Editing B cell (section)

==Activation==
[[File:B cell activation naive to plasma cell.png|thumb|left|B cell activation: from immature B cell to plasma cell or memory B cell]]
[[File:B cell function.png|thumb|Basic B cell function: bind to an antigen, receive help from a cognate helper T cell, and differentiate into a [[plasma cell]] that secretes large numbers of antibodies]]

B cell activation occurs in the [[secondary lymphoid organs]] (SLOs), such as the [[spleen]] and [[lymph nodes]].<ref name=":0" /> After B cells mature in the bone marrow, they migrate through the blood to SLOs, which receive a constant supply of antigen through circulating [[lymph]].<ref>{{cite journal | vauthors = Harwood NE, Batista FD | title = Early events in B cell activation | journal = Annual Review of Immunology | volume = 28 | issue = 1 | pages = 185–210 | date = 2010-01-01 | pmid = 20192804 | doi = 10.1146/annurev-immunol-030409-101216 }}</ref> At the SLO, B cell activation begins when the B cell binds to an antigen via its BCR.<ref name=":7">{{cite journal | vauthors = Yuseff MI, Pierobon P, Reversat A, Lennon-Duménil AM | title = How B cells capture, process and present antigens: a crucial role for cell polarity | journal = Nature Reviews. Immunology | volume = 13 | issue = 7 | pages = 475–486 | date = July 2013 | pmid = 23797063 | doi = 10.1038/nri3469 | s2cid = 24791216 }}</ref>  Although the events taking place immediately after activation have yet to be completely determined, it is believed that B cells are activated in accordance with the kinetic segregation model {{Citation needed|reason = the mechanism of activation is actually quite controversial|date=April 2019}}, initially determined in T lymphocytes. This model denotes that before antigen stimulation, receptors diffuse through the membrane coming into contact with [[Lck]] and [[CD45]] in equal frequency, rendering a net equilibrium of phosphorylation and non-phosphorylation. It is only when the cell comes in contact with an antigen presenting cell that the larger CD45 is displaced due to the close distance between the two membranes. This allows for net phosphorylation of the BCR and the initiation of the signal transduction pathway{{Citation needed|date=April 2019}}. Of the three B cell subsets, FO B cells preferentially undergo T cell-dependent activation while MZ B cells and B1 B cells preferentially undergo T cell-independent activation.<ref name=":8">{{cite journal | vauthors = Nutt SL, Hodgkin PD, Tarlinton DM, Corcoran LM | title = The generation of antibody-secreting plasma cells | journal = Nature Reviews. Immunology | volume = 15 | issue = 3 | pages = 160–171 | date = March 2015 | pmid = 25698678 | doi = 10.1038/nri3795 | s2cid = 9769697 }}</ref>

B cell activation is enhanced through the activity of [[Complement receptor 2|CD21]], a surface receptor in complex with surface proteins [[CD19]] and [[CD81]] (all three are collectively known as the B cell coreceptor complex).<ref>{{cite journal | vauthors = Asokan R, Banda NK, Szakonyi G, Chen XS, Holers VM | title = Human complement receptor 2 (CR2/CD21) as a receptor for DNA: implications for its roles in the immune response and the pathogenesis of systemic lupus erythematosus (SLE) | journal = Molecular Immunology | volume = 53 | issue = 1–2 | pages = 99–110 | date = January 2013 | pmid = 22885687 | pmc = 3439536 | doi = 10.1016/j.molimm.2012.07.002 }}</ref> When a BCR binds an antigen tagged with a fragment of the C3 complement protein, CD21 binds the C3 fragment, co-ligates with the bound BCR, and signals are transduced through CD19 and CD81 to lower the activation threshold of the cell.<ref>{{cite journal | vauthors = Zabel MD, Weis JH | title = Cell-specific regulation of the CD21 gene | journal = International Immunopharmacology | volume = 1 | issue = 3 | pages = 483–493 | date = March 2001 | pmid = 11367532 | doi = 10.1016/S1567-5769(00)00046-1 | series = Unraveling Mechanisms and Discovering Novel Roles for Complement }}</ref>

===T cell-dependent activation===
Antigens that activate B cells with the help of T-cell are known as T cell-dependent (TD) antigens and include foreign proteins.<ref name=":0" /> They are named as such because they are unable to induce a humoral response in organisms that lack T cells.<ref name=":0" /> B cell responses to these antigens takes multiple days, though antibodies generated have a higher affinity and are more functionally versatile than those generated from T cell-independent activation.<ref name=":0" />

Once a BCR binds a TD antigen, the antigen is taken up into the B cell through [[receptor-mediated endocytosis]], [[Proteolysis|degraded]], and presented to T cells as peptide pieces in complex with [[MHC class II|MHC-II molecules]] on the cell membrane.<ref>{{cite journal | vauthors = Blum JS, Wearsch PA, Cresswell P | title = Pathways of antigen processing | journal = Annual Review of Immunology | volume = 31 | issue = 1 | pages = 443–473 | date = 2013-01-01 | pmid = 23298205 | pmc = 4026165 | doi = 10.1146/annurev-immunol-032712-095910 }}</ref> [[T helper cell|T helper (T<sub>H</sub>) cells]], typically [[Follicular B helper T cells|follicular T helper (T<sub>FH</sub>) cells]] recognize and bind these MHC-II-peptide complexes through their [[T cell receptor|T cell receptor (TCR)]].<ref name=":9">{{cite journal | vauthors = Crotty S | title = A brief history of T cell help to B cells | journal = Nature Reviews. Immunology | volume = 15 | issue = 3 | pages = 185–189 | date = March 2015 | pmid = 25677493 | pmc = 4414089 | doi = 10.1038/nri3803 }}</ref> Following TCR-MHC-II-peptide binding, T cells express the surface protein [[CD154|CD40L]] as well as cytokines such as [[Interleukin 4|IL-4]] and [[Interleukin 21|IL-21]].<ref name=":9" /> CD40L serves as a necessary co-stimulatory factor for B cell activation by binding the B cell surface receptor [[CD40 (protein)|CD40]], which promotes B cell [[Cell growth|proliferation]], [[immunoglobulin class switching]], and [[somatic hypermutation]] as well as sustains T cell growth and differentiation.<ref name=":0" /> T cell-derived cytokines bound by B cell [[cytokine receptor]]s also promote B cell proliferation, immunoglobulin class switching, and somatic hypermutation as well as guide differentiation.<ref name=":9" /> After B cells receive these signals, they are considered activated.<ref name=":9" /> [[File:T-dependent B cell activation.png|thumb|T-dependent B cell activation]]

Once activated, B cells participate in a two-step differentiation process that yields both short-lived plasmablasts for immediate protection and [[long-lived plasma cell]]s and memory B cells for persistent protection.<ref name=":8" /> The first step, known as the extrafollicular response, occurs outside lymphoid follicles but still in the SLO.<ref name=":8" /> During this step activated B cells proliferate, may undergo immunoglobulin class switching, and differentiate into plasmablasts that produce early, weak antibodies mostly of class IgM.<ref>{{cite journal | vauthors = MacLennan IC, Toellner KM, Cunningham AF, Serre K, Sze DM, Zúñiga E, Cook MC, Vinuesa CG | display-authors = 6 | title = Extrafollicular antibody responses | journal = Immunological Reviews | volume = 194 | pages = 8–18 | date = August 2003 | pmid = 12846803 | doi = 10.1034/j.1600-065x.2003.00058.x | s2cid = 2455541 }}</ref>
[[File:Dark, light, mantle and marginal zones of a secondary follicle.png|thumb|Histology of a normal [[lymphoid follicle]], with germinal center in the middle.]]
The second step consists of activated B cells entering a lymphoid follicle and forming a [[Germinal center|germinal center (GC)]], which is a specialized microenvironment where B cells undergo extensive proliferation, immunoglobulin class switching, and [[affinity maturation]] directed by somatic hypermutation.<ref name=":10">{{cite journal | vauthors = Shlomchik MJ, Weisel F | title = Germinal center selection and the development of memory B and plasma cells | journal = Immunological Reviews | volume = 247 | issue = 1 | pages = 52–63 | date = May 2012 | pmid = 22500831 | doi = 10.1111/j.1600-065X.2012.01124.x | s2cid = 5362003 | url = https://zenodo.org/record/1064236 }}</ref> These processes are facilitated by T<sub>FH</sub>  and follicular dendritic cells within the GC and generate both high-affinity memory B cells and long-lived plasma cells.<ref name=":8" /><ref>{{Cite journal |last1=Heesters |first1=Balthasar A. |last2=Chatterjee |first2=Priyadarshini |last3=Kim |first3=Young-A. |last4=Gonzalez |first4=Santiago F. |last5=Kuligowski |first5=Michael P. |last6=Kirchhausen |first6=Tomas |last7=Carroll |first7=Michael C. |date=2013-06-27 |title=Endocytosis and Recycling of Immune Complexes by Follicular Dendritic Cells Enhances B Cell Antigen Binding and Activation |journal=Immunity |volume=38 |issue=6 |pages=1164–1175 |doi=10.1016/j.immuni.2013.02.023 |pmid=23770227 |issn=1074-7613|pmc=3773956 }}</ref> Resultant plasma cells secrete large numbers of antibodies and either stay within the SLO or, more preferentially, migrate to bone marrow.<ref name=":10" />

===T cell-independent activation===
{{Main|T independent antigen (TI)}}
Antigens that activate B cells without T cell help are known as [[T independent antigen (TI)|T cell-independent (TI) antigens]]<ref name=":0" /> and include foreign polysaccharides and unmethylated CpG DNA.<ref name=":8" /> They are named as such because they are able to induce a humoral response in organisms that lack T cells.<ref name=":0" /> B cell response to these antigens is rapid, though antibodies generated tend to have lower affinity and are less functionally versatile than those generated from T cell-dependent activation.<ref name=":0" />

As with TD antigens, B cells activated by TI antigens need additional signals to complete activation, but instead of receiving them from T cells, they are provided either by recognition and binding of a common microbial constituent to [[Toll-like receptor|toll-like receptors (TLRs)]] or by extensive crosslinking of BCRs to repeated epitopes on a bacterial cell.<ref name=":0" /> B cells activated by TI antigens go on to proliferate outside lymphoid follicles but still in SLOs (GCs do not form), possibly undergo immunoglobulin class switching, and differentiate into short-lived plasmablasts that produce early, weak antibodies mostly of class IgM, but also some populations of long-lived plasma cells.<ref name=":11">{{cite journal | vauthors = Bortnick A, Chernova I, Quinn WJ, Mugnier M, Cancro MP, Allman D | title = Long-lived bone marrow plasma cells are induced early in response to T cell-independent or T cell-dependent antigens | journal = Journal of Immunology | volume = 188 | issue = 11 | pages = 5389–5396 | date = June 2012 | pmid = 22529295 | pmc = 4341991 | doi = 10.4049/jimmunol.1102808 }}</ref>

=== Memory B cell activation ===
Memory B cell activation begins with the detection and binding of their target antigen, which is shared by their parent B cell.<ref name=":13">{{cite journal | vauthors = McHeyzer-Williams M, Okitsu S, Wang N, McHeyzer-Williams L | title = Molecular programming of B cell memory | journal = Nature Reviews. Immunology | volume = 12 | issue = 1 | pages = 24–34 | date = December 2011 | pmid = 22158414 | pmc = 3947622 | doi = 10.1038/nri3128 }}</ref> Some memory B cells can be activated without T cell help, such as certain virus-specific memory B cells, but others need T cell help.<ref name=":12" /> Upon antigen binding, the memory B cell takes up the antigen through receptor-mediated endocytosis, degrades it, and presents it to T cells as peptide pieces in complex with MHC-II molecules on the cell membrane.<ref name=":13" /> Memory T helper (T<sub>H</sub>) cells, typically memory follicular T helper (T<sub>FH</sub>) cells, that were derived from T cells activated with the same antigen recognize and bind these MHC-II-peptide complexes through their TCR.<ref name=":13" /> Following TCR-MHC-II-peptide binding and the relay of other signals from the memory T<sub>FH</sub> cell, the memory B cell is activated and differentiates either into plasmablasts and plasma cells via an extrafollicular response or enter a germinal center reaction where they generate plasma cells and more memory B cells.<ref name=":13" /><ref name=":12" /> It is unclear whether the memory B cells undergo further affinity maturation within these secondary GCs.<ref name=":13" /> ''[[In vitro]]'' activation of memory B cells can be achieved through stimulation with various activators, such as pokeweed mitogen or anti-[[CD40 (protein)|CD40]] [[Monoclonal antibody|monoclonal antibodies]], however, a study found a combination of [[Resiquimod|R-848]] and [[Interleukin 2|recombinant human IL-2]] to be the most efficient activator.<ref>{{Cite journal |last1=Jahnmatz |first1=Maja |last2=Kesa |first2=Gun |last3=Netterlid |first3=Eva |last4=Buisman |first4=Anne-Marie |last5=Thorstensson |first5=Rigmor |last6=Ahlborg |first6=Niklas |date=2013-05-31 |title=Optimization of a human IgG B-cell ELISpot assay for the analysis of vaccine-induced B-cell responses |journal=Journal of Immunological Methods |language=en |volume=391 |issue=1 |pages=50–59 |doi=10.1016/j.jim.2013.02.009 |pmid=23454005 |issn=0022-1759|doi-access=free }}</ref>