Increased Expression of B Lymphocyte Induced Maturation Protein 1 (BLIMP1) in Patients with Common Variable Immunodeficiency (CVID)
-
Shockrollah Farrokhi
,
Faezeh Abbasi-rad
,
Nafiseh Esmaeil
,
Roya Sherkat
,
Reza Yazdani
,
Sanaz Afshar-Ghasemlou
,
Saba Fekrvand
,
Mazdak Ganjalikhani-Hakemi
Abstract
Common variable immunodeficiency (CVID) is a primary immune deficiency disorder characterized by a failure in B cell differentiation, impaired immunoglobulin production,and defect in response to vaccines. As a result of defective B cell maturation and differentiation in CVID, the affected patients commonly present with reduced numbers of memory B cell and antibody-secreting plasma cells. B-cell lymphoma 6 protein (BCL6) and B lymphocyte induced maturation protein 1 (BLIMP1) molecules are two important transcription factors that have key roles in the maturation of B cells to plasma cells. Hence, in the current survey, we aimed to evaluate the mRNA and protein expression levels of BCL6 and BLIMP1 in B lymphocytes isolated from peripheral blood in CVID patients.
We collected blood samples from 12 CVID patients and 12 healthy controls. We isolated peripheral blood mononuclear cells (PBMCs) using Ficoll density gradient separation. Then, CD19+ B cells were purified using MACS. The protein expression and transcriptional level of BCL6 and BLIMP1 were respectively measured using flow cytometry and real-time PCR.
Our results showed that the BLIMP1 mRNA expression, as well as BLIMP1 protein expression, were significantly higher in CVID patients compared to control subjects (p=0.009 and p=0.007, respectively). However, we found no significant difference in mRNA and protein expression of BCL6 between patients and healthy controls.
According to our findings, increased mRNA and protein expression levels of BLIMP1 could be involved in defective maturation of B cells in patients with CVID and elucidate mechanistic insights into the pathogenesis of this disorder.
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2. Hammarström L, Vorechovsky I, Webster D. Selective IgA deficiency (SIgAD) and common variable immunodeficiency (CVID). Clin Exp Immunol. 2000;120(2):225-31.
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6. 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 Immunopath. 2017;45(6):602-15.
7. 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(3):209-11.
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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(4):233-43.
10. 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.
11. 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 Immunopath. 2017;45(2):183-92.
12. Yazdani R, Ganjalikhani-Hakemi M, Esmaeili M, et al. Impaired Akt phosphorylation in B-cells of patients with common variable immunodeficiency. Clin Immunol. 2017;175:124-32.
13. Sharifi L, Tavakolinia N, Kiaee F, Rezaei N, Mohsenzadegan M, Azizi G, et al. A Review on Defects of Dendritic Cells in Common Variable Immunodeficiency. ENDOCR METAB IMMUNE. 2017;17(2):100-13.
14. Tam JS, Routes JM. Common variable immunodeficiency. Am J RhinolAllergy. 2013;27(4):260.
15. Warnatz K, Schlesier M. Flowcytometric phenotyping of common variable immunodeficiency. Cytometry B Clin Cytom. 2008;74(5):261-71.
16. Taubenheim N, von Hornung M, Durandy A, Warnatz K, Corcoran L, Peter H-H, et al. Defined blocks in terminal plasma cell differentiation of common variable immunodeficiency patients. J Immunol. 2005;175(8):5498-503.
17. Nutt SL, Taubenheim N, Hasbold J, Corcoran LM, Hodgkin PD, editors. The genetic network controlling plasma cell differentiation. Semin Immunol. 2011;23(5):341-9.
18. Kuo TC, Shaffer AL, Haddad J, Choi YS, Staudt LM, Calame K. Repression of BCL-6 is required for the formation of human memory B cells in vitro. J Exp Med. 2007;204(4):819-30.
19. Phan RT, Dalla-Favera R. The BCL6 proto-oncogene suppresses p53 expression in germinal-centre B cells. Nature. 2004;432(7017):635-9.
20. Nurieva RI, Chung Y, Martinez GJ, Yang XO, Tanaka S, Matskevitch TD, et al. Bcl6 mediates the development of T follicular helper cells. Science. 2009;325(5943):1001-5.
21. Crotty S, Johnston RJ, Schoenberger SP. Effectors and memories: Bcl-6 and Blimp-1 in T and B lymphocyte differentiation. Nat Immunol. 2010;11(2):114.
22. Shapiro-Shelef M, Lin K-I, McHeyzer-Williams LJ, Liao J, McHeyzer-Williams MG, Calame K. Blimp-1 is required for the formation of immunoglobulin secreting plasma cells and pre-plasma memory B cells. Immunity. 2003;19(4):607-20.
23. Tsuji S, Cortesão C, Bram RJ, Platt JL, Cascalho M. TACI deficiency impairs sustained Blimp-1 expression in B cells decreasing long-lived plasma cells in the bone marrow. Blood. 2011;118(22):5832-9.
24. Kallies A, Hasbold J, Tarlinton DM, Dietrich W, Corcoran LM, Hodgkin PD, et al. Plasma cell ontogeny defined by quantitative changes in blimp-1 expression. J Exp Med. 2004;200(8):967-77.
25. Turner CA, Mack DH, Davis MM. Blimp-1, a novel zinc finger-containing protein that can drive the maturation of B lymphocytes into immunoglobulin-secreting cells. Cell. 1994;77(2):297-306.
26. Seidel MG, Kindle G, Gathmann B, Quinti I, Buckland M, van Montfrans J, et al. The European Society for Immunodeficiencies (ESID) Registry Working Definitions for the Clinical Diagnosis of Inborn Errors of Immunity. J Allergy CIin Immunol Pract. 2019;7(6):1763-70.
27. Reichert T, DeBruyère M, Deneys V, Tötterman T, Lydyard P, Yuksel F, et al. Lymphocyte subset reference ranges in adult Caucasians. Clin Immunol Immunopathol. 1991;60(2):190-208.
28. Jacquot S, Maçon-Lemaître L, Paris E, Kobata T, Tanaka Y, Morimoto C, et al. B cell co-receptors regulating T cell-dependent antibody production in common variable immunodeficiency: CD27 pathway defects identify subsets of severely immuno-compromised patients. Int Immunol. 2001;13(7):871-6.
29. Martins G, Calame K. Regulation and functions of Blimp-1 in T and B lymphocytes. Annu Rev Immunol. 2008;26:133-69.
30. Ansari M, Yazdani R, Sherkat R, Homayouni V, Ganjalikhani-Hakemi M, Rezaei A. Decreased Expression of B cell Maturation Antigen in Patients with Common Variable Immunodeficiency. Pediat Aller Imm Pul. 2017;30:7-13.
31. Afshar-Ghasemlou S, Esmaeil N, Sherkat R, Yazdani R, Abbasi-Rad F, Ganjalikhani hakemi M, et al. Increased IRF4 expression in isolated B cells from Common variable immunodeficiency (CVID) patients. Allergol Immunopath. 2019;47(1):52-9.
32. 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(6844):300.
33. 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(6):615-26.
34. Nutt SL, Fairfax KA, Kallies A. BLIMP1 guides the fate of effector B and T cells. Nat Rev Immunol. 2007;7(12):923-7.
2. Hammarström L, Vorechovsky I, Webster D. Selective IgA deficiency (SIgAD) and common variable immunodeficiency (CVID). Clin Exp Immunol. 2000;120(2):225-31.
3. Chapel H, Lucas M, Lee M, Bjorkander J, Webster D, Grimbacher B, et al. Common variable immunodeficiency disorders: division into distinct clinical phenotypes. Blood. 2008;112(2):277-86.
4. 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.
5. Cunningham-Rundles C, Bodian C. Common variable immunodeficiency: clinical and immunological features of 248 patients. Clin Immunol. 1999;92(1):34-48.
6. 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 Immunopath. 2017;45(6):602-15.
7. 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(3):209-11.
8. Azizi G, Abolhassani H, Asgardoon MH, Rahnavard J, Dizaji MZ, Yazdani R, et al. The use of Immunoglobulin Therapy in Primary Immunodeficiency Diseases. Endocr MetabImmune. 2016;16(2):80-8.
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(4):233-43.
10. 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.
11. 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 Immunopath. 2017;45(2):183-92.
12. Yazdani R, Ganjalikhani-Hakemi M, Esmaeili M, et al. Impaired Akt phosphorylation in B-cells of patients with common variable immunodeficiency. Clin Immunol. 2017;175:124-32.
13. Sharifi L, Tavakolinia N, Kiaee F, Rezaei N, Mohsenzadegan M, Azizi G, et al. A Review on Defects of Dendritic Cells in Common Variable Immunodeficiency. ENDOCR METAB IMMUNE. 2017;17(2):100-13.
14. Tam JS, Routes JM. Common variable immunodeficiency. Am J RhinolAllergy. 2013;27(4):260.
15. Warnatz K, Schlesier M. Flowcytometric phenotyping of common variable immunodeficiency. Cytometry B Clin Cytom. 2008;74(5):261-71.
16. Taubenheim N, von Hornung M, Durandy A, Warnatz K, Corcoran L, Peter H-H, et al. Defined blocks in terminal plasma cell differentiation of common variable immunodeficiency patients. J Immunol. 2005;175(8):5498-503.
17. Nutt SL, Taubenheim N, Hasbold J, Corcoran LM, Hodgkin PD, editors. The genetic network controlling plasma cell differentiation. Semin Immunol. 2011;23(5):341-9.
18. Kuo TC, Shaffer AL, Haddad J, Choi YS, Staudt LM, Calame K. Repression of BCL-6 is required for the formation of human memory B cells in vitro. J Exp Med. 2007;204(4):819-30.
19. Phan RT, Dalla-Favera R. The BCL6 proto-oncogene suppresses p53 expression in germinal-centre B cells. Nature. 2004;432(7017):635-9.
20. Nurieva RI, Chung Y, Martinez GJ, Yang XO, Tanaka S, Matskevitch TD, et al. Bcl6 mediates the development of T follicular helper cells. Science. 2009;325(5943):1001-5.
21. Crotty S, Johnston RJ, Schoenberger SP. Effectors and memories: Bcl-6 and Blimp-1 in T and B lymphocyte differentiation. Nat Immunol. 2010;11(2):114.
22. Shapiro-Shelef M, Lin K-I, McHeyzer-Williams LJ, Liao J, McHeyzer-Williams MG, Calame K. Blimp-1 is required for the formation of immunoglobulin secreting plasma cells and pre-plasma memory B cells. Immunity. 2003;19(4):607-20.
23. Tsuji S, Cortesão C, Bram RJ, Platt JL, Cascalho M. TACI deficiency impairs sustained Blimp-1 expression in B cells decreasing long-lived plasma cells in the bone marrow. Blood. 2011;118(22):5832-9.
24. Kallies A, Hasbold J, Tarlinton DM, Dietrich W, Corcoran LM, Hodgkin PD, et al. Plasma cell ontogeny defined by quantitative changes in blimp-1 expression. J Exp Med. 2004;200(8):967-77.
25. Turner CA, Mack DH, Davis MM. Blimp-1, a novel zinc finger-containing protein that can drive the maturation of B lymphocytes into immunoglobulin-secreting cells. Cell. 1994;77(2):297-306.
26. Seidel MG, Kindle G, Gathmann B, Quinti I, Buckland M, van Montfrans J, et al. The European Society for Immunodeficiencies (ESID) Registry Working Definitions for the Clinical Diagnosis of Inborn Errors of Immunity. J Allergy CIin Immunol Pract. 2019;7(6):1763-70.
27. Reichert T, DeBruyère M, Deneys V, Tötterman T, Lydyard P, Yuksel F, et al. Lymphocyte subset reference ranges in adult Caucasians. Clin Immunol Immunopathol. 1991;60(2):190-208.
28. Jacquot S, Maçon-Lemaître L, Paris E, Kobata T, Tanaka Y, Morimoto C, et al. B cell co-receptors regulating T cell-dependent antibody production in common variable immunodeficiency: CD27 pathway defects identify subsets of severely immuno-compromised patients. Int Immunol. 2001;13(7):871-6.
29. Martins G, Calame K. Regulation and functions of Blimp-1 in T and B lymphocytes. Annu Rev Immunol. 2008;26:133-69.
30. Ansari M, Yazdani R, Sherkat R, Homayouni V, Ganjalikhani-Hakemi M, Rezaei A. Decreased Expression of B cell Maturation Antigen in Patients with Common Variable Immunodeficiency. Pediat Aller Imm Pul. 2017;30:7-13.
31. Afshar-Ghasemlou S, Esmaeil N, Sherkat R, Yazdani R, Abbasi-Rad F, Ganjalikhani hakemi M, et al. Increased IRF4 expression in isolated B cells from Common variable immunodeficiency (CVID) patients. Allergol Immunopath. 2019;47(1):52-9.
32. 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(6844):300.
33. 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(6):615-26.
34. Nutt SL, Fairfax KA, Kallies A. BLIMP1 guides the fate of effector B and T cells. Nat Rev Immunol. 2007;7(12):923-7.
| Files | ||
| Issue | Vol 19 No 4 (2020) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijaai.v19i4.4118 | |
| PMID | 33463110 | |
| Keywords | ||
| B-cell lymphoma 6 protein (BCL6) Common variable immunodeficiency (CVID) Plasma cell | ||
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How to Cite
1.
Farrokhi S, Abbasi-rad F, Esmaeil N, Sherkat R, Yazdani R, Afshar-Ghasemlou S, Fekrvand S, Ganjalikhani-Hakemi M. Increased Expression of B Lymphocyte Induced Maturation Protein 1 (BLIMP1) in Patients with Common Variable Immunodeficiency (CVID). Iran J Allergy Asthma Immunol. 2020;19(4):437-446.
