Analysis of B cell proliferation in response to in vitro stimulation in patients with CVID
Main Article Content
Keywords
B cells proliferation, CVID, T-dependent response, T-independent response
Abstract
Background: Common variable immunodeficiency (CVID) is a heterogeneous disorder characterized by defective antibody production and impaired differentiation of B cells. B cell proliferation is an essential step for antibody synthesis. Depending on the nature of the stimulus, their response may be either T-cell-dependent or T-cell-independent.
Methods: We studied 23 CVID patients and 14 healthy donors (HD). The patients were categorized based on their percentage of memory B cells. In addition to standard immunophenotyping of circulating human B and T cell subsets, an in vitro CFSE dilution assay was used to assess the proliferative capacity of B cells and to compare the activation of the T cell-dependent and T cell-independent response among the patients.
Results: Patients with a reduction in memory B cells exhibited an increase in follicular T cells (Tfh) and showed low proliferation in response to PKW, CpG, and SAC stimuli (Condition II) (p= 0.0073). In contrast, patients with a normal percentage of memory B cells showed a high expression of IL-21R and low proliferation in response to CPG (Condition III); IL-21, CD40L, and anti-IgM (Condition IV) stimuli (p= 0.0163 and p = 0.0475, respectively).
Conclusion: Defective proliferation in patients depends on the type of stimulus used and the phenotypic characteristics of the patients. Further studies are necessary to understand the disease mechanisms, which may guide us toward identifying genetic defects associated with CVID.
References
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27. Ueno H. Human circulating T follicular helper cell subsets in health and disease. J Clin Immunol. 2016; 36:34–9. 10.1080/25785826.2020.1776079
28. Yesillik S, Agrawal S, Gollapudi S V., Gupta S. Phenotypic analysis of CD4+ Treg, CD8+ Treg, and Breg cells in adult common variable immunodeficiency patients. Int Arch Allergy Immunol. 2019; 180(2):150–8. 10.1159/000501457
29. Good KL, Bryant VL, Tangye SG. Kinetics of human B cell behavior and amplification of proliferative responses following stimulation with IL-21. J Immunol. 2006; 177(8):5236–47. 10.4049/jimmunol.177.8.5236
30. Clemente A, Pons J, Matamoros N, Iglesias J, Ferrer JM. B cells from common variable immunodeficiency patients fail to differentiate to antibody secreting cells in response to TLR9 ligand (CpG-ODN) or anti-CD40+IL21. Cell Immunol. 2011; 268(1):9–15. 10.1016/j.cellimm.2011.01.004
31. Cunningham-Rundles C, Radigan L, Knight AK, Zhang L, Bauer L, Nakazawa A. TLR9 activation is defective in common variable immune deficiency. J Immunol. 2006; 176(3):1978–87. 10.4049/jimmunol.176.3.1978
2. Wiesik-Szewczyk E, Jahnz-Rózyk K. From infections to autoimmunity: Diagnostic challenges in common variable immunodeficiency. World J Clin Cases. 2020; 8(18):3942–55. 10.12998/wjcc.v8.i18.3942
3. Ebbo M, Gérard L, Carpentier S, Vély F, Cypowyj S, Farnarier C, et al. Low circulating natural killer cell counts are associated with severe disease in patients with common variable immunodeficiency. EBioMedicine. 2016; 6:222–30. 10.1016/j.ebiom.2016.02.025
4. Giovannetti A, Pierdominici M, Mazzetta F, Marziali M, Renzi C, Mileo AM, et al. Unravelling the complexity of T cell abnormalities in common variable immunodeficiency. J Immunol. 2007; 178(6):3932–43. 10.4049/jimmunol.178.6.3932
5. Turpin D, Furudoi A, Parrens M, Blanco P, Viallard JF, Duluc D. Increase of follicular helper T cells skewed toward a Th1 profile in CVID patients with non-infectious clinical complications. Clin Immunol. 2018; 197:130–8. 10.1016/j.clim.2018.09.006
6. Unger S, Seidl M, van Schouwenburg P, Rakhmanov M, Bulashevska A, Frede N, et al. The TH1 phenotype of follicular helper T cells indicates an IFN-γ–associated immune dysregulation in patients with CD21low common variable immunodeficiency. J Allergy Clin Immunol. 2018; 141(2):730–40. 10.1016/j.jaci.2017.04.041
7. Bonilla FA, Barlan I, Chapel H, Costa-Carvalho BT, Cunningham-Rundles C, de la Morena MT, et al. International Consensus Document (ICON): common variable immunodeficiency disorders. J Allergy and Clin Immunol Pract. 2016; 4(1):38–59. 10.1016/j.jaip.2015.07.025
8. Mokhtari M, Shakeri A, Mirminachi B, Abolhassani H, Yazdani R, Grimbacher B, Aghamohammadi A. Important Factors Influencing Severity of Common Variable Immunodeficiency. Arch Iran Med. 2016;19(8):544–50.
9. Warnatz K, Denz A, Dräger R, Braun M, Groth C, Wolff-Vorbeck G, et al. Severe deficiency of switched memory B cells (CD27+IgM-IgD-) in subgroups of patients with common variable immunodeficiency: A new approach to classify a heterogeneous disease. Blood. 2002; 99(5):1544–51. 10.1182/blood.v99.5.1544
10. Wehr C, Kivioja T, Schmitt C, Ferry B, Witte T, Eren E, et al. The EUROclass trial: Defining subgroups in common variable immunodeficiency. Blood. 2008; 111(1):77–85. 10.1182/blood-2007-06-091744
11. Maffucci P, Filion CA, Boisson B, Itan Y, Shang L, Casanova JL, et al. Genetic diagnosis using whole exomesequencing in common variable immunodeficiency. Front Immunol. 2016; 7(Jun):1–9. 10.3389/fimmu.2016.00220
12. McHeyzer-Williams M, Okitsu S, Wang N, McHeyzer-Williams L. Molecular programming of B cell memory. Nat Rev Immunol. 2012; 12(1):24–34. 10.1038/nri3128
13. Ettinger R, Sims GP, Fairhurst AM, Robbins R, da Silva YS, Spolski R, et al. IL-21 Induces differentiation of human naive and memory b cells into antibody-secreting plasma cells. J Immunol. 2005; 175(12):7867–79. 10.4049/jimmunol.175.12.7867
14. Lanzavecchia A, Sallusto F. Human B cell memory. Curr Opin Immunol. 2009; 21(3):298–304. 10.1016/j.coi.2009.05.019
15. Fagarasan S, Honjo T. T-independent immune response: new aspects of B cell biology. Science. 2000; 290(5489):89–92. 10.1016/j.isci.2022.105002
16. Capolunghi F, Cascioli S, Giorda E, Rosado MM, Plebani A, Auriti C, et al. CpG drives human transitional B cells to terminal differentiation and production of natural antibodies. J Immunol. 2008;180(2):800–8. 10.4049/jimmunol.180.2.800
17. Ameratunga R, Allan C, Woon ST. Defining common variable immunodeficiency disorders in 2020 (Vol. 40). In Immunology and Allergy Clinics of North America. W.B. Saunders; 2020. p. 403–20.
18. Cunningham-Rundles C. Common variable immune deficiency: case studies. Hematology. 2019; 2019(1):449–56. 10.1182/hematology.2019002062
19. López-Herrera G, Segura-Méndez N, O’Farril-Romanillos P, Nuñez-Nuñez M, Zarate-Hernández M, Mogica-Martínez D, et al. Low percentages of regulatory T cells in common variable immunodeficiency ( CVID ) patients with autoimmune diseases and its association with increased numbers of CD4 + CD45RO + T and CD21 low B cells. Allergol Immunopathol. 2019; 47(5):457–66. 10.1016/j.aller.2019.01.003
20. Azizi G, Abolhassani H, Kiaee F, Tavakolinia N, Rafiemanesh H, Yazdani R, et al. Autoimmunity and its association with regulatory T cells and B cell subsets in patients with common variable immunodeficiency. Allergol Immunopathol. 2018; 46(2):127–35. 10.1016/j.aller.2017.04.004
21. Grześk E, Dąbrowska A, Urbańczyk A, Ewertowska M, Wysocki M, Kołtan S. Common variable immunodeficiency: different faces of the same disease. Postepy Dermatol Alergol. 2021; 38(5):873–80. 10.5114/ada.2021.110067
22. Warnatz K, Schlesier M. Flowcytometric phenotyping of common variable immunodeficiency. Cytometry B Clin Cytom. 2008; 74(5):261–71. 10.1002/cyto.b.20432
23. Fekrvand S, Khanmohammadi S, Abolhassani H, Yazdani R. B-and T-Cell Subset Abnormalities in Monogenic common variable immunodeficiency. Front Immunol. 2022; 13(June):1–16. 10.3389/fimmu.2022.912826
24. Azizi G, Rezaei N, Kiaee F, Tavakolinia N, Yazdani R, Mirshafiey A, et al. T-cell abnormalities in common variable immunodeficiency. J Investig Allergol Clin Immunol. 2016; 26(4):233–43. 10.18176/jiaci.0069
25. Więsik-Szewczyk E, Rutkowska E, Kwiecień I, Korzeniowska M, Sołdacki D, Jahnz-Różyk K. Patients with common variable immunodeficiency complicated by autoimmune phenomena have lymphopenia and reduced treg, Th17, and NK cells. J Clin Med. 2021; 10(15). 10.3390/jcm10153356
26. Yesillik S, Gupta S. Phenotypically defined subpopulations of circulating follicular helper T cells in common variable immunodeficiency. Immun Inflamm Dis. 2020; 8(3):441–6. 10.3389/fimmu.2017.00174
27. Ueno H. Human circulating T follicular helper cell subsets in health and disease. J Clin Immunol. 2016; 36:34–9. 10.1080/25785826.2020.1776079
28. Yesillik S, Agrawal S, Gollapudi S V., Gupta S. Phenotypic analysis of CD4+ Treg, CD8+ Treg, and Breg cells in adult common variable immunodeficiency patients. Int Arch Allergy Immunol. 2019; 180(2):150–8. 10.1159/000501457
29. Good KL, Bryant VL, Tangye SG. Kinetics of human B cell behavior and amplification of proliferative responses following stimulation with IL-21. J Immunol. 2006; 177(8):5236–47. 10.4049/jimmunol.177.8.5236
30. Clemente A, Pons J, Matamoros N, Iglesias J, Ferrer JM. B cells from common variable immunodeficiency patients fail to differentiate to antibody secreting cells in response to TLR9 ligand (CpG-ODN) or anti-CD40+IL21. Cell Immunol. 2011; 268(1):9–15. 10.1016/j.cellimm.2011.01.004
31. Cunningham-Rundles C, Radigan L, Knight AK, Zhang L, Bauer L, Nakazawa A. TLR9 activation is defective in common variable immune deficiency. J Immunol. 2006; 176(3):1978–87. 10.4049/jimmunol.176.3.1978
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Sep 1, 2024
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Velásquez-Ortiz, M. G. V.-O., Saldaña-Solano, A. J., O’Farrill-Romanillos, P., Herrera-Sánchez, D. A., Scheffer-Mendoza, S., Yamazaki-Nakashimada, M. A., Zarate-Hernández, M. C., Espinosa-Padilla, S. E., & Berrón-Ruiz, L. (2024). Analysis of B cell proliferation in response to in vitro stimulation in patients with CVID. Allergologia Et Immunopathologia, 52(5), 94-102. https://doi.org/10.15586/aei.v52i5.1106
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How to Cite
Velásquez-Ortiz, M. G. V.-O., Saldaña-Solano, A. J., O’Farrill-Romanillos, P., Herrera-Sánchez, D. A., Scheffer-Mendoza, S., Yamazaki-Nakashimada, M. A., Zarate-Hernández, M. C., Espinosa-Padilla, S. E., & Berrón-Ruiz, L. (2024). Analysis of B cell proliferation in response to in vitro stimulation in patients with CVID. Allergologia Et Immunopathologia, 52(5), 94-102. https://doi.org/10.15586/aei.v52i5.1106