Ritz J, Peña J, Solana R. CD69 is a stimulatory receptor for natural killer cell and its cytotoxic effect is blocked by CD94 inhibitory receptor. Immunology. 1999;97(1):159–65.
Krechetova LV, Vtorushina VV, Nikolaeva MA, Golubeva EL, Van’ko LV, Saribegova VA, et al. Expression of early activation marker CD69 on peripheral blood lymphocytes from pregnant women after first trimester alloimmunization. Bull Exp Biol Med. 2016;161(4):529–32.
DOI: https://doi.org/10.29313/gmhc.v9i1.6346
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