Increased IRF4 expression in isolated B cells from common variable immunodeficiency (CVID) patients
Main Article Content
Keywords
Common variable immunodeficiency, IRF4, XBP1, Transcription factors, Plasma cells
Abstract
Background: Common variable immunodeficiency (CVID) is a heterogeneous disorder characterized by low serum levels of immunoglobulins (Igs) and recurrent infection. In most CVID patients, a defect in the differentiation of B cells into plasma cells has been observed. Several factors play an important role in the proliferation and differentiation of B cells, including IRF4 and XBP1 transcription factors.
Methods: In the present study we investigated the expression of IRF4 and XBP1 in the B-cells of CVID and healthy controls (HCs). For this purpose, we assessed the expression of IRF4 and XBP1 at both mRNA and protein levels by real-time-PCR and flow cytometry, respectively.
Results: We found that IRF4 expression was significantly increased in CVID patients compared with controls. Although the XBP1 protein level was lower in patients in comparison to controls, this difference was not significant.
Conclusion: Taken together, increased IRF4 expression could be involved in defective functions of B cells in CVID patients.
References
1. Cunningham-Rundles C. How I treat common variable immune deficiency. Blood. 2010;116:7-15.
2. Aghamohammadi A, Farhoudi A, Moin M, Rezaei N, Kouhi A, Pourpak Z, et al. Clinical and immunological features of 65 Iranian patients with common variable immunodeficiency. Clin Diagn Lab Immunol. 2005;12:825-32.
3. Mokhtari M, Shakeri A, Mirminachi B, Abolhassani H, Yazdani R, Grimbacher B, et al. Important factors influencing severity of common variable immunodeficiency. Arch Iran Med. 2016;19:544-50.
4. Azizi G, Abolhassani H, Asgardoon MH, Alinia T, Yazdani R, Mohammadi J, et al. Autoimmunity in common variable immunodeficiency: epidemiology, pathophysiology and management. Expert Rev Clin Immunol. 2017;13:101-15.
5. Yazdani R, Heydari A, Azizi G, Abolhassani H, Aghamohammadi A. Asthma and allergic diseases in a selected group of patients with common variable immunodeficiency. J Investig Allergol Clin Immunol. 2016;26:209-11.
6. Cunningham-Rundles C. Human B cell defects in perspective. Immunol Res. 2012;54(1-3):227-32.
7. Yazdani R, Ganjalikhani-Hakemi M, Esmaeili M, Abolhassani H, Vaeli S, Rezaei A, et al. Impaired Akt phosphorylation in B cells of patients with common variable immunodeficiency. Clin Immunol. 2017;175:124-32.
8. Azizi G, Abolhassani H, Rezaei N, Aghamohammadi A, Asgardoon MH, Rahnavard J, et al. The use of immunoglobulin therapy in primary immunodeficiency diseases. Endocr Metab Immune Disord Drug Targets. 2016.
9. 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: 233-43.
10. Ansari M, Yazdani R, Sherkat R, Homayouni V, Hakemi MG, Rezaei A. Decreased expression of B cell maturation antigen in patients with common variable immunodeficiency. Pediatr Allergy Immunol Pulmonol. 2017;30:7-13.
11. Azizi G, Hafezi N, Mohammadi H, Yazdani R, Alinia T, Tavakol M, et al. Abnormality of regulatory T cells in common variable immunodeficiency. Cell Immunol. 2017;315:11-7.
12. Berron-Ruiz L, Lopez-Herrera G, Vargas-Hernandez A, MogicaMartinez D, Garcia-Latorre E, Blancas-Galicia L, et al. Lymphocytes and B-cell abnormalities in patients with common variable immunodeficiency (CVID). Allergol Immunopathol (Madr). 2014;42:35-43.
13. Yazdani R, Seify R, Ganjalikhani-Hakemi M, Abolhassani H, Eskandari N, Golsaz-Shirazi F, et al. Comparison of various classifications for patients with common variable immunodeficiency (CVID) using measurement of B-cell subsets. Allergol Immunopathol (Madr). 2017;45:183-92.
14. Yazdani R, Fatholahi M, Ganjalikhani-Hakemi M, Abolhassani H, Azizi G, Hamid KM, et al. Role of apoptosis in common variable immunodeficiency and selective immunoglobulin A deficiency. Mol Immunol. 2016;71:1-9.
15. Klein U, Dalla-Favera R. Germinal centres: role in B-cell physiology and malignancy. Nat Rev Immunol. 2008;8:22-33.
16. Shapiro-Shelef M, Calame K. Regulation of plasma-cell development. Nat Rev Immunol. 2005;5:230-42.
17. del Pozo N, Lopez-Mejias R, Fernandez-Arquero M, Ferreira A, Garcia-Rodriguez MC, de la Concha EG, et al. Lack of evidence of a role of XBP1 and PRDM1 polymorphisms in Spanish patients with immunoglobulin A deficiency. Hum Immunol. 2009;70:950-2.
18. Taubenheim N, Tarlinton DM, Crawford S, Corcoran LM, Hodgkin PD, Nutt SL. High rate of antibody secretion is not integral to plasma cell differentiation as revealed by XBP-1 deficiency. J Immunol. 2012;189:3328-38.
19. Jackson DA, Elsawa SF. Factors regulating immunoglobulin production by normal and disease-associated plasma cells. Biomolecules. 2015;5:20-40.
20. Reimold AM, Iwakoshi NN, Manis J, Vallabhajosyula P, Szomolanyi-Tsuda E, Gravallese EM, et al. Plasma cell differentiation requires the transcription factor XBP-1. Nature. 2001;412:300-7.
21. Unger S, Seidl M, Schmitt-Graeff A, Böhm J, Schrenk K, Wehr C, et al. Ill-defined germinal centers and severely reduced plasma cells are histological hallmarks of lymphadenopathy in patients with common variable immunodeficiency. J Clin Immunol. 2014;34:615-26.
22. Lehtonen A, Veckman V, Nikula T, Lahesmaa R, Kinnunen L, Matikainen S, et al. Differential expression of IFN regulatory factor 4 gene in human monocyte-derived dendritic cells and macrophages. J Immunol. 2005;175:6570-9.
23. Chevrier S, Emslie D, Shi W, Kratina T, Wellard C, Karnowski A, et al. The BTB-ZF transcription factor Zbtb20 is driven by Irf4 to promote plasma cell differentiation and longevity. J Exp Med. 2014;211:827-40.
24. Corcoran LM, Tarlinton DM. Regulation of germinal center responses, memory B cells and plasma cell formation-an update. Curr Opin Immunol. 2016;39:59-67.
25. Klein U. Programming plasma cell survival. J Exp Med. 2014;211(744.10):1084.
26. Kaku H, Rothstein TL. Fas apoptosis inhibitory molecule enhances CD40 signaling in B cells and augments the plasma cell compartment. J Immunol. 2009;183:1667-74.
27. Eklund EA, Jalava A, Kakar R. PU.1, interferon regulatory factor 1, and interferon consensus sequence-binding protein cooperate to increase gp91 phox expression. J Biol Chem. 1998;273:13957-65.
28. Gupta S, Jiang M, Anthony A, Pernis AB. Lineage-specific modulation of interleukin 4 signaling by interferon regulatory factor 4. J Exp Med. 1999;190:1837-48.
29. Hu C-M, Jang SY, Fanzo JC, Pernis AB. Modulation of T cell cytokine production by interferon regulatory factor-4. J Biol Chem. 2002;277:49238-46.
30. Rengarajan J, Mowen KA, McBride KD, Smith ED, Singh H, Glimcher LH. Interferon regulatory factor 4 (IRF4) interacts with NFATc2 to modulate interleukin 4 gene expression. J Exp Med. 2002;195:1003-12.
31. Sciammas R, Li Y, Warmflash A, Song Y, Dinner AR, Singh H. An incoherent regulatory network architecture that orchestrates B cell diversification in response to antigen signaling. Mol Syst Biol. 2011;7:495.
32. Indrevær RL, Moskaug JØ, Paur I, Bøhn SK, Jørgensen SF, Blomhoff R, et al. IRF4 is a critical gene in retinoic acid-mediated plasma cell formation and is deregulated in common variable immunodeficiency-derived B cells. J Immunol. 2015;195:2601-11.
33. Jiang X-X, Chou Y, Jones L, Wang T, Sanchez S, Huang XF, et al. Epigenetic regulation of antibody responses by the histone H2A deubiquitinase MYSM1. Sci Rep. 2015;5:13755.
34. Shen T, Sanchez HN, Zan H, Casali P. Genome-wide analysis reveals selective modulation of microRNAs and mRNAs by histone deacetylase inhibitor in B cells induced to undergo class-switch DNA recombination and plasma cell differentiation. Front Immunol. 2015;6:627.
35. Wang L, Yao ZQ, Moorman JP, Xu Y, Ning S. Gene expression profiling identifies IRF4-associated molecular signatures in hematological malignancies. PLOS ONE. 2014; 9:e106788.
36. Shukla V, Ma S, Hardy RR, Joshi SS, Lu R. A role for IRF4 in the development of CLL. Blood. 2013;122:2848-55.
37. Lech M, Weidenbusch M, Kulkarni OP, Ryu M, Darisipudi MN, Susanti HE, et al. IRF4 deficiency abrogates lupus nephritis despite enhancing systemic cytokine production. JASN. 2011;22:1443-52.
38. Xu W-D, Pan H-F, Ye D-Q, Xu Y. Targeting IRF4 in autoimmune diseases. Autoimmun Rev. 2012;11:918-24.
39. Tak Manesh A, Azizi G, Heydari A, Kiaee F, Shaghaghi M, Hossein-Khannazer N, et al. Epidemiology and pathophysiology of malignancy in common variable immunodeficiency? Allergol Immunopathol (Madr). 2017.
2. Aghamohammadi A, Farhoudi A, Moin M, Rezaei N, Kouhi A, Pourpak Z, et al. Clinical and immunological features of 65 Iranian patients with common variable immunodeficiency. Clin Diagn Lab Immunol. 2005;12:825-32.
3. Mokhtari M, Shakeri A, Mirminachi B, Abolhassani H, Yazdani R, Grimbacher B, et al. Important factors influencing severity of common variable immunodeficiency. Arch Iran Med. 2016;19:544-50.
4. Azizi G, Abolhassani H, Asgardoon MH, Alinia T, Yazdani R, Mohammadi J, et al. Autoimmunity in common variable immunodeficiency: epidemiology, pathophysiology and management. Expert Rev Clin Immunol. 2017;13:101-15.
5. Yazdani R, Heydari A, Azizi G, Abolhassani H, Aghamohammadi A. Asthma and allergic diseases in a selected group of patients with common variable immunodeficiency. J Investig Allergol Clin Immunol. 2016;26:209-11.
6. Cunningham-Rundles C. Human B cell defects in perspective. Immunol Res. 2012;54(1-3):227-32.
7. Yazdani R, Ganjalikhani-Hakemi M, Esmaeili M, Abolhassani H, Vaeli S, Rezaei A, et al. Impaired Akt phosphorylation in B cells of patients with common variable immunodeficiency. Clin Immunol. 2017;175:124-32.
8. Azizi G, Abolhassani H, Rezaei N, Aghamohammadi A, Asgardoon MH, Rahnavard J, et al. The use of immunoglobulin therapy in primary immunodeficiency diseases. Endocr Metab Immune Disord Drug Targets. 2016.
9. 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: 233-43.
10. Ansari M, Yazdani R, Sherkat R, Homayouni V, Hakemi MG, Rezaei A. Decreased expression of B cell maturation antigen in patients with common variable immunodeficiency. Pediatr Allergy Immunol Pulmonol. 2017;30:7-13.
11. Azizi G, Hafezi N, Mohammadi H, Yazdani R, Alinia T, Tavakol M, et al. Abnormality of regulatory T cells in common variable immunodeficiency. Cell Immunol. 2017;315:11-7.
12. Berron-Ruiz L, Lopez-Herrera G, Vargas-Hernandez A, MogicaMartinez D, Garcia-Latorre E, Blancas-Galicia L, et al. Lymphocytes and B-cell abnormalities in patients with common variable immunodeficiency (CVID). Allergol Immunopathol (Madr). 2014;42:35-43.
13. Yazdani R, Seify R, Ganjalikhani-Hakemi M, Abolhassani H, Eskandari N, Golsaz-Shirazi F, et al. Comparison of various classifications for patients with common variable immunodeficiency (CVID) using measurement of B-cell subsets. Allergol Immunopathol (Madr). 2017;45:183-92.
14. Yazdani R, Fatholahi M, Ganjalikhani-Hakemi M, Abolhassani H, Azizi G, Hamid KM, et al. Role of apoptosis in common variable immunodeficiency and selective immunoglobulin A deficiency. Mol Immunol. 2016;71:1-9.
15. Klein U, Dalla-Favera R. Germinal centres: role in B-cell physiology and malignancy. Nat Rev Immunol. 2008;8:22-33.
16. Shapiro-Shelef M, Calame K. Regulation of plasma-cell development. Nat Rev Immunol. 2005;5:230-42.
17. del Pozo N, Lopez-Mejias R, Fernandez-Arquero M, Ferreira A, Garcia-Rodriguez MC, de la Concha EG, et al. Lack of evidence of a role of XBP1 and PRDM1 polymorphisms in Spanish patients with immunoglobulin A deficiency. Hum Immunol. 2009;70:950-2.
18. Taubenheim N, Tarlinton DM, Crawford S, Corcoran LM, Hodgkin PD, Nutt SL. High rate of antibody secretion is not integral to plasma cell differentiation as revealed by XBP-1 deficiency. J Immunol. 2012;189:3328-38.
19. Jackson DA, Elsawa SF. Factors regulating immunoglobulin production by normal and disease-associated plasma cells. Biomolecules. 2015;5:20-40.
20. Reimold AM, Iwakoshi NN, Manis J, Vallabhajosyula P, Szomolanyi-Tsuda E, Gravallese EM, et al. Plasma cell differentiation requires the transcription factor XBP-1. Nature. 2001;412:300-7.
21. Unger S, Seidl M, Schmitt-Graeff A, Böhm J, Schrenk K, Wehr C, et al. Ill-defined germinal centers and severely reduced plasma cells are histological hallmarks of lymphadenopathy in patients with common variable immunodeficiency. J Clin Immunol. 2014;34:615-26.
22. Lehtonen A, Veckman V, Nikula T, Lahesmaa R, Kinnunen L, Matikainen S, et al. Differential expression of IFN regulatory factor 4 gene in human monocyte-derived dendritic cells and macrophages. J Immunol. 2005;175:6570-9.
23. Chevrier S, Emslie D, Shi W, Kratina T, Wellard C, Karnowski A, et al. The BTB-ZF transcription factor Zbtb20 is driven by Irf4 to promote plasma cell differentiation and longevity. J Exp Med. 2014;211:827-40.
24. Corcoran LM, Tarlinton DM. Regulation of germinal center responses, memory B cells and plasma cell formation-an update. Curr Opin Immunol. 2016;39:59-67.
25. Klein U. Programming plasma cell survival. J Exp Med. 2014;211(744.10):1084.
26. Kaku H, Rothstein TL. Fas apoptosis inhibitory molecule enhances CD40 signaling in B cells and augments the plasma cell compartment. J Immunol. 2009;183:1667-74.
27. Eklund EA, Jalava A, Kakar R. PU.1, interferon regulatory factor 1, and interferon consensus sequence-binding protein cooperate to increase gp91 phox expression. J Biol Chem. 1998;273:13957-65.
28. Gupta S, Jiang M, Anthony A, Pernis AB. Lineage-specific modulation of interleukin 4 signaling by interferon regulatory factor 4. J Exp Med. 1999;190:1837-48.
29. Hu C-M, Jang SY, Fanzo JC, Pernis AB. Modulation of T cell cytokine production by interferon regulatory factor-4. J Biol Chem. 2002;277:49238-46.
30. Rengarajan J, Mowen KA, McBride KD, Smith ED, Singh H, Glimcher LH. Interferon regulatory factor 4 (IRF4) interacts with NFATc2 to modulate interleukin 4 gene expression. J Exp Med. 2002;195:1003-12.
31. Sciammas R, Li Y, Warmflash A, Song Y, Dinner AR, Singh H. An incoherent regulatory network architecture that orchestrates B cell diversification in response to antigen signaling. Mol Syst Biol. 2011;7:495.
32. Indrevær RL, Moskaug JØ, Paur I, Bøhn SK, Jørgensen SF, Blomhoff R, et al. IRF4 is a critical gene in retinoic acid-mediated plasma cell formation and is deregulated in common variable immunodeficiency-derived B cells. J Immunol. 2015;195:2601-11.
33. Jiang X-X, Chou Y, Jones L, Wang T, Sanchez S, Huang XF, et al. Epigenetic regulation of antibody responses by the histone H2A deubiquitinase MYSM1. Sci Rep. 2015;5:13755.
34. Shen T, Sanchez HN, Zan H, Casali P. Genome-wide analysis reveals selective modulation of microRNAs and mRNAs by histone deacetylase inhibitor in B cells induced to undergo class-switch DNA recombination and plasma cell differentiation. Front Immunol. 2015;6:627.
35. Wang L, Yao ZQ, Moorman JP, Xu Y, Ning S. Gene expression profiling identifies IRF4-associated molecular signatures in hematological malignancies. PLOS ONE. 2014; 9:e106788.
36. Shukla V, Ma S, Hardy RR, Joshi SS, Lu R. A role for IRF4 in the development of CLL. Blood. 2013;122:2848-55.
37. Lech M, Weidenbusch M, Kulkarni OP, Ryu M, Darisipudi MN, Susanti HE, et al. IRF4 deficiency abrogates lupus nephritis despite enhancing systemic cytokine production. JASN. 2011;22:1443-52.
38. Xu W-D, Pan H-F, Ye D-Q, Xu Y. Targeting IRF4 in autoimmune diseases. Autoimmun Rev. 2012;11:918-24.
39. Tak Manesh A, Azizi G, Heydari A, Kiaee F, Shaghaghi M, Hossein-Khannazer N, et al. Epidemiology and pathophysiology of malignancy in common variable immunodeficiency? Allergol Immunopathol (Madr). 2017.
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Feb 15, 2019
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Afshar-Ghasemlou, S., Esmaeil, N., Sherkat, R., Yazdani, R., Abbasi-Rad, F., Ganjalikhani-Hakemi, M., & Rezaei, A. (2019). Increased IRF4 expression in isolated B cells from common variable immunodeficiency (CVID) patients. Allergologia Et Immunopathologia, 47(1), 52-59. https://all-imm.com/index.php/aei/article/view/344
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Afshar-Ghasemlou, S., Esmaeil, N., Sherkat, R., Yazdani, R., Abbasi-Rad, F., Ganjalikhani-Hakemi, M., & Rezaei, A. (2019). Increased IRF4 expression in isolated B cells from common variable immunodeficiency (CVID) patients. Allergologia Et Immunopathologia, 47(1), 52-59. https://all-imm.com/index.php/aei/article/view/344