Marginal-zone B cell

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Histology of a normal lymphoid follicle, with marginal zone annotated at bottom. Dark, light, mantle and marginal zones of a secondary follicle.png
Histology of a normal lymphoid follicle, with marginal zone annotated at bottom.

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

Contents

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 antibodies in humans. [5]

Development and differentiation

The spleen's marginal zone contains multiple subtypes of macrophages and dendritic cells 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 of lymph nodes, the epithelium of tonsillar crypts, and the sub-epithelial area of mucosa-associated lymphoid tissues including the sub-epithelial dome of intestinal Peyer's patches. [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 high IgD low CD21 high CD23 low population of B cells. They are furthermore distinguished by the expression of CD9 [3] and CD27 (in humans). [2] In mice, MZ B cells characteristically express high levels of CD1d, which is an MHC class I-like molecule involved in the presentation of lipid molecules to NKT cells. [8] Unlike FO B cells, MZ B cells express polyreactive BCRs that bind to multiple microbial molecular patterns. Additionally, they express high levels of TLRs. [2]

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

Activation and function

Similar to B1 B cells, MZ B cells can be rapidly recruited into the early adaptive immune responses in a 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, circulating granulocytes or MZ macrophages, 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. In mice, it has been shown that these cells shear flow via the LFA-1 integrin ligand ICAM-1 and adhere or migrate down the flow via the VLA-4 integrin ligand VCAM-1. While CXCR5/CXCL13 signaling is required for MZ B cells to enter the follicle, Sphingosine-1-phosphate signaling 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 such as Streptococcus pneumoniae , Haemophilus influenzae and Neisseria meningitidis . TLRs often activate MZ B cells after recognizing microbial molecular structures in cooperation with the BCR. [7] These innate-like B cells provide a rapid first line of defense against blood-borne pathogens and produce low-affinity antibodies 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. [8] MZ B cells also display a lower activation threshold than their FO B cell counterparts, with a heightened propensity for plasma cell differentiation that contributes further to the accelerated primary antibody response. [2] [12] They have been acknowledged as the main producers of IgM 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, that are able to activate CD4+ T cells more effectively than FO B cells due to their elevated expression levels of MHC class II, CD80 and CD86 molecules. [2] [7]

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

Memory

In humans the splenic marginal zone B cells have evidence of somatic hypermutation in their immunoglobulin genes, indicating that they have been generated through a germinal centre reaction to become memory cells. 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+ and IgA+). In humans, MZ B cells express 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. 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, diabetes and arthritis. [7] However, their levels in human vasculitis are reduced. [5]

Role in tumors

Marginal zone B cells are the malignant cells in marginal zone lymphomas, a heterogeneous group of generally indolent lymphomas. [13]

Related Research Articles

<span class="mw-page-title-main">Antibody</span> Protein(s) forming a major part of an organisms immune system

An antibody (Ab) is the secreted form of a B cell receptor; the term immunoglobulin (Ig) can refer to either the membrane-bound form or the secreted form of the B cell receptor, but they are, broadly speaking, the same protein, and so the terms are often treated as synonymous. Antibodies are large, Y-shaped proteins belonging to the immunoglobulin superfamily which are used by the immune system to identify and neutralize antigens such as bacteria and viruses, including those that cause disease. Antibodies can recognize virtually any size antigen with diverse chemical compositions from molecules. Each antibody recognizes one or more specific antigens. Antigen literally means "antibody generator", as it is the presence of an antigen that drives the formation of an antigen-specific antibody. Each tip of the "Y" of an antibody contains a paratope that specifically binds to one particular epitope on an antigen, allowing the two molecules to bind together with precision. Using this mechanism, antibodies can effectively "tag" a microbe or an infected cell for attack by other parts of the immune system, or can neutralize it directly.

<span class="mw-page-title-main">B cell</span> Type of white blood cell

B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or inserted into the plasma membrane where they serve as a part of B-cell receptors. When a naïve or memory B cell is activated by an antigen, it proliferates and differentiates into an antibody-secreting effector cell, known as a plasmablast or plasma cell. In addition, B cells present antigens and secrete cytokines. In mammals, including marsupials B cells mature in the bone marrow, which is at the core of most bones. In birds, B cells mature in the bursa of Fabricius, a lymphoid organ where they were first discovered by Chang and Glick, which is why the B stands for bursa and not bone marrow, as commonly believed.

<span class="mw-page-title-main">Natural killer cell</span> Type of cytotoxic lymphocyte

Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system. They belong to the rapidly expanding family of known innate lymphoid cells (ILC) and represent 5–20% of all circulating lymphocytes in humans. The role of NK cells is analogous to that of cytotoxic T cells in the vertebrate adaptive immune response. NK cells provide rapid responses to virus-infected cells, stressed cells, tumor cells, and other intracellular pathogens based on signals from several activating and inhibitory receptors. Most immune cells detect the antigen presented on major histocompatibility complex I (MHC-I) on infected cell surfaces, but NK cells can recognize and kill stressed cells in the absence of antibodies and MHC, allowing for a much faster immune reaction. They were named "natural killers" because of the notion that they do not require activation to kill cells that are missing "self" markers of MHC class I. This role is especially important because harmful cells that are missing MHC I markers cannot be detected and destroyed by other immune cells, such as T lymphocyte cells.

<span class="mw-page-title-main">CD32</span> Surface receptor glycoprotein

CD32, also known as FcγRII or FCGR2, is a surface receptor glycoprotein belonging to the Ig gene superfamily. CD32 can be found on the surface of a variety of immune cells. CD32 has a low-affinity for the Fc region of IgG antibodies in monomeric form, but high affinity for IgG immune complexes. CD32 has two major functions: cellular response regulation, and the uptake of immune complexes. Cellular responses regulated by CD32 include phagocytosis, cytokine stimulation, and endocytic transport. Dysregulated CD32 is associated with different forms of autoimmunity, including systemic lupus erythematosus. In humans, there are three major CD32 subtypes: CD32A, CD32B, and CD32C. While CD32A and CD32C are involved in activating cellular responses, CD32B is inhibitory.

<span class="mw-page-title-main">Plasma cell</span> White blood cell that secretes large volumes of antibodies

Plasma cells, also called plasma B cells or effector B cells, are white blood cells that originate in the lymphoid organs as B cells and secrete large quantities of proteins called antibodies in response to being presented specific substances called antigens. These antibodies are transported from the plasma cells by the blood plasma and the lymphatic system to the site of the target antigen, where they initiate its neutralization or destruction. B cells differentiate into plasma cells that produce antibody molecules closely modeled after the receptors of the precursor B cell.

A splenocyte is a white blood cell that resides in the spleen and are involved in functions of the spleen, like filtering blood and the immune response.

<span class="mw-page-title-main">Memory B cell</span> Cell of the adaptive immune system

In immunology, a memory B cell (MBC) is a type of B lymphocyte that forms part of the adaptive immune system. These cells develop within germinal centers of the secondary lymphoid organs. Memory B cells circulate in the blood stream in a quiescent state, sometimes for decades. Their function is to memorize the characteristics of the antigen that activated their parent B cell during initial infection such that if the memory B cell later encounters the same antigen, it triggers an accelerated and robust secondary immune response. Memory B cells have B cell receptors (BCRs) on their cell membrane, identical to the one on their parent cell, that allow them to recognize antigen and mount a specific antibody response.

<span class="mw-page-title-main">CD23</span> Low-affinity" receptor for IgE

CD23, also known as Fc epsilon RII, or FcεRII, is the "low-affinity" receptor for IgE, an antibody isotype involved in allergy and resistance to parasites, and is important in regulation of IgE levels. Unlike many of the antibody receptors, CD23 is a C-type lectin. It is found on mature B cells, activated macrophages, eosinophils, follicular dendritic cells, and platelets.

<span class="mw-page-title-main">Marginal zone</span> Part of the spleen

The marginal zone is the region at the interface between the non-lymphoid red pulp and the lymphoid white-pulp of the spleen.

<span class="mw-page-title-main">CD40 (protein)</span> Mammalian protein found in humans

Cluster of differentiation 40, CD40 is a type I transmembrane protein found on antigen-presenting cells and is required for their activation. The binding of CD154 (CD40L) on TH cells to CD40 activates antigen presenting cells and induces a variety of downstream effects.

<span class="mw-page-title-main">Germinal center</span> Lymphatic tissue structure

Germinal centers or germinal centres (GCs) are transiently formed structures within B cell zone (follicles) in secondary lymphoid organs – lymph nodes, ileal Peyer's patches, and the spleen – where mature B cells are activated, proliferate, differentiate, and mutate their antibody genes during a normal immune response; most of the germinal center B cells (BGC) are removed by tingible body macrophages. There are several key differences between naive B cells and GC B cells, including level of proliferative activity, size, metabolic activity and energy production. The B cells develop dynamically after the activation of follicular B cells by T-dependent antigen. The initiation of germinal center formation involves the interaction between B and T cells in the interfollicular area of the lymph node, CD40-CD40L ligation, NF-kB signaling and expression of IRF4 and BCL6.

<span class="mw-page-title-main">Follicular dendritic cells</span> Immune cells found in lymph nodes

Follicular dendritic cells (FDC) are cells of the immune system found in primary and secondary lymph follicles of the B cell areas of the lymphoid tissue. Unlike dendritic cells (DC), FDCs are not derived from the bone-marrow hematopoietic stem cell, but are of mesenchymal origin. Possible functions of FDC include: organizing lymphoid tissue's cells and microarchitecture, capturing antigen to support B cell, promoting debris removal from germinal centers, and protecting against autoimmunity. Disease processes that FDC may contribute include primary FDC-tumor, chronic inflammatory conditions, HIV-1 infection development, and neuroinvasive scrapie.

<span class="mw-page-title-main">CD19</span> Biomarker for B cell lineage

B-lymphocyte antigen CD19, also known as CD19 molecule, B-Lymphocyte Surface Antigen B4, T-Cell Surface Antigen Leu-12 and CVID3 is a transmembrane protein that in humans is encoded by the gene CD19. In humans, CD19 is expressed in all B lineage cells. Contrary to some early doubts, human plasma cells do express CD19, as confirmed by others. CD19 plays two major roles in human B cells: on the one hand, it acts as an adaptor protein to recruit cytoplasmic signaling proteins to the membrane; on the other, it works within the CD19/CD21 complex to decrease the threshold for B cell receptor signaling pathways. Due to its presence on all B cells, it is a biomarker for B lymphocyte development, lymphoma diagnosis and can be utilized as a target for leukemia immunotherapies.

CD70 is a protein that in humans is encoded by CD70 gene. CD70 is also known as a ligand for CD27.

B1 cells are a sub-class of B cell lymphocytes that are involved in the humoral immune response. They are not part of the adaptive immune system, as they have no memory, but otherwise, B1 cells perform many of the same roles as other B cells: making antibodies against antigens and acting as antigen-presenting cells. These B1 cells are commonly found in peripheral sites, but less commonly found in the blood. These cells are involved in antibody response during an infection or vaccination.

<span class="mw-page-title-main">GPR183</span> Protein-coding gene in the species Homo sapiens

G-protein coupled receptor 183 also known as Epstein-Barr virus-induced G-protein coupled receptor 2 (EBI2) is a protein (GPCR) expressed on the surface of some immune cells, namely B cells and T cells; in humans it is encoded by the GPR183 gene. Expression of EBI2 is one critical mediator of immune cell localization within lymph nodes, responsible in part for the coordination of B cell, T cell, and dendritic cell movement and interaction following antigen exposure. EBI2 is a receptor for oxysterols. The most potent activator is 7α,25-dihydroxycholesterol (7α,25-OHC), with other oxysterols exhibiting varying affinities for the receptor. Oxysterol gradients drive chemotaxis, attracting the EBI2-expressing cells to locations of high ligand concentration. The GPR183 gene was identified due to its upregulation during Epstein-Barr virus infection of the Burkitt's lymphoma cell line BL41, hence its name: EBI2.

Within the immune system, Follicular B cells are a type of B cell that reside in primary and secondary lymphoid follicles of secondary and tertiary lymphoid organs, including spleen and lymph nodes. Antibody responses against proteins are believed to involve follicular B cell pathways in secondary lymphoid organs.

<span class="mw-page-title-main">Follicular B helper T cells</span>

Follicular helper T cells (also known as T follicular helper cells and abbreviated as TFH), are antigen-experienced CD4+ T cells found in the periphery within B cell follicles of secondary lymphoid organs such as lymph nodes, spleen and Peyer's patches, and are identified by their constitutive expression of the B cell follicle homing receptor CXCR5. Upon cellular interaction and cross-signaling with their cognate follicular (Fo B) B cells, TFH cells trigger the formation and maintenance of germinal centers through the expression of CD40 ligand (CD40L) and the secretion of IL-21 and IL-4. TFH cells also migrate from T cell zones into these seeded germinal centers, predominantly composed of rapidly dividing B cells mutating their Ig genes. Within germinal centers, TFH cells play a critical role in mediating the selection and survival of B cells that go on to differentiate either into long-lived plasma cells capable of producing high affinity antibodies against foreign antigen, or germinal center-dependent memory B cells capable of quick immune re-activation in the future if ever the same antigen is re-encountered. TFH cells are also thought to facilitate negative selection of potentially autoimmune-causing mutated B cells in the germinal center. However, the biomechanisms by which TFH cells mediate germinal center tolerance are yet to be fully understood.

<span class="mw-page-title-main">Centroblast</span>

A centroblast generally refers to an activated B cell that is enlarged and is rapidly proliferating in the germinal center of a lymphoid follicle. They are specifically located in the dark zone of the germinal center. Centroblasts form from naive B cells being exposed to follicular dendritic cell cytokines, such as IL-6, IL-15, 8D6, and BAFF. Stimulation from helper T cells is also required for centroblast development. Interaction between CD40 ligand on an activated T helper cell and the B cell CD40 receptor induces centroblasts to express activation-induced cytidine deaminase, leading to somatic hypermutation, allowing the B cell receptor to potentially gain stronger affinity for an antigen. In the absence of FDC and helper T cell stimulation, centroblasts are unable to differentiate and will undergo CD95-mediated apoptosis.

B10 cells are a sub-class of regulatory B-cells that are involved in inhibiting immune responses in both humans and mice. B10 cells are named for their ability to produce inhibitory interleukin: Interleukin-10 (IL-10). One of their unique abilities is that they suppress the innate and adaptive immune signals, making them important for regulating the inflammatory response. Like the B cell, the B10 cell requires antigen specific binding to the surface of CD5 receptor to illicit a response from the T-cell. Once an antigen binds to the CD19 receptor, immediate downregulation in B-cell receptor (BCR) signal expression occurs and mediates the release of IL-10 cytokines. In mice and humans, B10 cells are distinguishable in their expression of measurable IL-10 due to the lack of unique cell surface markers expressed by regulatory B cells. However, IL-10 competence is not limited to any one subset of B cells. B10 cells do not possess unique phenotypic markers or transcription factors for further identification. B10 cells predominantly localize in the spleen, though they are also found in the blood, lymph nodes, Peyer's patches, intestinal tissues, central nervous system, and peritoneal cavity. B10 cells proliferate during inflammatory and disease responses.

References

  1. ↑ Martin F, Kearney JF (2002). "Marginal-zone B cells". Nat Rev Immunol. 2 (5): 323–335. doi:10.1038/nri799. PMID   12033738. S2CID   22573840.
  2. 1 2 3 4 5 6 7 8 9 10 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. PMC   3652659 . PMID   23348416.
  3. 1 2 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 . ISSN   0022-1767. PMID   12023357.
  4. 1 2 3 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. ISSN   1365-2567. PMC   5461100 . PMID   28369800.
  5. 1 2 3 4 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: 2242. doi: 10.3389/fimmu.2018.02242 . ISSN   1664-3224. PMC   6190848 . PMID   30356862.
  6. ↑ 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. Advances in Experimental Medicine and Biology. Vol. 186. pp. 139–144. doi:10.1007/978-1-4613-2463-8_17. ISBN   978-1-4612-9495-5. PMID   3876699.{{cite book}}: CS1 maint: multiple names: authors list (link)
  7. 1 2 3 4 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): 27687. Bibcode:2016NatSR...627687P. doi: 10.1038/srep27687 . ISSN   2045-2322. PMC   4899733 . PMID   27277419.
  8. 1 2 3 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. ISSN   1040-8401. PMC   5989013 . PMID   29887727.
  9. 1 2 Hardy, Richard (2008). "Chapter 7: B Lymphocyte Development and Biology". In Paul, William (ed.). Fundamental Immunology (Book) (6th ed.). Philadelphia: Lippincott Williams & Wilkins. pp. 237–269. ISBN   978-0-7817-6519-0.
  10. ↑ 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 . PMID   12354386.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  11. ↑ 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. doi: 10.1038/s41467-017-02482-4 . ISSN   2041-1723. PMC   5741619 . PMID   29273735.
  12. ↑ 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. PMID   15886113.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  13. ↑ 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. PMID   31246587. S2CID   195765608.
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