# Marginal-zone B cell

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**Marginal-zone B cells** (MZ B cells) are noncirculating mature [B cells](/source/B_cell) that in humans segregate anatomically into the [marginal zone](/source/Marginal_zone) (MZ) of the [spleen](/source/Spleen)[1] and certain other types of [lymphoid tissue](/source/Lymphoid_tissue).[2] The MZ B cells within this region typically express low-affinity polyreactive [B-cell receptors](/source/B-cell_receptor) (BCR), high levels of [IgM](/source/IgM), [Toll-like receptors](/source/Toll-like_receptor) (TLRs), [CD21](/source/CD21), [CD1](/source/CD1), [CD9](/source/CD9), [CD27](/source/CD27) with low to negligible levels of secreted-[IgD](/source/IgD), [CD23](/source/CD23), [CD5](/source/CD5_(protein)), and [CD11b](/source/CD11b) that help to distinguish them phenotypically from [follicular (FO) B cells](/source/Follicular_B_cell) and [B1 B cells](/source/B-1_cell).[2][3]

MZ B cells are innate-like B cells specialized to mount rapid T-independent, but also T-dependent responses against blood-borne pathogens.[4] They are also known to be the main producers of [IgM](/source/Immunoglobulin_M) antibodies in humans.[5]

## Development and differentiation

The spleen's [marginal zone](/source/Marginal_zone) contains multiple subtypes of [macrophages](/source/Macrophage) and [dendritic cells](/source/Dendritic_cell) interlaced with the MZ B cells; it is not fully formed until 2 to 3 weeks after birth in rodents and 1 to 2 years in humans.[6] In humans, but not rodents, marginal zone B cells are also located in the inner wall of the [subcapsular sinus](/source/Subcapsular_sinus) of lymph nodes, the epithelium of [tonsillar crypts](/source/Tonsillar_crypts), and the sub-epithelial area of mucosa-associated lymphoid tissues including the sub-epithelial dome of intestinal [Peyer's patches](/source/Peyer's_patch).[2] Human MZ B cells are also present in peripheral blood, suggesting that they recirculate.[7] However, in mice they seem to be noncirculating and only limited to follicular shuttling.[2]

In rodents, MZ B cells are recognized as [IgM](/source/Immunoglobulin_M)high[IgD](/source/Immunoglobulin_D)low[CD21](/source/CD21)high[CD23](/source/CD23)low population of B cells. They are furthermore distinguished by the expression of [CD9](/source/CD9)[3] and [CD27](/source/CD27) (in humans).[2] In mice, MZ B cells characteristically express high levels of [CD1d](/source/CD1D), which is an [MHC class I](/source/MHC_class_I)-like molecule involved in the presentation of lipid molecules to [NKT cells](/source/Natural_killer_T_cell).[8] Unlike FO B cells, MZ B cells express polyreactive [BCRs](/source/B-cell_receptor) that bind to multiple [microbial molecular patterns](/source/Pathogen-associated_molecular_pattern). Additionally, they express high levels of [TLRs](/source/Toll-like_receptor).[2]

In specimens where the tyrosine kinase for [Pyk-2](/source/PTK2B) has been knocked-out, marginal zone B-cells will fail to develop while [B-1 cells](/source/B-1_cell) will still be present. MZ B-cells are the only B-cells dependent on [NOTCH2](/source/NOTCH2) signaling for proliferation.[9]

## Activation and function

Similar to [B1 B cells](/source/B-1_cell), MZ B cells can be rapidly recruited into the early adaptive immune responses in a [T cell](/source/T_cell)-independent manner.[9] The MZ B cells are especially well-positioned as the first line of defense against systemic blood-borne antigens that enter the circulation and become trapped in the spleen.[10] While large blood-borne antigens are captured by [dendritic cells](/source/Dendritic_cell), circulating [granulocytes](/source/Granulocyte) or MZ [macrophages](/source/Macrophage), smaller blood-borne antigens may directly interact with MZ B cells situated on the exterior of the marginal sinus.[2][4] MZ B cells shuttle between the blood-filled marginal zone for antigen collection and the follicle for antigen delivery to [follicular dendritic cells](/source/Follicular_dendritic_cells). In mice, it has been shown that these cells shear flow via the [LFA-1](/source/LFA-1) integrin ligand [ICAM-1](/source/ICAM-1) and adhere or migrate down the flow via the [VLA-4](/source/VLA-4) integrin ligand [VCAM-1](/source/VCAM-1). While [CXCR5](/source/CXCR5)/[CXCL13](/source/CXCL13) signaling is required for MZ B cells to enter the follicle, [Sphingosine-1-phosphate signaling](/source/Sphingosine-1-phosphate) is required for them to exit from the follicle.[11]

MZ B cells respond to a wide spectrum of T-independent, but also T-dependent antigens. It is believed that MZ B cells are especially reactive to microbial polysaccharide antigens of [encapsulated bacteria](/source/Encapsulated_bacteria) such as *[Streptococcus pneumoniae](/source/Streptococcus_pneumoniae)*, *[Haemophilus influenzae](/source/Haemophilus_influenzae)* and *[Neisseria meningitidis](/source/Neisseria_meningitidis)*. TLRs often activate MZ B cells after recognizing [microbial molecular structures](/source/Pathogen-associated_molecular_pattern) in cooperation with the [BCR](/source/B-cell_receptor).[7] These innate-like B cells provide a rapid first line of defense against blood-borne pathogens and produce low-affinity [antibodies](/source/Antibody) of wide specificity before the induction of T-cell-dependent high-affinity antibody responses. Therefore, MZ B cells may play an important role in the prevention of [sepsis](/source/Sepsis).[8] MZ B cells also display a lower activation threshold than their FO B cell counterparts, with a heightened propensity for [plasma cell](/source/Plasma_cell) differentiation that contributes further to the accelerated primary antibody response.[2][12] They have been acknowledged as the main producers of [IgM](/source/Immunoglobulin_M) antibodies in humans.[5]

They are important for antibody-response toward invading pathogens and maintaining homeostasis via opsonization of dead cells and cellular debris.[5] Moreover, MZ B cells are potent [antigen-presenting cells](/source/Antigen-presenting_cell), that are able to activate [CD4+ T cells](/source/T_helper_cell) more effectively than FO B cells due to their elevated expression levels of [MHC class II](/source/MHC_class_II), [CD80](/source/CD80) and [CD86](/source/CD86) molecules.[2][7]

Deficiencies of MZ B cells are associated with a higher risk of [pneumococcal infection](/source/Pneumococcal_infection), [meningitis](/source/Meningitis) and insufficient antibody response to capsular polysaccharides.[2][4]

## Memory

In humans the splenic marginal zone B cells have evidence of [somatic hypermutation](/source/Somatic_hypermutation) in their immunoglobulin genes, indicating that they have been generated through a germinal centre reaction to become [memory cells](/source/Memory_B_cell). While naive MZ B cells produce low-affinity IgM antibodies, memory MZ B cells express high-affinity Ig molecules. Besides unswitched cells (IgM+), class-switched B cells can be found in the human and rodent marginal zone ([IgG](/source/Immunoglobulin_G)+ and [IgA](/source/Immunoglobulin_A)+). In humans, MZ B cells express [CD27](/source/CD27), which is a member of the TNF-receptor family expressed by human memory B cells.[8]

## Role in autoimmune diseases

Many of MZ B cell-receptors are self-reactive, which may be a factor that contributes to their expansion in some [autoimmune diseases](/source/Autoimmune_disease). On the other hand, aiding in the clearance of self-antigens is considered an important mechanism to prevent the development of autoimmune diseases. The role of expanded self-reactive MZ B cells has been observed on mice models of [lupus](/source/Lupus), [diabetes](/source/Diabetes) and [arthritis](/source/Arthritis).[7] However, their levels in human [vasculitis](/source/Vasculitis) are reduced.[5]

## Role in tumors

Marginal zone B cells are the malignant cells in [marginal zone lymphomas](/source/Marginal_zone_lymphoma), a heterogeneous group of generally indolent [lymphomas](/source/Lymphomas).[13]

## References

1. Martin F, Kearney JF (2002). "Marginal-zone B cells". *Nat Rev Immunol*. **2** (5): 323–335. [doi:10.1038/nri799](https://doi.org/10.1038/nri799). [PMID 12033738](https://pubmed.ncbi.nlm.nih.gov/12033738). [S2CID 22573840](https://api.semanticscholar.org/CorpusID:22573840)

1. Cerutti A, Cols M, Puga I (February 2013). "Marginal zone B cells: virtues of innate-like antibody-producing lymphocytes". *Nature Reviews. Immunology*. **13** (2): 118–32. [doi:10.1038/nri3383](https://doi.org/10.1038/nri3383). [PMC 3652659](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3652659). [PMID 23348416](https://pubmed.ncbi.nlm.nih.gov/23348416)

1. Won, Woong-Jai & Kearney, John F. (2002-06-01). "CD9 is a unique marker for marginal zone B cells, B1 cells, and plasma cells in mice". *Journal of Immunology*. **168** (11): 5605–5611. [doi:10.4049/jimmunol.168.11.5605](https://doi.org/10.4049/jimmunol.168.11.5605). [ISSN 0022-1767](https://www.worldcat.org/issn/0022-1767). [PMID 12023357](https://pubmed.ncbi.nlm.nih.gov/12023357)

1. Turner, Vivian M. & Mabbott, Neil A. (July 2017). "Ageing adversely affects the migration and function of marginal zone B cells". *Immunology*. **151** (3): 349–362. [doi:10.1111/imm.12737](https://doi.org/10.1111/imm.12737). [ISSN 1365-2567](https://www.worldcat.org/issn/1365-2567). [PMC 5461100](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5461100). [PMID 28369800](https://pubmed.ncbi.nlm.nih.gov/28369800)

1. Appelgren, Daniel; Eriksson, Per; Ernerudh, Jan; Segelmark, Mårten (2018-10-02). "Marginal-Zone B-Cells Are Main Producers of IgM in Humans, and Are Reduced in Patients With Autoimmune Vasculitis". *Frontiers in Immunology*. **9**. [doi:10.3389/fimmu.2018.02242](https://doi.org/10.3389/fimmu.2018.02242). [ISSN 1664-3224](https://www.worldcat.org/issn/1664-3224). [PMC 6190848](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6190848). [PMID 30356862](https://pubmed.ncbi.nlm.nih.gov/30356862)

1. MacLennan IC, Bazin H, Chassoux D et al. (1985). "Comparative Analysis of the Development of B Cells in Marginal Zones and Follicles". *Microenvironments in the Lymphoid System*. Vol. 186. Advances in Experimental Medicine and Biology. pp. 139–144. [doi:10.1007/978-1-4613-2463-8_17](https://doi.org/10.1007/978-1-4613-2463-8_17). ISBN 978-1-4612-9495-5. [PMID 3876699](https://pubmed.ncbi.nlm.nih.gov/3876699)

1. Palm, Anna-Karin E.; Friedrich, Heike C.; Kleinau, Sandra (2016-06-09). "Nodal marginal zone B cells in mice: a novel subset with dormant self-reactivity". *Scientific Reports*. **6** (1). [Bibcode:2016NatSR...627687P](https://ui.adsabs.harvard.edu/abs/2016NatSR...627687P). [doi:10.1038/srep27687](https://doi.org/10.1038/srep27687). [ISSN 2045-2322](https://www.worldcat.org/issn/2045-2322). [PMC 4899733](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4899733). [PMID 27277419](https://pubmed.ncbi.nlm.nih.gov/27277419)

1. Hendricks, Jacobus; Bos, Nicolaas A.; Kroese, Frans G.M. (2018). "Heterogeneity of Memory Marginal Zone B Cells". *Critical Reviews in Immunology*. **38** (2): 145–158. [doi:10.1615/CritRevImmunol.2018024985](https://doi.org/10.1615/CritRevImmunol.2018024985). [ISSN 1040-8401](https://www.worldcat.org/issn/1040-8401). [PMC 5989013](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5989013). [PMID 29887727](https://pubmed.ncbi.nlm.nih.gov/29887727)

1. Hardy, Richard (2008). "Chapter 7: B Lymphocyte Development and Biology". *Fundamental Immunology* (Book). 6th ed. Philadelphia: Lippincott Williams & Wilkins. pp. 237–269. ISBN 978-0-7817-6519-0.

1. Balazs M, Martin F, Zhou T et al. (2002). "Blood dendritic cells interact with splenic marginal zone B cells to initiate T-independent immune responses". *Immunity*. **17** (3): 341–352. [doi:10.1016/s1074-7613(02)00389-8](https://doi.org/10.1016/s1074-7613(02)00389-8). [PMID 12354386](https://pubmed.ncbi.nlm.nih.gov/12354386)

1. Tedford, Kerry; Steiner, Michael; Koshutin, Stanislav; Richter, Karin; Tech, Laura; Eggers, Yannik; Jansing, Inga; Schilling, Kerstin; Hauser, Anja Erika; Korthals, Mark; Fischer, Klaus-Dieter (2017-12-22). "The opposing forces of shear flow and sphingosine-1-phosphate control marginal zone B cell shuttling". *Nature Communications*. **8** (1): 2261. [Bibcode:2017NatCo...8.2261T](https://ui.adsabs.harvard.edu/abs/2017NatCo...8.2261T). [doi:10.1038/s41467-017-02482-4](https://doi.org/10.1038/s41467-017-02482-4). [ISSN 2041-1723](https://www.worldcat.org/issn/2041-1723). [PMC 5741619](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5741619). [PMID 29273735](https://pubmed.ncbi.nlm.nih.gov/29273735)

1. Lopes-Carvalho T, Foote J, Kearney JF (2005). "Marginal zone B cells in lymphocyte activation and regulation". *Curr Opin Immunol*. **17** (3): 244–250. [doi:10.1016/j.coi.2005.04.009](https://doi.org/10.1016/j.coi.2005.04.009). [PMID 15886113](https://pubmed.ncbi.nlm.nih.gov/15886113)

1. Bron D, Meuleman N (September 2019). "Marginal zone lymphomas: second most common lymphomas in older patients". *Current Opinion in Oncology*. **31** (5): 386–393. [doi:10.1097/CCO.0000000000000554](https://doi.org/10.1097/CCO.0000000000000554). [PMID 31246587](https://pubmed.ncbi.nlm.nih.gov/31246587). [S2CID 195765608](https://api.semanticscholar.org/CorpusID:195765608)

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Adapted from the Wikipedia article [Marginal-zone B cell](https://en.wikipedia.org/wiki/Marginal-zone_B_cell) by Wikipedia contributors ([contributor history](https://en.wikipedia.org/wiki/Marginal-zone_B_cell?action=history)). Available under [Creative Commons Attribution-ShareAlike 4.0 International](https://creativecommons.org/licenses/by-sa/4.0/). Changes may have been made.