Research progress of regulatory B cells in diseases_West China Medical Journal

Authors：

CUI Jian ^1,2 , ZOU Zhongqing ^1,3 ,  ZHANG Li ¹

1. Department of Hematology / Institute of Hematology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;
2. West China School of Medicine, Sichuan University, Chengdu, Sichuan 610041, P. R. China;
3. Department of Hematology, Clinical Medical College & Affiliated Hospital of Chengdu University, Chengdu University, Chengdu, Sichuan 610081, P. R. China;

Corresponding author：

ZHANG Li, Email: drzhangli2014@sina.com

Keywords：

Regulatory B cells; disease; immunity; tumor

DOI：

10.7507/1002-0179.202005018

Video：

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Regulatory B cells (Bregs) are a subset of B cells with immunomodulatory effects. The study of Bregs began with a variety of animal models of immune diseases. Studies in patients with autoimmune diseases have further clarified that Bregs are a group of immune cells that secrete inhibitory cytokines such as interleukin-10. Abnormal functions and numbers of Bregs have been found in a variety of autoimmune diseases. The study of the negative immune regulatory network involving Bregs is expected to provide new therapeutic ideas for diseases such as immune diseases, cancer, infection and inflammation. Starting from the discovery and immune regulation mechanism of Bregs, this paper focuses on its regulatory mechanism and clinical research value in the occurrence and development of autoimmune diseases, tumors, infectious diseases and inflammation.

Citation： CUI Jian, ZOU Zhongqing, ZHANG Li. Research progress of regulatory B cells in diseases. West China Medical Journal, 2022, 37(4): 632-636. doi: 10.7507/1002-0179.202005018 Copy

1.	Netea MG, Domínguez-Andrés J, Barreiro LB, et al. Defining trained immunity and its role in health and disease. Nat Rev Immunol, 2020, 20(6): 375-388.
2.	Togashi Y, Shitara K, Nishikawa H. Regulatory T cells in cancer immunosuppression - implications for anticancer therapy. Nat Rev Clin Oncol, 2019, 16(6): 356-371.
3.	Dominguez-Villar M, Hafler DA. Regulatory T cells in autoimmune disease. Nat Immunol, 2018, 19(7): 665-673.
4.	Rosser EC, Mauri C. Regulatory B cells: origin, phenotype, and function. Immunity, 2015, 42(4): 607-612.
5.	Cai X, Zhang L, Wei W. Regulatory B cells in inflammatory diseases and tumor. Int Immunopharmacol, 2019, 67: 281-286.
6.	Cui J, Zou Z, Duan J, et al. Predictive values of PET/CT in combination with regulatory B cells for therapeutic response and survival in contemporary patients with newly diagnosed multiple myeloma. Front Immunol, 2021, 12: 671904.
7.	Siewe B, Stapleton JT, Martinson J, et al. Regulatory B cell frequency correlates with markers of HIV disease progression and attenuates anti-HIV CD8⁺ T cell function in vitro. J Leukoc Biol, 2013, 93(5): 811-818.
8.	Peng B, Ming Y, Yang C. Regulatory B cells: the cutting edge of immune tolerance in kidney transplantation. Cell Death Dis, 2018, 9(2): 109.
9.	Neta R, Salvin SB. Specific suppression of delayed hypersensitivity: the possible presence of a suppressor B cell in the regulation of delayed hypersensitivity. J Immunol, 1974, 113(6): 1716-1725.
10.	Wolf SD, Dittel BN, Hardardottir F, et al. Experimental autoimmune encephalomyelitis induction in genetically B cell-deficient mice. J Exp Med, 1996, 184(6): 2271-2278.
11.	Mizoguchi A, Mizoguchi E, Smith RN, et al. Suppressive role of B cells in chronic colitis of T cell receptor alpha mutant mice. J Exp Med, 1997, 186(10): 1749-1756.
12.	Zhao Q, Jung LK. Frequency of CD19⁺CD24^hiCD38^hi regulatory B cells is decreased in peripheral blood and synovial fluid of patients with juvenile idiopathic arthritis: a preliminary study. Pediatr Rheumatol Online J, 2018, 16(1): 44.
13.	Dasgupta S, Dasgupta S, Bandyopadhyay M. Regulatory B cells in infection, inflammation, and autoimmunity. Cell Immunol, 2020, 352: 104076.
14.	Hong M, Liao Y, Liang J, et al. Immunomodulation of human CD19⁺CD25^high regulatory B cells via Th17/Foxp3 regulatory T cells and Th1/Th2 cytokines. Hum Immunol, 2019, 80(10): 863-870.
15.	Zacca ER, Onofrio LI, Acosta CDV, et al. PD-L1⁺ regulatory B cells are significantly decreased in rheumatoid arthritis patients and increase after successful treatment. Front Immunol, 2018, 9: 2241.
16.	Wang T, Mei Y, Li Z. Research progress on regulatory B cells in systemic lupus erythematosus. Biomed Res Int, 2019, 2019: 7948687.
17.	Kim Y, Kim G, Shin HJ, et al. Restoration of regulatory B cell deficiency following alemtuzumab therapy in patients with relapsing multiple sclerosis. J Neuroinflammation, 2018, 15(1): 300.
18.	Gray M, Miles K, Salter D, et al. Apoptotic cells protect mice from autoimmune inflammation by the induction of regulatory B cells. Proc Natl Acad Sci U S A, 2007, 104(35): 14080-14085.
19.	Gao N, Dresel J, Eckstein V, et al. Impaired suppressive capacity of activation-induced regulatory B cells in systemic lupus erythematosus. Arthritis Rheumatol, 2014, 66(10): 2849-2861.
20.	Blair PA, Noreña LY, Flores-Borja F, et al. CD19⁺CD24^hiCD38^hi B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic lupus erythematosus patients. Immunity, 2010, 32(1): 129-140.
21.	Lepse N, Abdulahad WH, Rutgers A, et al. Altered B cell balance, but unaffected B cell capacity to limit monocyte activation in anti-neutrophil cytoplasmic antibody-associated vasculitis in remission. Rheumatology (Oxford), 2014, 53(9): 1683-1692.
22.	Yang X, Yang J, Chu Y, et al. T follicular helper cells and regulatory B cells dynamics in systemic lupus erythematosus. PLoS One, 2014, 9(2): e88441.
23.	Duddy M, Niino M, Adatia F, et al. Distinct effector cytokine profiles of memory and naive human B cell subsets and implication in multiple sclerosis. J Immunol, 2007, 178(10): 6092-6099.
24.	Murakami Y, Saito H, Shimizu S, et al. Increased regulatory B cells are involved in immune evasion in patients with gastric cancer. Sci Rep, 2019, 9(1): 13083.
25.	Zhang L, Tai YT, Ho M, et al. Regulatory B cell-myeloma cell interaction confers immunosuppression and promotes their survival in the bone marrow milieu. Blood Cancer J, 2017, 7(3): e547.
26.	Zou Z, Guo T, Cui J, et al. Real-world data combined with studies on regulatory B cells for newly diagnosed multiple myeloma from a tertiary referral hospital in south-western China. J Cancer, 2021, 12(9): 2633-2642.
27.	Wejksza K, Lee-Chang C, Bodogai M, et al. Cancer-produced metabolites of 5-lipoxygenase induce tumor-evoked regulatory B cells via peroxisome proliferator-activated receptor α. J Immunol, 2013, 190(6): 2575-2584.
28.	Lee-Chang C, Bodogai M, Martin-Montalvo A, et al. Inhibition of breast cancer metastasis by resveratrol-mediated inactivation of tumor-evoked regulatory B cells. J Immunol, 2013, 191(8): 4141-4151.
29.	Xiao X, Lao XM, Chen MM, et al. PD-1^hi identifies a novel regulatory B-cell population in human hepatoma that promotes disease progression. Cancer Discov, 2016, 6(5): 546-559.
30.	Ye L, Zhang Q, Cheng Y, et al. Tumor-derived exosomal HMGB1 fosters hepatocellular carcinoma immune evasion by promoting TIM-1⁺ regulatory B cell expansion. J Immunother Cancer, 2018, 6(1): 145.
31.	Brinkhoff A, Zeng Y, Sieberichs A, et al. B-cell dynamics during experimental endotoxemia in humans. Biosci Rep, 2019, 39(5): BSR20182347.
32.	Dai YC, Wang WD, Zhang JA, et al. MTB driven B cells producing IL-35 and secreting high level of IL-10 in the patients with active pulmonary tuberculosis. Mol Immunol, 2019, 112: 175-181.
33.	Mishima Y, Oka A, Liu B, et al. Microbiota maintain colonic homeostasis by activating TLR2/MyD88/PI3K signaling in IL-10-producing regulatory B cells. J Clin Invest, 2019, 129(9): 3702-3716.
34.	Zhang M, Zeng G, Yang Q, et al. Anti-tuberculosis treatment enhances the production of IL-22 through reducing the frequencies of regulatory B cell. Tuberculosis (Edinb), 2014, 94(3): 238-244.
35.	Newell KA, Asare A, Kirk AD, et al. Identification of a B cell signature associated with renal transplant tolerance in humans. J Clin Invest, 2010, 120(6): 1836-1847.
36.	Tebbe B, Wilde B, Ye Z, et al. Renal transplant recipients treated with calcineurin-inhibitors lack circulating immature transitional CD19⁺CD24^hiCD38^hi regulatory B-lymphocytes. PLoS One, 2016, 11(4): e0153170.

1. Netea MG, Domínguez-Andrés J, Barreiro LB, et al. Defining trained immunity and its role in health and disease. Nat Rev Immunol, 2020, 20(6): 375-388.
2. Togashi Y, Shitara K, Nishikawa H. Regulatory T cells in cancer immunosuppression - implications for anticancer therapy. Nat Rev Clin Oncol, 2019, 16(6): 356-371.
3. Dominguez-Villar M, Hafler DA. Regulatory T cells in autoimmune disease. Nat Immunol, 2018, 19(7): 665-673.
4. Rosser EC, Mauri C. Regulatory B cells: origin, phenotype, and function. Immunity, 2015, 42(4): 607-612.
5. Cai X, Zhang L, Wei W. Regulatory B cells in inflammatory diseases and tumor. Int Immunopharmacol, 2019, 67: 281-286.
6. Cui J, Zou Z, Duan J, et al. Predictive values of PET/CT in combination with regulatory B cells for therapeutic response and survival in contemporary patients with newly diagnosed multiple myeloma. Front Immunol, 2021, 12: 671904.
7. Siewe B, Stapleton JT, Martinson J, et al. Regulatory B cell frequency correlates with markers of HIV disease progression and attenuates anti-HIV CD8⁺ T cell function in vitro. J Leukoc Biol, 2013, 93(5): 811-818.
8. Peng B, Ming Y, Yang C. Regulatory B cells: the cutting edge of immune tolerance in kidney transplantation. Cell Death Dis, 2018, 9(2): 109.
9. Neta R, Salvin SB. Specific suppression of delayed hypersensitivity: the possible presence of a suppressor B cell in the regulation of delayed hypersensitivity. J Immunol, 1974, 113(6): 1716-1725.
10. Wolf SD, Dittel BN, Hardardottir F, et al. Experimental autoimmune encephalomyelitis induction in genetically B cell-deficient mice. J Exp Med, 1996, 184(6): 2271-2278.
11. Mizoguchi A, Mizoguchi E, Smith RN, et al. Suppressive role of B cells in chronic colitis of T cell receptor alpha mutant mice. J Exp Med, 1997, 186(10): 1749-1756.
12. Zhao Q, Jung LK. Frequency of CD19⁺CD24^hiCD38^hi regulatory B cells is decreased in peripheral blood and synovial fluid of patients with juvenile idiopathic arthritis: a preliminary study. Pediatr Rheumatol Online J, 2018, 16(1): 44.
13. Dasgupta S, Dasgupta S, Bandyopadhyay M. Regulatory B cells in infection, inflammation, and autoimmunity. Cell Immunol, 2020, 352: 104076.
14. Hong M, Liao Y, Liang J, et al. Immunomodulation of human CD19⁺CD25^high regulatory B cells via Th17/Foxp3 regulatory T cells and Th1/Th2 cytokines. Hum Immunol, 2019, 80(10): 863-870.
15. Zacca ER, Onofrio LI, Acosta CDV, et al. PD-L1⁺ regulatory B cells are significantly decreased in rheumatoid arthritis patients and increase after successful treatment. Front Immunol, 2018, 9: 2241.
16. Wang T, Mei Y, Li Z. Research progress on regulatory B cells in systemic lupus erythematosus. Biomed Res Int, 2019, 2019: 7948687.
17. Kim Y, Kim G, Shin HJ, et al. Restoration of regulatory B cell deficiency following alemtuzumab therapy in patients with relapsing multiple sclerosis. J Neuroinflammation, 2018, 15(1): 300.
18. Gray M, Miles K, Salter D, et al. Apoptotic cells protect mice from autoimmune inflammation by the induction of regulatory B cells. Proc Natl Acad Sci U S A, 2007, 104(35): 14080-14085.
19. Gao N, Dresel J, Eckstein V, et al. Impaired suppressive capacity of activation-induced regulatory B cells in systemic lupus erythematosus. Arthritis Rheumatol, 2014, 66(10): 2849-2861.
20. Blair PA, Noreña LY, Flores-Borja F, et al. CD19⁺CD24^hiCD38^hi B cells exhibit regulatory capacity in healthy individuals but are functionally impaired in systemic lupus erythematosus patients. Immunity, 2010, 32(1): 129-140.
21. Lepse N, Abdulahad WH, Rutgers A, et al. Altered B cell balance, but unaffected B cell capacity to limit monocyte activation in anti-neutrophil cytoplasmic antibody-associated vasculitis in remission. Rheumatology (Oxford), 2014, 53(9): 1683-1692.
22. Yang X, Yang J, Chu Y, et al. T follicular helper cells and regulatory B cells dynamics in systemic lupus erythematosus. PLoS One, 2014, 9(2): e88441.
23. Duddy M, Niino M, Adatia F, et al. Distinct effector cytokine profiles of memory and naive human B cell subsets and implication in multiple sclerosis. J Immunol, 2007, 178(10): 6092-6099.
24. Murakami Y, Saito H, Shimizu S, et al. Increased regulatory B cells are involved in immune evasion in patients with gastric cancer. Sci Rep, 2019, 9(1): 13083.
25. Zhang L, Tai YT, Ho M, et al. Regulatory B cell-myeloma cell interaction confers immunosuppression and promotes their survival in the bone marrow milieu. Blood Cancer J, 2017, 7(3): e547.
26. Zou Z, Guo T, Cui J, et al. Real-world data combined with studies on regulatory B cells for newly diagnosed multiple myeloma from a tertiary referral hospital in south-western China. J Cancer, 2021, 12(9): 2633-2642.
27. Wejksza K, Lee-Chang C, Bodogai M, et al. Cancer-produced metabolites of 5-lipoxygenase induce tumor-evoked regulatory B cells via peroxisome proliferator-activated receptor α. J Immunol, 2013, 190(6): 2575-2584.
28. Lee-Chang C, Bodogai M, Martin-Montalvo A, et al. Inhibition of breast cancer metastasis by resveratrol-mediated inactivation of tumor-evoked regulatory B cells. J Immunol, 2013, 191(8): 4141-4151.
29. Xiao X, Lao XM, Chen MM, et al. PD-1^hi identifies a novel regulatory B-cell population in human hepatoma that promotes disease progression. Cancer Discov, 2016, 6(5): 546-559.
30. Ye L, Zhang Q, Cheng Y, et al. Tumor-derived exosomal HMGB1 fosters hepatocellular carcinoma immune evasion by promoting TIM-1⁺ regulatory B cell expansion. J Immunother Cancer, 2018, 6(1): 145.
31. Brinkhoff A, Zeng Y, Sieberichs A, et al. B-cell dynamics during experimental endotoxemia in humans. Biosci Rep, 2019, 39(5): BSR20182347.
32. Dai YC, Wang WD, Zhang JA, et al. MTB driven B cells producing IL-35 and secreting high level of IL-10 in the patients with active pulmonary tuberculosis. Mol Immunol, 2019, 112: 175-181.
33. Mishima Y, Oka A, Liu B, et al. Microbiota maintain colonic homeostasis by activating TLR2/MyD88/PI3K signaling in IL-10-producing regulatory B cells. J Clin Invest, 2019, 129(9): 3702-3716.
34. Zhang M, Zeng G, Yang Q, et al. Anti-tuberculosis treatment enhances the production of IL-22 through reducing the frequencies of regulatory B cell. Tuberculosis (Edinb), 2014, 94(3): 238-244.
35. Newell KA, Asare A, Kirk AD, et al. Identification of a B cell signature associated with renal transplant tolerance in humans. J Clin Invest, 2010, 120(6): 1836-1847.
36. Tebbe B, Wilde B, Ye Z, et al. Renal transplant recipients treated with calcineurin-inhibitors lack circulating immature transitional CD19⁺CD24^hiCD38^hi regulatory B-lymphocytes. PLoS One, 2016, 11(4): e0153170.

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