Volume 28, Issue 3 (5-2021)
RJMS 2021, 28(3): 80-94 |
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Baharlooi H, Seraji B, Izad M. Regulatory B cells and their role in the pathogenesis of multiple sclerosis: A Review Articl. RJMS 2021; 28 (3) :80-94
URL: http://rjms.iums.ac.ir/article-1-6051-en.html
URL: http://rjms.iums.ac.ir/article-1-6051-en.html
Tehran University of Medical Sciences, Tehran, Iran , izadm@sina.tums.ac.ir
Abstract: (1890 Views)
Multiple sclerosis (MS) is an autoimmune disorder of the central nervous system which is caused by impaired immune response against self-antigens (2). In 2016, more than 2 million MS patients were reported worldwide (3). The prevalence of the disease in Iran is estimated to be 29.3 and its incidence 3.4 per 1000 (4). The disease usually occurs in adults in the age range of 20 to 40 years and is twice as common in women as men (5).
Despite extensive efforts to identify the mechanisms involved in the disease process, the cause of the disease remains unknown. However, it is believed that of genetic factors, viral infections and some other environmental factors increase the risk of the disease (7). Most studies show high titers of anti-EBV antibodies in the serum of patients as well as an increased risk of MS in people with a history of mononucleosis (9, 8). Although there have been conflicting reports, other infectious agents including herpes virus type 6, retroviruses and Chlamydia pneumoniae are reported to involved in the development of MS (10-13). In addition to environmental factors, many evidences showed that genetic factors can also be effective in the incidence of the disease. There is a strong association between DQB1 * 0602, DQA1 * 0102, DRB1 * 1501, HLA-DRB1 * 03 alleles and MS, while HLA-DRB1 * 01 and HLA-DRB1 * 11 alleles reduce the risk of disease. (15, 16). It also appears to be a link between genes involved in the immune system responses, such as genes for T cells beta receptor, cytokines, TIM3, NLRP3, and MS, which need further investigation (14: 17-19). Both innate and acquired immune responses against self-antigens are involved in the development of MS. CD4 + T, CD8 + T lymphocytes, B lymphocytes, NK cells, NKT and mast cells and molecules such as antibodies, TLRs, complement and cytokines have been reported to be major mediators of disease progression. In the past, it was mostly thought that MS is caused only by T lymphocytes, but proving the presence of B lymphocytes in the meninges of patients, provided important evidence for playing an essential role of B lymphocytes in the disease process. (24). B lymphocytes are involved in the progression of MS in three pathways: 1) the production of antibodies against self-antigens. 2) Antigen delivery to specific CD4 + and CD8 + T cells by MHC class I and II expression 3) Cytokine production including IL-4, IL-6, IL-10, IFN-γ, and TGF-β (32-34).
Some studies have suggested the presence of abnormal lymphoid follicles containing B lymphocytes and plasma cells in the meninges of groups of secondary progressive MS (SP-MS) patients. The presence of lymphoid-like structures in the brains of patients with MS can be a site for the proliferation and maturation of B cells, which eventually leads to locall production of immunoglobulins which is associated with the severity and clinical signs of the disease (36, 37).
More than two decades ago, it was discovered that B cells in experimental autoimmune encephalomyelitis (EAE), the animal model of MS, could have regulatory properties. Several studies have shown that B cells secrete a variety of anti-inflammatory factors such as IL-10 and IL-35 in response to autoantigens stimulation to prevent disease progression (59). In the absence of IL-10-producing cells, the Th1-mediated pro-inflammatory immune response persisted and mice did not recover from the disease (60). These findings eventually led to B cells being considered as important cells in the production of IL-10 for control of EAE. There are also supporting evidence for regulatory B cell (Breg) abnormalities in the MS patients (25, 26). Therefore, the present study reviews the latest findings provided for the subsets and roles of the Bregs contributing to the MS pathogenesis.
Regulatory B cells (Bregs) have been functionally defined mostly due to their capacity to produce anti-inflammatory cytokines including transforming growth factor beta (TGF-β), interleukin-35 (IL-35) and more importantly interleukin-10 (IL-10) following stimulation most often by toll-like receptor 9 agonists, CD40 ligand, and B cell receptors (59, 68, 72).
Numerous studies suggest that regulatory B cells are formed at different stages of B lymphocyte development and are involved in the homeostasis of immune responses (61). The phenotype and mode of action of these cells vary depending on the cell from which they are derived. Thus, Transitional, mature and memory B cells in the germinal centers are the origins of CD19 + CD20+ CD24hi CD38hi CD27-, CD19 + CD20low/int CD24- CD38- CD27int and CD1dhiCD5+ CD19+ CD20+ CD24hi CD38low/int CD27+ regulatory B cells respectively. The regulatory activity of these cells is mainly through the production and secretion of IL-10 (62)
Transitional Breg cells which express high levels of IL-10, can play an inhibitory role in the autoimmune diseases (73). One of the most important activities of these cells is to suppress the proliferation and production of inflammatory cytokines from Th1 and Th17 cells (74). This observation suggests that functional defects of Bregs during disease may have reduced their effectiveness.
Plasmablast Breg cells are regulatory B cells was first identified and introduced in two consecutive reports in 2014. In humans, their surface markers are CD19 + CD20low / int CD24-CD38-CD27int and produce and secrete IL-10, IL-35, IRF4 and Blimp1 (78, 79). During induction of EAE in mice, the above cells form in the lymph nodes and suppress inflammation through IL-10 production (78).
Another class of regulatory B cells known as B10 were first identified in contact hypersensitivity with the CD1dhiCD5 + phenotype. These cells suppressed inflammation induced by T lymphocyte activity through secreting IL-10 (80). IL-10 is produced by regulatory B cells following stimulation of TLR2 and TLR4 (80). In a study on patients with lupus (SLE), human regulatory B cells with CD19 + CD24hiCD38hi phenotype were isolated from peripheral blood. The cells produced IL-10 under CD40L stimulation, which in turn inhibited CD4 + T cells producing IFN- γ and TNF-α (87).
In addition to producing soluble factors such as IL-10, physical contact between T CD4 + and regulatory B cells is also necessary to exert an inhibitory effect by B cells. This means that antigen detection by regulatory B cells is one of the essential processes and antigen stimulation is important for complete inhibition of Th1 cells differentiation (88). Recent findings point to the fact that Bregs have lower quantity and IL-10 producing capacity in MS patients particularly in relapse phase (66). Many studies show that disease modifying drugs (DMDs) which have been approved for the treatment of multiple sclerosis, are able to improve the function and number of regulatory B cells in multiple sclerosis patients and EAE (63-72).
Overall, this study demonstrates the importance of proper regulatory B cell activity in preventing autoimmune reactions, especially MS. Modulation of these cells may be a way to prevent the progression of MS in the early stages of the disease. Better understanding the origin and specific markers for the separation and improving the function of Breg cells is one of the most essential issues that will touch the subject of regulatory B cell therapy. These changes should affect goals such as increasing the number and secretion of anti-inflammatory cytokines such as IL-10 and TGF-β.
Despite extensive efforts to identify the mechanisms involved in the disease process, the cause of the disease remains unknown. However, it is believed that of genetic factors, viral infections and some other environmental factors increase the risk of the disease (7). Most studies show high titers of anti-EBV antibodies in the serum of patients as well as an increased risk of MS in people with a history of mononucleosis (9, 8). Although there have been conflicting reports, other infectious agents including herpes virus type 6, retroviruses and Chlamydia pneumoniae are reported to involved in the development of MS (10-13). In addition to environmental factors, many evidences showed that genetic factors can also be effective in the incidence of the disease. There is a strong association between DQB1 * 0602, DQA1 * 0102, DRB1 * 1501, HLA-DRB1 * 03 alleles and MS, while HLA-DRB1 * 01 and HLA-DRB1 * 11 alleles reduce the risk of disease. (15, 16). It also appears to be a link between genes involved in the immune system responses, such as genes for T cells beta receptor, cytokines, TIM3, NLRP3, and MS, which need further investigation (14: 17-19). Both innate and acquired immune responses against self-antigens are involved in the development of MS. CD4 + T, CD8 + T lymphocytes, B lymphocytes, NK cells, NKT and mast cells and molecules such as antibodies, TLRs, complement and cytokines have been reported to be major mediators of disease progression. In the past, it was mostly thought that MS is caused only by T lymphocytes, but proving the presence of B lymphocytes in the meninges of patients, provided important evidence for playing an essential role of B lymphocytes in the disease process. (24). B lymphocytes are involved in the progression of MS in three pathways: 1) the production of antibodies against self-antigens. 2) Antigen delivery to specific CD4 + and CD8 + T cells by MHC class I and II expression 3) Cytokine production including IL-4, IL-6, IL-10, IFN-γ, and TGF-β (32-34).
Some studies have suggested the presence of abnormal lymphoid follicles containing B lymphocytes and plasma cells in the meninges of groups of secondary progressive MS (SP-MS) patients. The presence of lymphoid-like structures in the brains of patients with MS can be a site for the proliferation and maturation of B cells, which eventually leads to locall production of immunoglobulins which is associated with the severity and clinical signs of the disease (36, 37).
More than two decades ago, it was discovered that B cells in experimental autoimmune encephalomyelitis (EAE), the animal model of MS, could have regulatory properties. Several studies have shown that B cells secrete a variety of anti-inflammatory factors such as IL-10 and IL-35 in response to autoantigens stimulation to prevent disease progression (59). In the absence of IL-10-producing cells, the Th1-mediated pro-inflammatory immune response persisted and mice did not recover from the disease (60). These findings eventually led to B cells being considered as important cells in the production of IL-10 for control of EAE. There are also supporting evidence for regulatory B cell (Breg) abnormalities in the MS patients (25, 26). Therefore, the present study reviews the latest findings provided for the subsets and roles of the Bregs contributing to the MS pathogenesis.
Regulatory B cells (Bregs) have been functionally defined mostly due to their capacity to produce anti-inflammatory cytokines including transforming growth factor beta (TGF-β), interleukin-35 (IL-35) and more importantly interleukin-10 (IL-10) following stimulation most often by toll-like receptor 9 agonists, CD40 ligand, and B cell receptors (59, 68, 72).
Numerous studies suggest that regulatory B cells are formed at different stages of B lymphocyte development and are involved in the homeostasis of immune responses (61). The phenotype and mode of action of these cells vary depending on the cell from which they are derived. Thus, Transitional, mature and memory B cells in the germinal centers are the origins of CD19 + CD20+ CD24hi CD38hi CD27-, CD19 + CD20low/int CD24- CD38- CD27int and CD1dhiCD5+ CD19+ CD20+ CD24hi CD38low/int CD27+ regulatory B cells respectively. The regulatory activity of these cells is mainly through the production and secretion of IL-10 (62)
Transitional Breg cells which express high levels of IL-10, can play an inhibitory role in the autoimmune diseases (73). One of the most important activities of these cells is to suppress the proliferation and production of inflammatory cytokines from Th1 and Th17 cells (74). This observation suggests that functional defects of Bregs during disease may have reduced their effectiveness.
Plasmablast Breg cells are regulatory B cells was first identified and introduced in two consecutive reports in 2014. In humans, their surface markers are CD19 + CD20low / int CD24-CD38-CD27int and produce and secrete IL-10, IL-35, IRF4 and Blimp1 (78, 79). During induction of EAE in mice, the above cells form in the lymph nodes and suppress inflammation through IL-10 production (78).
Another class of regulatory B cells known as B10 were first identified in contact hypersensitivity with the CD1dhiCD5 + phenotype. These cells suppressed inflammation induced by T lymphocyte activity through secreting IL-10 (80). IL-10 is produced by regulatory B cells following stimulation of TLR2 and TLR4 (80). In a study on patients with lupus (SLE), human regulatory B cells with CD19 + CD24hiCD38hi phenotype were isolated from peripheral blood. The cells produced IL-10 under CD40L stimulation, which in turn inhibited CD4 + T cells producing IFN- γ and TNF-α (87).
In addition to producing soluble factors such as IL-10, physical contact between T CD4 + and regulatory B cells is also necessary to exert an inhibitory effect by B cells. This means that antigen detection by regulatory B cells is one of the essential processes and antigen stimulation is important for complete inhibition of Th1 cells differentiation (88). Recent findings point to the fact that Bregs have lower quantity and IL-10 producing capacity in MS patients particularly in relapse phase (66). Many studies show that disease modifying drugs (DMDs) which have been approved for the treatment of multiple sclerosis, are able to improve the function and number of regulatory B cells in multiple sclerosis patients and EAE (63-72).
Overall, this study demonstrates the importance of proper regulatory B cell activity in preventing autoimmune reactions, especially MS. Modulation of these cells may be a way to prevent the progression of MS in the early stages of the disease. Better understanding the origin and specific markers for the separation and improving the function of Breg cells is one of the most essential issues that will touch the subject of regulatory B cell therapy. These changes should affect goals such as increasing the number and secretion of anti-inflammatory cytokines such as IL-10 and TGF-β.
Type of Study: review article |
Subject:
Immunology
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