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]
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 IgMhighIgDlowCD21highCD23low 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]
References
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