First report of expansion of CD4+/CD28 null T-helper lymphocytes in adult patients with idiopathic autoimmune hemolytic anemia

Soha R Youssef, Walaa A Elsalakawy, Soha R Youssef, Walaa A Elsalakawy

Abstract

CD28 null T helper (Th) cells are rare in healthy individuals, but they are increased in various inflammatory and immune-mediated diseases. In this study, we determined the size of the CD4+/CD28 null T lymphocyte compartment in the peripheral blood of 40 autoimmune hemolytic anemia (AIHA) patients (idiopathic and secondary) and 20 healthy control subjects, using tri-color flow cytometry. The frequency and absolute count of CD4+/CD28 null T helper (Th) cells was significantly higher in idiopathic AIHA patients, compared to healthy controls (p = 0.001 and 0.001, respectively) and to patients with secondary AIHA (p = 0.04 and 0.01, respectively). The percentage of CD4+/CD28 null Th cells was also negatively correlated to the hemoglobin (Hb) level (p = 0.03). These findings demonstrate, for the first time, the expansion of this phenotypically-defined population of T lymphocytes in patients with idiopathic AIHA and indicate that it likely plays an etiological role in the development of this disease. However, establishing the use of this marker for diagnosis or monitoring treatment of such patients needs further studies.

Keywords: Autoimmune hemolytic anemia; Autoimmunity; CD4 helper T cells; CD4(+)/CD28 null T lymphocyte; Flow cytometry; T lymphocytes; T(h) cells.

Copyright © 2020 Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular. Published by Elsevier España, S.L.U. All rights reserved.

Figures

Figure 1
Figure 1
Comparison between controls and patient groups in relation to compartments of T helper effector populations. This figure shows that the percentage of CD4+CD28 null T cells was significantly higher among group 1 (idiopathic AIHA) patients (median percentage of 10.6%), compared to controls (median percentage of 2.2%) (p = 0.001 and 0.001, respectively) and to group 2 (secondary AIHA) patients (median percentage of 3.7%) (p = 0.04 and 0.01, respectively). The percentage of CD4+CD28− T cells in group 2 patients were comparable to the control group (p > 0.05 and p > 0.05, respectively).

References

    1. Porciello N., Kunkl M., Tuosto L. CD28 between tolerance and autoimmunity: the side effects of animal models [version 1; referees: 2 approved] F1000Research. 2018;7(F1000 Faculty Rev):682.
    1. Liuzzo G., Kopecky S.L., Frye R.L., O’Fallon W.M., Maseri A., Goronzy J.J. Perturbation of the T-cell repertoire in patients with unstable angina. Circulation. 1999;100:2135–2139.
    1. Vallejo A.N., Schirmer M., Weyand C.M., Goronzy J.J. Clonality and longevity of CD4qCD28null T cells are associated with defects in apoptotic pathways. J Immunol. 2000;165:6301–6307.
    1. Mou D., Espinosa J., Lo D.J., Kirk A.D. CD28 negative T cells: is their loss our gain? Am J Transplant. 2014;14(November (11)):2460–2466.
    1. ElAlfy M.S., Adly A.A., Ebeid F.S., Eissa D.S., Ismail E.A., Mohammed Y.H. Immunological role of CD4+CD28null T lymphocytes, natural killer cells, and interferon-gamma in pediatric patients with sickle cell disease: relation to disease severity and response to therapy. Immunol Res. 2018;66(4):480–490.
    1. Pieper J., Johansson S., Snir O., Linton L., Rieck M., Buckner J. Peripheral and site-specific CD4+CD28null T cells from Rheumatoid Arthritis patients show distinct characteristics. Scand J Immunol. 2014;79(2):149–155.
    1. Zahran A.M., Abdallah A.M., Saad K., Osman N.S., Youssef M.A., Abdel-Raheem Y.F. Peripheral blood B and T cell profiles in children with active juvenile idiopathic arthritis. Arch Immunol Ther Exp. 2019;67(6):427–432.
    1. Hodge G., Hodge S., Ahern J., Holmes-Liew C.L., Reynolds P.N., Holmes M. Up-regulation of alternate co-stimulatory molecules on proinflammatory CD28null T cells in bronchiolitis obliterans syndrome. Clin Exp Immunol. 2013;173(1):150–160.
    1. Roberts S.D., Kohli L.L., Wood K.L., Wilkes D.S., Knox K.S. CD4+CD28-T cells are expanded in sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis. 2005;22(1):13–19.
    1. Kobayashi T., Okamoto S., Iwakami Y., Nakazawa A., Hisamatsu T., Chinen H. Exclusive increase of CX3CR1+CD28-CD4+ T cells in inflammatory bowel disease and their recruitment as intraepithelial lymphocytes. Inflamm Bowel Dis. 2007;13(July (7)):837–846.
    1. García de Tena J., Manzano L., Leal J.C., San Antonio E., Sualdea V., Alvarez-Mon M. Active Crohn’s disease patients show a distinctive expansion of circulating memory CD4+CD45RO+CD28null T cells. J Clin Immunol. 2004;24(2):185–196.
    1. Miyazaki Y., Iwabuchi K., Kikuchi S., Fukazawa T., Niino M., Hirotani M. Expansion of CD4+CD28- T cells producing high levels of interferon-{gamma} in peripheral blood of patients with multiple sclerosis. Mult Scler. 2008;14(8):1044–1055.
    1. Sun Z., Zhong W., Lu X., Shi B., Zhu Y., Chen L. Association of Graves’ disease and prevalence of circulating IFN-gamma-producing CD28(-) T cells. J Clin Immunol. 2008;28(5):464–472.
    1. Wang Y., Bai J., Li F., Wang H., Fu X., Zhao T. Characteristics of expanded CD4+CD28null T cells in patients with chronic hepatitis B. Immunol Invest. 2009;38(5):434–446.
    1. Escarra-Senmarti M., Bueno-Topete M.R., Jave-Suarez L.F., Gomez-Bañuelos E., Gutierrez-Franco J., Vega-Magaña N. Loss of CD28 within CD4+ T cell subsets from cervical cancer patients is accompanied by the acquisition of intracellular perforin, and is further enhanced by NKG2D expression. Immunol Lett. 2017;182:30–38.
    1. Shabir S., Smith H., Kaul B., Pachnio A., Jham S., Kuravi S. Cytomegalovirus-associated CD4(+) CD28(null) Cells in NKG2D-dependent glomerular endothelial injury and kidney allograft dysfunction. Am J Transplant. 2016;16(4):1113–1128.
    1. Sulzgruber P., Thaler B., Koller L., Baumgartner J., Pilz A., Steininger M. CD4+CD28null T lymphocytes are associated with the development of atrial fibrillation after elective cardiac surgery. Sci Rep. 2018;8(1):9624.
    1. Giubilato S., Liuzzo G., Brugaletta S., Pitocco D., Graziani F., Smaldone C. Expansion of CD4+CD28null T-lymphocytes in diabetic patients: exploring new pathogenetic mechanisms of increased cardiovascular risk in diabetes mellitus. Eur Heart J. 2011;32(10):1214–1226.
    1. Sun Z., Ye H., Tang B., Shen X., Wu X., Zhong H. Prevalence of circulating CD4+CD28null T cells is associated with early atherosclerotic damage in patients with end-stage renal disease undergoing hemodialysis. Hum Immunol. 2013;74(1):6–13.
    1. Cooper A.C., Breen C.P., Vyas B., Ochola J., Kemeny D.M., Macdougall I.C. Poor response to recombinant erythropoietin is associated with loss of T-lymphocyte CD28 expression and altered interleukin-10 production. Nephrol Dial Transplant. 2003;18:133–140.
    1. Langenhorst D., Tabares P., Gulde T., Becklund B.R., Berr S., Surh C.D. Self-recognition sensitizes mouse and human regulatory T cells to low-dose CD28 superagonist stimulation. Front Immunol. 2018;8:1985.
    1. Vanhove B., Poirier N., Fakhouri F., Laurent L., Hart B., Papotto P.H. Antagonist anti-CD28 therapeutics for the treatment of autoimmune disorders. Antibodies (Basel) 2017;6(November (4)):19.
    1. Blair Hannah A., Deeks Emma D. Abatacept: a review in rheumatoid arthritis. Drugs. 2017;77:1221–1233.
    1. Genant H.K., Peterfy C.G., Westhovens R., Becker J.-C., Aranda R., Vratsanos G. Abatacept inhibits progression of structural damage in rheumatoid arthritis: results from the long-term extension of the AIM trial. Ann Rheum Dis. 2008;67:1084–1089.
    1. Del Bello A., Marion O., Milongo D., Rostaing L., Kamar N. Belatacept prophylaxis against organ rejection in adult kidney transplant recipients. Expert Rev Clin Pharmacol. 2016;9(2):215–227.
    1. Poirier N., Blancho G., Hiance M., Mary C., Assche T., Lempoels J. First-in-human study in healthy subjects with FR104, a pegylated monoclonal antibody fragment antagonist of CD28. J Immunol. 2016;197(December (12)):4593–4602.
    1. Vierboom M.P., Breedveld E., Kap Y.S., Mary C., Poirier N., ’t Hart B.A. Clinical efficacy of a new CD28-targeting antagonist of T cell co-stimulation in a non-human primate model of collagen-induced arthritis. Clin Exp Immunol. 2016;183(3):405–418.
    1. Ville S., Poirier N., Branchereau J., Charpy V., Pengam S., Nerriere-Daguin V. Anti-CD28 antibody and belatacept exert differential effects on mechanisms of renal allograft rejection. J Am Soc Nephrol. 2016;27:3577–3588.
    1. Dumitriu I.E., Araguás E.T., Baboonian C., Kaski J.C. CD4+ CD28 null T cells in coronary artery disease: when helpers become killers. Cardiovasc Res. 2009;81(January (1)):11–19.

Source: PubMed

3
Sottoscrivi