Generic placeholder image

Endocrine, Metabolic & Immune Disorders - Drug Targets

Editor-in-Chief

ISSN (Print): 1871-5303
ISSN (Online): 2212-3873

Research Article

The Effects of Stimulation with PMA/Ionomycin on CD4+ T Cell Proliferation and Surface CD4 Molecule Modulation of Patients with LRBA Deficiency and CVID with the Unsolved Genetic Defect

Author(s): Fereshte Salami, Sahar Shariati, Seyed Erfan Rasouli, Samaneh Delavari, Marzieh Tavakol, Homa Sadri, Babak Asghari, Reza Yazdani, Nima Rezaei, Hassan Abolhassani and Gholamreza Azizi*

Volume 22, Issue 5, 2022

Published on: 27 January, 2022

Page: [539 - 544] Pages: 6

DOI: 10.2174/1871530321666211209162834

Abstract

Background: Common variable immunodeficiency (CVID) is the most prevalent symptomatic primary immunodeficiencies. LPS-responsive beige-like anchor protein (LRBA) deficiency is a combined immunodeficiency characterized by a CVID-like phenotype. Affected patients by LRBA and CVID present a wide range of clinical manifestations, including hypogammaglobulinemia, recurrent infections, autoimmunity, as well as T cell abnormality.

Methods: The study population comprised of patients with CVID (n=10), LRBA deficiency (n=11), and healthy controls (n=12). CD4+ T cell frequency and CD4 MFI (mean fluorescence intensity) were evaluated using flow cytometry before and after stimulation with PMA/ION.

Results: The frequencies of CD4+ T cells were significantly lower in patients with LRBA deficiency than in HCs before and after treatment. In the unstimulated state, the CD4+ T cells frequency in CVID patients was significantly lower than in HCs. There were no statistically significant differences between patients and healthy individuals in CD4+ T cell proliferation. Compared to HCs, LRBA and CVID patients showed a lower CD4 MFI in unstimulated conditions. Furthermore, CD4 MFI decreased in both patients and the control group following activation.

Conclusion: Despite the reported decrease in CD4+ T cell frequency in patients with CVID and LRBA deficiency, our findings demonstrated that their CD4+ T cells have a normal proliferative response to stimuli similar to healthy individuals.

Keywords: Common variable immunodeficiency, primary immunodeficiencies, LRBA deficiency, proliferation, CD4+ T cell, stimulation.

« Previous
Graphical Abstract
[1]
Alkhairy, O.K.; Abolhassani, H.; Rezaei, N.; Fang, M.; Andersen, K.K.; Chavoshzadeh, Z.; Mohammadzadeh, I.; El-Rajab, M.A.; Massaad, M.; Chou, J.; Aghamohammadi, A.; Geha, R.S.; Hammarström, L. Spectrum of phenotypes associated with mutations in LRBA. J. Clin. Immunol., 2016, 36(1), 33-45.
[http://dx.doi.org/10.1007/s10875-015-0224-7] [PMID: 26707784]
[2]
Azizi, G.; Bagheri, Y.; Yazdani, R.; Zaki-Dizaji, M.; Jamee, M.; Jadidi-Niaragh, F.; Kamali, A.N.; Abolhassani, H.; Aghamohammadi, A. The profile of IL-4, IL-5, IL-10 and GATA3 in patients with LRBA deficiency and CVID with no known monogenic disease: Association with disease severity. Allergol. Immunopathol. (Madr.), 2019, 47(2), 172-178.
[http://dx.doi.org/10.1016/j.aller.2018.06.003] [PMID: 30193889]
[3]
Cagdas, D.; Halaçlı, S.O.; Tan, Ç.; Lo, B.; Çetinkaya, P.G.; Esenboğa, S.; Karaatmaca, B.; Matthews, H.; Balcı-Hayta, B.; Arıkoğlu, T.; Ezgü, F.; Aladağ, E.; Saltık-Temizel, İ.N.; Demir, H.; Kuşkonmaz, B.; Okur, V.; Gümrük, F.; Göker, H.; Çetinkaya, D.; Boztuğ, K.; Lenardo, M.; Sanal, Ö.; Tezcan, İ. A spectrum of clinical findings from ALPS to CVID: several novel LRBA defects. J. Clin. Immunol., 2019, 39(7), 726-738.
[http://dx.doi.org/10.1007/s10875-019-00677-6] [PMID: 31432443]
[4]
Meshaal, S.; El Hawary, R.; Adel, R.; Abd Elaziz, D.; Erfan, A.; Lotfy, S.; Hafez, M.; Hassan, M.; Johnson, M.; Rojas-Restrepo, J.; Gamez-Diaz, L.; Grimbacher, B.; Shoman, W.; Abdelmeguid, Y.; Boutros, J.; Galal, N.; El-Guindy, N.; Elmarsafy, A. Clinical phenotypes and immunological characteristics of 18 Egyptian LRBA deficiency patients. J. Clin. Immunol., 2020, 40(6), 820-832.
[http://dx.doi.org/10.1007/s10875-020-00799-2] [PMID: 32506362]
[5]
Cunningham-Rundles, C.; Bodian, C. Common variable immunodeficiency: clinical and immunological features of 248 patients. Clin. Immunol., 1999, 92(1), 34-48.
[http://dx.doi.org/10.1006/clim.1999.4725] [PMID: 10413651]
[6]
Boileau, J.; Mouillot, G.; Gérard, L.; Carmagnat, M.; Rabian, C.; Oksenhendler, E.; Pasquali, J.L.; Korganow, A.S. Autoimmunity in common variable immunodeficiency: correlation with lymphocyte phenotype in the French DEFI study. J. Autoimmun., 2011, 36(1), 25-32.
[http://dx.doi.org/10.1016/j.jaut.2010.10.002] [PMID: 21075598]
[7]
Farrant, J.; Spickett, G.; Matamoros, N.; Copas, D.; Hernandez, M.; North, M.; Chapel, H.; Webster, A.D. Study of B and T cell phenotypes in blood from patients with common variable immunodeficiency (CVID). Immunodeficiency, 1994, 5(2), 159-169.
[PMID: 7913365]
[8]
Wong, G.K.; Huissoon, A.P. T-cell abnormalities in common variable immunodeficiency: the hidden defect. J. Clin. Pathol., 2016, 69(8), 672-676.
[http://dx.doi.org/10.1136/jclinpath-2015-203351] [PMID: 27153873]
[9]
Charbonnier, L.M.; Janssen, E.; Chou, J.; Ohsumi, T.K.; Keles, S.; Hsu, J.T.; Massaad, M.J.; Garcia-Lloret, M.; Hanna-Wakim, R.; Dbaibo, G.; Alangari, A.A.; Alsultan, A.; Al-Zahrani, D.; Geha, R.S.; Chatila, T.A. Regulatory T-cell deficiency and immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like disorder caused by loss-of-function mutations in LRBA. J. Allergy Clin. Immunol., 2015, 135(1), 217-227.
[http://dx.doi.org/10.1016/j.jaci.2014.10.019] [PMID: 25468195]
[10]
O’Neil-Andersen, N.J.; Lawrence, D.A. Differential modulation of surface and intracellular protein expression by T cells after stimulation in the presence of monensin or brefeldin A. Clin. Diagn. Lab. Immunol., 2002, 9(2), 243-250.
[PMID: 11874859]
[11]
Baran, J; Kowalczyk, D; Ożóg, M; Zembala, M Three-color flow cytometry detection of intracellular cytokines in peripheral blood mononuclear cells: comparative analysis of phorbol myristate acetate-ionomycin and phytohemagglutinin stimulation. Clin Diagn Lab Immunol, 2001, 8, 303-313.
[http://dx.doi.org/10.1128/CDLI.8.2.303-313.2001]
[12]
Petersen, C.M.; Christensen, E.I.; Andresen, B.S.; Møller, B.K. Internalization, lysosomal degradation and new synthesis of surface membrane CD4 in phorbol ester-activated T-lymphocytes and U-937 cells. Exp. Cell Res., 1992, 201(1), 160-173.
[http://dx.doi.org/10.1016/0014-4827(92)90360-K] [PMID: 1612121]
[13]
Pelchen-Matthews, A.; Parsons, I.J.; Marsh, M. Phorbol ester-induced downregulation of CD4 is a multistep process involving dissociation from p56lck, increased association with clathrin-coated pits, and altered endosomal sorting. J. Exp. Med., 1993, 178(4), 1209-1222.
[http://dx.doi.org/10.1084/jem.178.4.1209] [PMID: 8376930]
[14]
Abolhassani, H.; Kiaee, F.; Tavakol, M.; Chavoshzadeh, Z.; Mahdaviani, S.A.; Momen, T.; Yazdani, R.; Azizi, G.; Habibi, S.; Gharagozlou, M.; Movahedi, M.; Hamidieh, A.A.; Behniafard, N.; Nabavi, M.; Bemanian, M.H.; Arshi, S.; Molatefi, R.; Sherkat, R.; Shirkani, A.; Amin, R.; Aleyasin, S.; Faridhosseini, R.; Jabbari-Azad, F.; Mohammadzadeh, I.; Ghaffari, J.; Shafiei, A.; Kalantari, A.; Mansouri, M.; Mesdaghi, M.; Babaie, D.; Ahanchian, H.; Khoshkhui, M.; Soheili, H.; Eslamian, M.H.; Cheraghi, T.; Dabbaghzadeh, A.; Tavassoli, M.; Kalmarzi, R.N.; Mortazavi, S.H.; Kashef, S.; Esmaeilzadeh, H.; Tafaroji, J.; Khalili, A.; Zandieh, F.; Sadeghi-Shabestari, M.; Darougar, S.; Behmanesh, F.; Akbari, H.; Zandkarimi, M.; Abolnezhadian, F.; Fayezi, A.; Moghtaderi, M.; Ahmadiafshar, A.; Shakerian, B.; Sajedi, V.; Taghvaei, B.; Safari, M.; Heidarzadeh, M.; Ghalebaghi, B.; Fathi, S.M.; Darabi, B.; Bazregari, S.; Bazargan, N.; Fallahpour, M.; Khayatzadeh, A.; Javahertrash, N.; Bashardoust, B.; Zamani, M.; Mohsenzadeh, A.; Ebrahimi, S.; Sharafian, S.; Vosughimotlagh, A.; Tafakoridelbari, M.; Rahimi, M.; Ashournia, P.; Razaghian, A.; Rezaei, A.; Mamishi, S.; Parvaneh, N.; Rezaei, N.; Hammarström, L.; Aghamohammadi, A. Fourth update on the iranian national registry of primary immunodeficiencies: integration of molecular diagnosis. J. Clin. Immunol., 2018, 38(7), 816-832.
[http://dx.doi.org/10.1007/s10875-018-0556-1] [PMID: 30302726]
[15]
Azizi, G.; Mirshafiey, A.; Abolhassani, H.; Yazdani, R.; Ghanavatinejad, A.; Noorbakhsh, F.; Rezaei, N.; Aghamohammadi, A. The imbalance of circulating T helper subsets and regulatory T cells in patients with LRBA deficiency: Correlation with disease severity. J. Cell. Physiol., 2018, 233(11), 8767-8777.
[http://dx.doi.org/10.1002/jcp.26772] [PMID: 29806698]
[16]
Gámez-Díaz, L.; August, D.; Stepensky, P.; Revel-Vilk, S.; Seidel, M.G.; Noriko, M.; Morio, T.; Worth, A.J.J.; Blessing, J.; Van de Veerdonk, F.; Feuchtinger, T.; Kanariou, M.; Schmitt-Graeff, A.; Jung, S.; Seneviratne, S.; Burns, S.; Belohradsky, B.H.; Rezaei, N.; Bakhtiar, S.; Speckmann, C.; Jordan, M.; Grimbacher, B. The extended phenotype of LPS-responsive beige-like anchor protein (LRBA) deficiency. J. Allergy Clin. Immunol., 2016, 137(1), 223-230.
[http://dx.doi.org/10.1016/j.jaci.2015.09.025] [PMID: 26768763]
[17]
Bateman, E.A.; Ayers, L.; Sadler, R.; Lucas, M.; Roberts, C.; Woods, A.; Packwood, K.; Burden, J.; Harrison, D.; Kaenzig, N.; Lee, M.; Chapel, H.M.; Ferry, B.L. T cell phenotypes in patients with common variable immunodeficiency disorders: Associations with clinical phenotypes in comparison with other groups with recurrent infections. Clin. Exp. Immunol., 2012, 170(2), 202-211.
[http://dx.doi.org/10.1111/j.1365-2249.2012.04643.x] [PMID: 23039891]
[18]
Azizi, G.; Mirshafiey, A.; Abolhassani, H.; Yazdani, R.; Jafarnezhad-Ansariha, F.; Shaghaghi, M.; Mortazavi-Jahromi, S.S.; Noorbakhsh, F.; Rezaei, N.; Aghamohammadi, A. Circulating helper T-cell subsets and regulatory T cells in patients with common variable immunodeficiency without known monogenic disease. J. Investig. Allergol. Clin. Immunol., 2018, 28(3), 172-181.
[http://dx.doi.org/10.18176/jiaci.0231] [PMID: 29345621]
[19]
Wang, J.; Lockey, R.; Haley, J. Lipopolysaccharide-Responsive Beige-like Anchor (LRBA), a novel regulator of human immune disorders. Austin J Clin Immunol., 2014, 1, 9.
[20]
Martínez Jaramillo, C.; Trujillo-Vargas, C.M. LRBA in the endomembrane system. Colomb. Med. (Cali), 2018, 49(3), 236-243.
[PMID: 30410199]

© 2022 Bentham Science Publishers | Privacy Policy