Evaluation of Regulatory B10 Cells in Common Variable Immunodeficiency Patients with and without Autoimmunity
-
Pouria Ghiaee
,
Sarehsadat Ebrahimi
,
Seyed Alireza Mahdaviani
,
Fatemeh Tarighat Monfared
,
Marzieh Tavakol
,
Mehrdad Dargahi Mal-Amir
,
Nima Rezaei
,
Abdollah Jafarzadeh
Abstract
Common variable immunodeficiency disease (CVID) is the most prevalent symptomatic inborn errors of immunity, determined by defective B cell function, impaired antibody production, and susceptibility to frequent respiratory infections, enteropathy, autoimmunity, and malignancy. Due to the importance of autoimmunity in CVID and the probable role of regulatory B lymphocytes, we aimed to determine the frequency of B10 cells in CVID patients with and without autoimmunity.
A total of 24 CVID patients and 12 healthy controls were enrolled in the study. Patients were divided into two equal groups, with and without autoimmunity. Peripheral blood cells were stained with monoclonal antibodies (mAbs) to identify CD24hiCD38hi B cells, CD27int CD38+ (plasmablasts), and CD24hiCD27+ B cells by flow cytometry.
The percentages of B10, CD24hiCD27+ and CD27int CD38+ cells were significantly lower in total CVID patients, CVID patients with autoimmunity and CVID patients without autoimmunity compared to healthy controls (mean±standard deviation (SD) percentage of B10 cells: 6.36±9.21(total CVID), 2.81±5.00 (CVID with autoimmunity), and 3.25±3.5 (CVID without autoimmunity) vs. 13.02±12.45 (healthy controls); CD24hiCD27+ cells: 2.39±3.89, 3±5.20 and 1.78±1.94 vs. 20.38±14.27; CD27int CD38+ cells: 6.80±18.49, 7.40±20.24 and 6.20±17.45 vs. 11.84±5.71). CVID patients without autoimmunity had a higher percentage of CD24hiCD38hi cells than CVID patients with autoimmunity (4.73±4.14 vs. 2.62±5.02).
The defect of regulatory B cells plays a significant role in the pathogenesis of autoimmunity in CVID. Further multicenter studies with higher sample sizes are suggested to determine the role of Breg cells in the clinical course of autoimmunity.
1. Tangye SG, Al-Herz W, Bousfiha A, Cunningham-Rundles C, Franco JL, Holland SM, et al. Human inborn errors of immunity: 2022 update on the classification from the International Union of Immunological Societies expert committee. J Clin Immunol. 2022;42(7):1473-507.
2. 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 Clin Immunol Pract. 2016;4(1):38-59.
3. Selenius JS, Nikoskelainen J, Siitonen S, Lindfors K, Sahi H, Hämäläinen S, et al. Unexpectedly high prevalence of common variable immunodeficiency in Finland. Front Immunol. 2017;8:1190.
4. Florí NM, Soler-Palacín P, Yagüe J, Segarra J, Díaz-Ricart M, Querol L, et al. Primary immunodeficiency syndrome in Spain: first report of the National Registry in Children and Adults. J Clin Immunol. 1997;17:333-9.
5. Kilic SS, Aydin M, Dogu F, Yegin O, Yazıcıoglu M, Karaca NE, et al. The prevalences and patient characteristics of primary immunodeficiency diseases in Turkey—two centers study. J Clin Immunol. 2013;33:74-83.
6. Bogaert DJ, Zhang Y, Loeys B, Lambrecht BN, Schrijvers R, Bossuyt X, et al. Genes associated with common variable immunodeficiency: one diagnosis to rule them all? J Med Genet. 2016;53(9):575-90.
7. Edwards ES, Martin JC, Matthews SP, Pillay B, Snelgrove SL, Sanchez E, et al. Beyond monogenetic rare variants: tackling the low rate of genetic diagnoses in predominantly antibody deficiency. Cell Mol Immunol. 2021;18(3):588-603.
8. Martelius T, Seppänen MRJ, Warnatz K. Editorial: updates on the pathogenesis of common variable immunodeficiency (CVID). Front Immunol. 2023;13:114200.
9. Salzer U, Warnatz K, Peter HH. Common variable immunodeficiency—an update. Arthritis Res Ther. 2012;14:223.
10. Mormile I, D’Antonio F, Ciprandi G, Pati I, Concolino D, Delia M, et al. Common variable immunodeficiency and autoimmune diseases: a retrospective study of 95 adult patients in a single tertiary care center. Front Immunol. 2021;12:652487.
11. Rizvi FS, Fasth A, Litzman J, Chinen J, Cunningham-Rundles C, Chapel H, et al. Autoimmunity in common variable immunodeficiency: a systematic review and meta-analysis. Expert Rev Clin Immunol. 2020;16(12):1227-35.
12. Resnick ES, Moshier EL, Godbold JH, Cunningham-Rundles C. Morbidity and mortality in common variable immune deficiency over 4 decades. Blood. 2012;119(7):1650-7.
13. 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.
14. Genre J, Isenberg DA, Salzer U, Warnatz K, Rizzi M, Busse PJ, et al. Reduced frequency of CD4+ CD25HIGH FOXP3+ cells and diminished FOXP3 expression in patients with common variable immunodeficiency: a link to autoimmunity? Clin Immunol. 2009;132(2):215-21.
15. Azizi G, Rezaei N, Bagheri M, Aghamohammadi A, Tavassoli M, Abolhassani H, et al. Autoimmunity and its association with regulatory T cells and B cell subsets in patients with common variable immunodeficiency. Allergol Immunopathol (Madr). 2018;46(2):127-35.
16. López-Gómez A, Salzer U, Warnatz K, Peter HH, Thiel A, Recher M, et al. IL-21 and anti-CD40 restore Bcl-2 family protein imbalance in vitro in low-survival CD27+ B cells from CVID patients. Cell Death Dis. 2018;9(12):1156.
17. Sharifi L, Tavakol M, Azizi G, Rezaei N, Mohammadi H, Aghamohammadi A, et al. The profile of toll-like receptor 2 (TLR2), TLR4 and their cytosolic downstream signaling pathway in common variable immunodeficiency (CVID) patients. Iran J Allergy Asthma Immunol. 2018;17:188-200.
18. Warnatz K, Voll RE. Pathogenesis of autoimmunity in common variable immunodeficiency. Front Immunol. 2012;3:210.
19. Mauri C, Bosma A. Immune regulatory function of B cells. Annu Rev Immunol. 2012;30:221-41.
20. Iwata Y, Matsushita T, Horikawa M, DiLillo DJ, Yanaba K, Venturi GM, et al. Characterization of a rare IL-10-competent B-cell subset in humans that parallels mouse regulatory B10 cells. Blood. 2011;117(2):530-41.
21. Yanaba K, Bouaziz JD, Matsushita T, Tsubata T, Tedder TF. The development and function of regulatory B cells expressing IL-10 (B10 cells) requires antigen receptor diversity and TLR signals. J Immunol. 2009;182(12):7459-72.
22. Yoshizaki A, Miyagaki T, DiLillo DJ, Matsushita T, Horikawa M, Kountikov EI, et al. Regulatory B cells control T-cell autoimmunity through IL-21-dependent cognate interactions. Nature. 2012;491(7423):264-8.
23. Kalampokis I, Yoshizaki A, Tedder TF. IL-10-producing regulatory B cells (B10 cells) in autoimmune disease. Arthritis Res Ther. 2013;15(1)\:S1.
24. Blair PA, Noreña LY, Flores-Borja F, Rawlings DJ,
Isenberg DA, Ehrenstein MR, et al. CD19+CD24hiCD38hi B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic lupus erythematosus patients. Immunity. 2010;32(1):129-40.
25. Daien CI, Duxbury B, Hao Y, Blair PA, Ehrenstein MR, Mauri C, et al. Regulatory B10 cells are decreased in patients with rheumatoid arthritis and are inversely correlated with disease activity. Arthritis Rheumatol. 2014;66(8):2037-46.
26. 26. Zha B, Shi Y, Li B, Xu X, Wang Y, Wang X, et al. Decrease in proportion of CD19+ CD24hi CD27+ B cells and impairment of their suppressive function in Graves' disease. PLoS One. 2012;7(11)\:e49835.
27. Yang M, Liu C, Li J, Li J, Wu Y, Wang L, et al. Regulatory B cells in autoimmune diseases. Cell Mol Immunol. 2013;10(2):122-32.
28. Carter NA, Vasconcellos R, Rosser EC, Tulone C, Munoz-Suano A, Kamanaka M, et al. Mice lacking endogenous IL-10-producing regulatory B cells develop exacerbated disease and present with an increased frequency of Th1/Th17 but a decrease in regulatory T cells. J Immunol. 2011;186(10):5569-79.
29. Bouaziz JD, Yanaba K, Venturi GM, Wang Y, Tisch RM, Tedder TF. IL-10 produced by activated human B cells regulates CD4+ T-cell activation in vitro. Eur J Immunol. 2010;40(10):2686-91.
30. Barsotti NS, da Silva JS, Pontillo A, Sant’Anna CC, de Carvalho JF, Bonfa E, et al. IL-10-producing regulatory B cells are decreased in patients with common variable immunodeficiency. PLoS One. 2016;11(3)\:e0151761.
31. Salami F, Bagheri M, Tavakol M, Rezaei N, Aghamohammadi A, Azizi G, et al. Evaluation of expression of LRBA and CTLA-4 proteins in common variable immunodeficiency patients. Immunol Invest. 2022;51(2):381-94.
32. Yazdani R, Bagheri Y, Rezaei N, Tavakol M, Aghamohammadi A, Azizi G, et al. Comparison of various classifications for patients with common variable immunodeficiency (CVID) using measurement of B-cell subsets. Allergol Immunopathol (Madr). 2017;45(2):183-92.
33. Zavareh FT, Bagheri Y, Keshtkar AA. Evaluation of B cell and T cell phenotypes in CVID patients and its correlation with the clinical phenotypes: study protocol. Immunol Genet J. 2021;1:1-8.
34. Warnatz K, Schlesier M. Flowcytometric phenotyping of common variable immunodeficiency. Cytometry B Clin Cytom. 2008;74(5):261-71.
35. Yazdani R, Rezaei N, Bagheri M, Tavakol M, Aghamohammadi A, Azizi G, et al. Role of apoptosis in common variable immunodeficiency and selective immunoglobulin A deficiency. Mol Immunol. 2016;71:1-9.
36. Ochtrop ML, Warnatz K, Schlesier M, Peter HH, Salzer U, Berger M, et al. T and B lymphocyte abnormalities in bone marrow biopsies of common variable immunodeficiency. Blood. 2011;118(2):309-18.
37. Blair PA, Noreña LY, Flores-Borja F, Rawlings DJ, Isenberg DA, Ehrenstein MR, et al. CD19+ CD24hiCD38hi B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic lupus erythematosus patients. Immunity. 2010;32(1):129-40.
38. Maravillas-Montero JL, Acevedo-Ochoa E. Human B regulatory cells: the new players in autoimmune disease. Rev Invest Clin. 2017;69(5):243-6.
39. Zhu Q, Li Y, Yang Y, Zhang Z, Wang C, Chen X, et al. Advances of regulatory B cells in autoimmune diseases. Front Immunol. 2021;12:592914.
40. Wang Y, Li X, Liu L, Chen H, Zhang J, Wu Y, et al. Decrease in the proportion of CD24hi CD38hi B cells and impairment of their regulatory capacity in type 1 diabetes patients. Clin Exp Immunol. 2020;200(1):22-32.
41. Flores-Borja F, Bosma A, Ng D, Reddy V, Ehrenstein MR, Isenberg DA, et al. CD19+ CD24hiCD38hi B cells maintain regulatory T cells while limiting TH1 and TH17 differentiation. Sci Transl Med. 2013;5(173):173ra23.
42. Sakkas LI, Bogdanos DP, Koutsilieris M, Tsezou A, Liaskos C, Mavropoulos A, et al. Regulatory B cells: new players in inflammatory and autoimmune rheumatic diseases. Semin Arthritis Rheum. 2019;49(1):107-14.
43. Zhu HQ, Tang T, Xu D, Wu J, Wang B, Tang J, et al. Impaired function of CD19+ CD24hiCD38hi regulatory B cells in patients with pemphigus. Br J Dermatol. 2015;172(1):101-10.
44. Matsumoto M, Baba A, Yokota T, Shibuya A, Otsuka M, Iwata Y, et al. Interleukin-10-producing plasmablasts exert regulatory function in autoimmune inflammation. Immunity. 2014;41(6):1040-51.
2. 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 Clin Immunol Pract. 2016;4(1):38-59.
3. Selenius JS, Nikoskelainen J, Siitonen S, Lindfors K, Sahi H, Hämäläinen S, et al. Unexpectedly high prevalence of common variable immunodeficiency in Finland. Front Immunol. 2017;8:1190.
4. Florí NM, Soler-Palacín P, Yagüe J, Segarra J, Díaz-Ricart M, Querol L, et al. Primary immunodeficiency syndrome in Spain: first report of the National Registry in Children and Adults. J Clin Immunol. 1997;17:333-9.
5. Kilic SS, Aydin M, Dogu F, Yegin O, Yazıcıoglu M, Karaca NE, et al. The prevalences and patient characteristics of primary immunodeficiency diseases in Turkey—two centers study. J Clin Immunol. 2013;33:74-83.
6. Bogaert DJ, Zhang Y, Loeys B, Lambrecht BN, Schrijvers R, Bossuyt X, et al. Genes associated with common variable immunodeficiency: one diagnosis to rule them all? J Med Genet. 2016;53(9):575-90.
7. Edwards ES, Martin JC, Matthews SP, Pillay B, Snelgrove SL, Sanchez E, et al. Beyond monogenetic rare variants: tackling the low rate of genetic diagnoses in predominantly antibody deficiency. Cell Mol Immunol. 2021;18(3):588-603.
8. Martelius T, Seppänen MRJ, Warnatz K. Editorial: updates on the pathogenesis of common variable immunodeficiency (CVID). Front Immunol. 2023;13:114200.
9. Salzer U, Warnatz K, Peter HH. Common variable immunodeficiency—an update. Arthritis Res Ther. 2012;14:223.
10. Mormile I, D’Antonio F, Ciprandi G, Pati I, Concolino D, Delia M, et al. Common variable immunodeficiency and autoimmune diseases: a retrospective study of 95 adult patients in a single tertiary care center. Front Immunol. 2021;12:652487.
11. Rizvi FS, Fasth A, Litzman J, Chinen J, Cunningham-Rundles C, Chapel H, et al. Autoimmunity in common variable immunodeficiency: a systematic review and meta-analysis. Expert Rev Clin Immunol. 2020;16(12):1227-35.
12. Resnick ES, Moshier EL, Godbold JH, Cunningham-Rundles C. Morbidity and mortality in common variable immune deficiency over 4 decades. Blood. 2012;119(7):1650-7.
13. 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.
14. Genre J, Isenberg DA, Salzer U, Warnatz K, Rizzi M, Busse PJ, et al. Reduced frequency of CD4+ CD25HIGH FOXP3+ cells and diminished FOXP3 expression in patients with common variable immunodeficiency: a link to autoimmunity? Clin Immunol. 2009;132(2):215-21.
15. Azizi G, Rezaei N, Bagheri M, Aghamohammadi A, Tavassoli M, Abolhassani H, et al. Autoimmunity and its association with regulatory T cells and B cell subsets in patients with common variable immunodeficiency. Allergol Immunopathol (Madr). 2018;46(2):127-35.
16. López-Gómez A, Salzer U, Warnatz K, Peter HH, Thiel A, Recher M, et al. IL-21 and anti-CD40 restore Bcl-2 family protein imbalance in vitro in low-survival CD27+ B cells from CVID patients. Cell Death Dis. 2018;9(12):1156.
17. Sharifi L, Tavakol M, Azizi G, Rezaei N, Mohammadi H, Aghamohammadi A, et al. The profile of toll-like receptor 2 (TLR2), TLR4 and their cytosolic downstream signaling pathway in common variable immunodeficiency (CVID) patients. Iran J Allergy Asthma Immunol. 2018;17:188-200.
18. Warnatz K, Voll RE. Pathogenesis of autoimmunity in common variable immunodeficiency. Front Immunol. 2012;3:210.
19. Mauri C, Bosma A. Immune regulatory function of B cells. Annu Rev Immunol. 2012;30:221-41.
20. Iwata Y, Matsushita T, Horikawa M, DiLillo DJ, Yanaba K, Venturi GM, et al. Characterization of a rare IL-10-competent B-cell subset in humans that parallels mouse regulatory B10 cells. Blood. 2011;117(2):530-41.
21. Yanaba K, Bouaziz JD, Matsushita T, Tsubata T, Tedder TF. The development and function of regulatory B cells expressing IL-10 (B10 cells) requires antigen receptor diversity and TLR signals. J Immunol. 2009;182(12):7459-72.
22. Yoshizaki A, Miyagaki T, DiLillo DJ, Matsushita T, Horikawa M, Kountikov EI, et al. Regulatory B cells control T-cell autoimmunity through IL-21-dependent cognate interactions. Nature. 2012;491(7423):264-8.
23. Kalampokis I, Yoshizaki A, Tedder TF. IL-10-producing regulatory B cells (B10 cells) in autoimmune disease. Arthritis Res Ther. 2013;15(1)\:S1.
24. Blair PA, Noreña LY, Flores-Borja F, Rawlings DJ,
Isenberg DA, Ehrenstein MR, et al. CD19+CD24hiCD38hi B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic lupus erythematosus patients. Immunity. 2010;32(1):129-40.
25. Daien CI, Duxbury B, Hao Y, Blair PA, Ehrenstein MR, Mauri C, et al. Regulatory B10 cells are decreased in patients with rheumatoid arthritis and are inversely correlated with disease activity. Arthritis Rheumatol. 2014;66(8):2037-46.
26. 26. Zha B, Shi Y, Li B, Xu X, Wang Y, Wang X, et al. Decrease in proportion of CD19+ CD24hi CD27+ B cells and impairment of their suppressive function in Graves' disease. PLoS One. 2012;7(11)\:e49835.
27. Yang M, Liu C, Li J, Li J, Wu Y, Wang L, et al. Regulatory B cells in autoimmune diseases. Cell Mol Immunol. 2013;10(2):122-32.
28. Carter NA, Vasconcellos R, Rosser EC, Tulone C, Munoz-Suano A, Kamanaka M, et al. Mice lacking endogenous IL-10-producing regulatory B cells develop exacerbated disease and present with an increased frequency of Th1/Th17 but a decrease in regulatory T cells. J Immunol. 2011;186(10):5569-79.
29. Bouaziz JD, Yanaba K, Venturi GM, Wang Y, Tisch RM, Tedder TF. IL-10 produced by activated human B cells regulates CD4+ T-cell activation in vitro. Eur J Immunol. 2010;40(10):2686-91.
30. Barsotti NS, da Silva JS, Pontillo A, Sant’Anna CC, de Carvalho JF, Bonfa E, et al. IL-10-producing regulatory B cells are decreased in patients with common variable immunodeficiency. PLoS One. 2016;11(3)\:e0151761.
31. Salami F, Bagheri M, Tavakol M, Rezaei N, Aghamohammadi A, Azizi G, et al. Evaluation of expression of LRBA and CTLA-4 proteins in common variable immunodeficiency patients. Immunol Invest. 2022;51(2):381-94.
32. Yazdani R, Bagheri Y, Rezaei N, Tavakol M, Aghamohammadi A, Azizi G, et al. Comparison of various classifications for patients with common variable immunodeficiency (CVID) using measurement of B-cell subsets. Allergol Immunopathol (Madr). 2017;45(2):183-92.
33. Zavareh FT, Bagheri Y, Keshtkar AA. Evaluation of B cell and T cell phenotypes in CVID patients and its correlation with the clinical phenotypes: study protocol. Immunol Genet J. 2021;1:1-8.
34. Warnatz K, Schlesier M. Flowcytometric phenotyping of common variable immunodeficiency. Cytometry B Clin Cytom. 2008;74(5):261-71.
35. Yazdani R, Rezaei N, Bagheri M, Tavakol M, Aghamohammadi A, Azizi G, et al. Role of apoptosis in common variable immunodeficiency and selective immunoglobulin A deficiency. Mol Immunol. 2016;71:1-9.
36. Ochtrop ML, Warnatz K, Schlesier M, Peter HH, Salzer U, Berger M, et al. T and B lymphocyte abnormalities in bone marrow biopsies of common variable immunodeficiency. Blood. 2011;118(2):309-18.
37. Blair PA, Noreña LY, Flores-Borja F, Rawlings DJ, Isenberg DA, Ehrenstein MR, et al. CD19+ CD24hiCD38hi B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic lupus erythematosus patients. Immunity. 2010;32(1):129-40.
38. Maravillas-Montero JL, Acevedo-Ochoa E. Human B regulatory cells: the new players in autoimmune disease. Rev Invest Clin. 2017;69(5):243-6.
39. Zhu Q, Li Y, Yang Y, Zhang Z, Wang C, Chen X, et al. Advances of regulatory B cells in autoimmune diseases. Front Immunol. 2021;12:592914.
40. Wang Y, Li X, Liu L, Chen H, Zhang J, Wu Y, et al. Decrease in the proportion of CD24hi CD38hi B cells and impairment of their regulatory capacity in type 1 diabetes patients. Clin Exp Immunol. 2020;200(1):22-32.
41. Flores-Borja F, Bosma A, Ng D, Reddy V, Ehrenstein MR, Isenberg DA, et al. CD19+ CD24hiCD38hi B cells maintain regulatory T cells while limiting TH1 and TH17 differentiation. Sci Transl Med. 2013;5(173):173ra23.
42. Sakkas LI, Bogdanos DP, Koutsilieris M, Tsezou A, Liaskos C, Mavropoulos A, et al. Regulatory B cells: new players in inflammatory and autoimmune rheumatic diseases. Semin Arthritis Rheum. 2019;49(1):107-14.
43. Zhu HQ, Tang T, Xu D, Wu J, Wang B, Tang J, et al. Impaired function of CD19+ CD24hiCD38hi regulatory B cells in patients with pemphigus. Br J Dermatol. 2015;172(1):101-10.
44. Matsumoto M, Baba A, Yokota T, Shibuya A, Otsuka M, Iwata Y, et al. Interleukin-10-producing plasmablasts exert regulatory function in autoimmune inflammation. Immunity. 2014;41(6):1040-51.
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How to Cite
1.
Ghiaee P, Ebrahimi S, Mahdaviani SA, Tarighat Monfared F, Tavakol M, Dargahi Mal-Amir M, Rezaei N, Jafarzadeh A. Evaluation of Regulatory B10 Cells in Common Variable Immunodeficiency Patients with and without Autoimmunity. Iran J Allergy Asthma Immunol. 2026;:1-13.
