Marginal-zone B cells (MZ B cells) are noncirculating matureB cells that in humans segregate anatomically into themarginal zone (MZ) of thespleen[1] and certain other types oflymphoid tissue.[2] The MZ B cells within this region typically express low-affinity polyreactiveB-cell receptors (BCR), high levels ofIgM,Toll-like receptors (TLRs),CD21,CD1,CD9,CD27 with low to negligible levels of secreted-IgD,CD23,CD5, andCD11b that help to distinguish them phenotypically fromfollicular (FO) B cells andB1 B cells.[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 ofIgM antibodies in humans.[5]
The spleen'smarginal zone contains multiple subtypes ofmacrophages anddendritic 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 thesubcapsular sinus of lymph nodes, the epithelium oftonsillar crypts, and the sub-epithelial area of mucosa-associated lymphoid tissues including the sub-epithelial dome of intestinalPeyer'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 asIgMhighIgDlowCD21highCD23low population of B cells. They are furthermore distinguished by the expression ofCD9[3] andCD27 (in humans).[2] In mice, MZ B cells characteristically express high levels ofCD1d, which is anMHC class I-like molecule involved in the presentation of lipid molecules toNKT cells.[8] Unlike FO B cells, MZ B cells express polyreactiveBCRs that bind to multiplemicrobial molecular patterns. Additionally, they express high levels ofTLRs.[2]
In specimens where the tyrosine kinase forPyk-2 has been knocked-out, marginal zone B-cells will fail to develop whileB-1 cells will still be present. MZ B-cells are the only B-cells dependent onNOTCH2 signaling for proliferation.[9]
Similar toB1 B cells, MZ B cells can be rapidly recruited into the early adaptive immune responses in aT 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 bydendritic cells, circulatinggranulocytes or MZmacrophages, 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 tofollicular dendritic cells. In mice, it has been shown that these cells shear flow via theLFA-1 integrin ligandICAM-1 and adhere or migrate down the flow via theVLA-4 integrin ligandVCAM-1. WhileCXCR5/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 ofencapsulated bacteria such asStreptococcus pneumoniae,Haemophilus influenzae andNeisseria meningitidis. TLRs often activate MZ B cells after recognizingmicrobial molecular structures in cooperation with theBCR.[7] These innate-like B cells provide a rapid first line of defense against blood-borne pathogens and produce low-affinityantibodies 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 ofsepsis.[8] MZ B cells also display a lower activation threshold than their FO B cell counterparts, with a heightened propensity forplasma cell differentiation that contributes further to the accelerated primary antibody response.[2][12] They have been acknowledged as the main producers ofIgM 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 potentantigen-presenting cells, that are able to activateCD4+ T cells more effectively than FO B cells due to their elevated expression levels ofMHC class II,CD80 andCD86 molecules.[2][7]
Deficiencies of MZ B cells are associated with a higher risk ofpneumococcal infection,meningitis and insufficient antibody response to capsular polysaccharides.[2][4]
In humans the splenic marginal zone B cells have evidence ofsomatic hypermutation in their immunoglobulin genes, indicating that they have been generated through a germinal centre reaction to becomememory 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+ andIgA+). In humans, MZ B cells expressCD27, which is a member of the TNF-receptor family expressed by human memory B cells.[8]
Many of MZ B cell-receptors are self-reactive, which may be a factor that contributes to their expansion in someautoimmune 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 oflupus,diabetes andarthritis.[7] However, their levels in humanvasculitis are reduced.[5]
Marginal zone B cells are the malignant cells inmarginal zone lymphomas, a heterogeneous group of generally indolentlymphomas.[13]
{{cite book}}: CS1 maint: multiple names: authors list (link){{cite journal}}: CS1 maint: multiple names: authors list (link){{cite journal}}: CS1 maint: multiple names: authors list (link)