100:, the BCR controls the activation of the B cell. B cells are able to gather and grab antigens by engaging biochemical modules for receptor clustering, cell spreading, generation of pulling forces, and receptor transport, which eventually culminates in endocytosis and antigen presentation. B cells' mechanical activity adheres to a pattern of negative and positive feedbacks that regulate the quantity of removed antigen by manipulating the dynamic of BCR–antigen bonds directly. Particularly, grouping and spreading increase the relation of antigen with BCR, thereby proving sensitivity and amplification. On the other hand, pulling forces delinks the antigen from the BCR, thus testing the quality of antigen binding.
256:. All these regions are recombined and spliced at the genetic level in a combinatorial process that is exceptional to the immune system. There are a number of genes that encode each of these regions in the genome and can be joined in various ways to generate a wide range of receptor molecules. The production of this variety is crucial since the body may encounter many more antigens than the available genes. Through this process, the body finds a way of producing multiple different combinations of antigen-recognizing receptor molecules. Heavy chain rearrangement of the BCR entails the initial steps in the development of B cell. The short J
470:(Pleckstrin homology) domains can bind to the newly created PIP3 and become activated. These include proteins of the FoxO family, which stimulate cell cycle progression, and protein kinase D, which enhances glucose metabolism. Another important protein with a PH domain is Bam32. This recruits and activates small GTPases such as Rac1 and Cdc42. These, in turn, are responsible for the cytoskeletal changes associated with BCR activation by modifying actin polymerisation.
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of BCRs as a key feature in a growing number of B cell neoplasias. B cell receptor signalling is currently a therapeutic target in various lymphoid neoplasms. It has been shown that BCR signaling is synchronised with CD40 pathway activation provided by B-T cell interactions, and this seems to be essential to trigger proliferation of leukemic B cells.
462:-like protein that cleaves A20, an inhibitory protein of NF-κB signaling (which acts by deubiquitylating NF-κB's ubiquitylation substrates, having an inhibitory effect). TAK1 phosphorylates the IKK trimer after it too has been recruited to the signaling complex by its associated ubiquitylation enzymes. IKK then phosphorylates
143:. The B cell receptor (BCR) has two crucial functions upon interaction with the antigen. One function is signal transduction, involving changes in receptor oligomerization. The second function is to mediate internalization for subsequent processing of the antigen and presentation of peptides to helper T cells.
466:(an inhibitor of and bound to NF-κB), which induces its destruction by marking it for proteolytic degradation, freeing cytosolic NF-κB. NF-κB then migrates to the nucleus to bind to DNA at specific response elements, causing recruitment of transcription molecules and beginning the transcription process.
479:
The B-cell receptor has been shown to be involved in the pathogenesis of various B cell derived lymphoid cancers. Although it may be possible that stimulation by antigen binding contributes to the proliferation of malignant B cells, increasing evidence implicates antigen-independent self-association
351:
There are several signaling pathways that the B-cell receptor can follow through. The physiology of B cells is intimately connected with the function of their B-cell receptor. The BCR signaling pathway is initiated when the mIg subunits of the BCR bind a specific antigen. The initial triggering of
264:(diversity) regions are recombined first in early pro-B cells in a process that is dependent on the enzymes RAG2 and RAG1. After the recombination of the D and J regions, the cell is now referred to as a “late pro-B” cell and the short DJ region can now be recombined with a longer segment of the V
469:
Ligand binding to the BCR also leads to the phosphorylation of the protein BCAP. This leads to the binding and activation of several proteins with phosphotyrosine-binding SH2 domains. One of these proteins is PI3K. Activation of PI3K leads to PIP2 phosphorylation, forming PIP3. Proteins with PH
275:
and the surface of the receptor, which often occurs by non-covalent forces. Mature B cells can only survive in the peripheral circulation for a limited time when there is no specific antigen. This is because when cells do not meet any antigen within this time, they will go through
280:. It is notable that in the peripheral circulation, apoptosis is important in maintaining an optimal circulation of B-lymphocytes. In structure, the BCR for antigens are almost identical to secreted antibodies. However, there is a distinctive structural dissimilarity in the
1164:
Dühren-von Minden M, Übelhart R, Schneider D, Wossning T, Bach MP, Buchner M, Hofmann D, Surova E, Follo M, Köhler F, Wardemann H, Zirlik K, Veelken H, Jumaa H (September 2012). "Chronic lymphocytic leukaemia is driven by antigen-independent cell-autonomous signalling".
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may exist in the B cells as either an association or combination with another pre B cell-specific proteins or alone, thereby replacing the mIgM molecule. Within the BCR, the part that recognizes antigens is composed of three distinct genetic regions, referred to as
239:
subunit known as the membrane immunoglobulin (mIg), which is composed of two immunoglobulin light chains (IgLs) and two immunoglobulin heavy chains (IgHs) as well as two heterodimer subunits of Ig-α and Ig-β. In order for membrane
244:
molecules to transport to the surface of the cell, there must be a combination of Ig-α and Ig-β with the mIgM molecules. Pre-B cells that do not generate any Ig molecule normally carry both Ig-α and Ig-β to the cell surface.
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376:. Multiple models have been proposed how BCR-antigen binding induces phosphorylation, including conformational change of the receptor and aggregation of multiple receptors upon antigen binding. Tyrosine kinase
151:
The first checkpoint in the development of a B cell is the production of a functional pre-BCR, which is composed of two surrogate light chains and two immunoglobulin heavy chains, which are normally linked to
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on multiple sites. After phosphorylation, downstream signalling molecules are recruited to BLNK, which results in their activation and the transduction of the signal to the interior.
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Corcos D (1990). "Oncogenic potential of the B cell antigen receptor and its relevance to heavy chain diseases and other B-cell neoplasias: a new model".
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667:
Multichain Immune
Recognition Receptor Signaling: From Spatiotemporal Organization to Human Disease (Advances in Experimental Medicine and Biology)
164:, is highly specific to an antigen. The BCR can be found in a number of identical copies of membrane proteins that are exposed at the cell surface.
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area of the heavy chains, as it consists of a hydrophobic stretch that is short, which spreads across the lipid bilayer of the membrane.
323:. As such, the process catalyzes the formation of a ‘signalosome’ that consists of the aforementioned tyrosine kinases, the BCR and the
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A membrane-bound immunoglobulin molecule of one isotype (IgD, IgM, IgA, IgG, or IgE). With the exception of the presence of a
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54:. The B- cell receptor extends both outside the cell (above the plasma membrane) and inside the cell (below the membrane).
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is activated by its first encounter with an antigen (its "cognate antigen") that binds to its receptor, resulting in
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1068:"Pre-B-cell development in the absence of lambda 5 in transgenic mice expressing a heavy-chain disease protein"
236:
132:
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Brenzski, Randall J.; Monroe, John G. (2010). "Chapter 2: B cell
Receptor". In Sigalov, Alexander B. (ed.).
296:
Schematic representation of the B-cell receptor signaling pathways. Aggregation of the BCR quickly activate
889:
Dushek O, Goyette J, van der Merwe PA (November 2012). "Non-catalytic tyrosine- phosphorylated receptors".
458:, by several ubiquitylation enzymes also associated with the CARMA1/BCL10/MALT1 complex. MALT1 itself is a
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669:. Springer; Softcover reprint of hardcover 1st ed. 2008 edition (November 23, 2010). pp. 12–21.
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binds to and is activated by phosphorylated ITAMs and in turn phosphorylates scaffold protein
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is a significant sensor that is required for B cell activation, survival, and development. A
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BCRs have distinctive binding sites that rely on the complementarity of the surface of the
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Davis RE, Ngo VN, Lenz G, Tolar P, Young RM, Romesser PB, et al. (January 2010).
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360:(ITAMs) in the associated Igα/Igβ heterodimer subunits by the tyrosine kinases of the
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Corcos D, Dunda O, Butor C, Cesbron JY, Lorès P, Bucchini D, Jami J (October 1995).
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from the calcium and DAG. PKCβ phosphorylates (either directly or indirectly) the
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after antigen recognition by the BCR and before it goes to associate into the
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1109:"Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma"
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765:"The Diversity and Molecular Evolution of B Cell Receptors during Infection"
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Hoehn, Kenneth B.; Fowler, Anna; Lunter, Gerton; Pybus, Oliver G. (2016).
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Dal Porto, JM; Gauld, SB (2014). "B cell antigen receptor signaling 101".
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Immunological
Synapse (Current Topics in Microbiology and Immunology, 340)
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Cancer
Immunotherapy: Chapter 3-Adaptive Immunity: B Cells and Antibodies
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The B-cell receptor (BCR) is a transmembrane protein on the surface of a
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connect the immunoglobulin isotype and the signal transduction region.
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cells. Through biochemical signaling and by physically acquiring
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221:. Each member of the dimer spans the plasma membrane and has a
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Pier, Gerland B.; Lyczak, Jeffrey B.; Wetzler, Lee M. (2005).
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Owen, J.; Punt, J.; Stranford, S; Jones, P.; Kuby, J. (2013).
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999:"Leukemia and auto-immunization- some possible relationships"
842:"B cell antigen-receptor signaling in lymphocyte development"
160:(or CD79B) signaling molecules. Each B cell, produced in the
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and a signal transduction moiety. The former forms a type 1
976:(8th ed.). Garland Science. 2011. pp. 258–260.
450:). These result in recruitment and summoning of the IKK (
544:. New York: W.H. Freeman and Company. pp. 102–104.
698:
Immunobiology: The Immune System in Health and
Disease
394:
and other proteins, microsignalosomes, go to activate
599:. London: Academic Press; 2 edition. pp. 25–40.
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immunoreceptor tyrosine-based activation motif (ITAM)
565:
Saito, Batista; Saito, Takashi; Facundo, D. (2010).
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family. The binding event allows phosphorylation of
70:. A B-cell receptor is composed of a membrane-bound
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926:"B cell receptor: from resting state to activated"
569:. Berlin: Heidelberg: Springer Berlin Heidelberg.
418:to dramatically increase ionic calcium inside the
235:More analytically, the BCR complex consists of an
695:Janeway, CA Jr; Travers, P.; Walport, M. (2015).
635:. Merrell KT, Mills D, Pugh-Bernard AE: 599–613.
595:Merlo, Lauren M. F.; Mandik-Nayak, Laura (2013).
426:or influx from the extracellular environment via
66:) is a transmembrane protein on the surface of a
733:. Washington D.C.: ASM Press. pp. 234–247.
147:Development and structure of the B cell receptor
27:Transmembrane protein on the surface of a B cell
358:immunoreceptor tyrosine-based activation motifs
135:to generate a population of antibody-secreting
1208:Woyach JA, Johnson AJ, Byrd JC (August 2012).
354:non-catalytic tyrosine-phosphorylated receptor
198:, these are identical to their secreted forms.
190:The B-cell receptor is composed of two parts:
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111:that, like all antibodies, has two identical
8:
352:the BCR is similar for all receptors of the
701:. New York: Garland Science (5th edition).
182:molecule and a signal transduction region.
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430:). This leads to eventual activation of
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442:(the complex itself comprising CARMA1,
389:IKK/NF-κB Transcription Factor Pathway:
840:Wan, Leo D.; Clark, Marcus R. (2003).
50:of a B cell is indicated by the green
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38:. A B-cell receptor includes both
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1419:Polymeric immunoglobulin receptor
475:The B-cell receptor in malignancy
997:Daneshek W, Schwartz RS (1959).
942:10.1111/j.1365-2567.2012.03564.x
858:10.1111/j.1365-2567.2003.01756.x
819:. Garland Science; 6th edition.
107:is composed of a membrane-bound
1631:(with two glycoprotein chains
201:Signal transduction moiety: a
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1727:Killer-cell IG-like receptors
1085:10.1016/S0960-9822(95)00230-2
817:Molecular Biology of the Cell
542:Kuby Immunology (Seventh ed.)
171:The general structure of the
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1306:immunoglobulin superfamily
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196:transmembrane alpha-helix
1265:Medical Subject Headings
1261:B-Cell+Antigen+Receptors
1302:Transmembrane receptors
974:Janeway's immunobiology
815:Alberts, Bruce (2014).
103:The receptor's binding
1033:Research in Immunology
422:(via release from the
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891:Immunological Reviews
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117:randomly determined
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924:Treanor B (2012).
402:. It then cleaves
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414:). IP3 acts as a
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184:Disulfide bridges
119:. The BCR for an
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1641:
1638:
1634:
1630:
1627:
1626:
1624:
1622:
1618:
1612:
1609:
1607:
1604:
1602:
1599:
1597:
1593:
1590:
1589:
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1583:
1575:
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1570:
1567:
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1565:
1562:
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1559:
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1553:
1550:
1548:
1544:
1533:
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1525:
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1515:
1505:
1502:
1501:
1499:
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1489:
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1478:
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1471:
1468:
1466:
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1456:
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1399:
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1387:
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1378:
1376:
1373:
1371:
1368:
1366:
1363:
1362:
1360:
1358:
1354:
1347:
1346:C-type lectin
1343:
1339:
1337:
1334:
1333:
1331:
1329:
1325:
1322:
1320:
1314:
1310:
1307:
1303:
1296:
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1289:
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1277:
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1273:
1266:
1262:
1259:
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1254:
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1227:
1223:
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1215:
1211:
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1201:
1196:
1192:
1188:
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1176:
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1168:
1160:
1157:
1152:
1148:
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1134:
1130:
1126:
1122:
1118:
1114:
1110:
1103:
1100:
1095:
1091:
1086:
1081:
1077:
1073:
1069:
1062:
1059:
1054:
1050:
1046:
1042:
1039:(6): 543–53.
1038:
1034:
1027:
1024:
1019:
1015:
1011:
1007:
1000:
993:
990:
985:
979:
975:
969:
966:
961:
957:
952:
947:
943:
939:
935:
931:
927:
920:
917:
912:
908:
904:
900:
896:
892:
885:
882:
877:
873:
868:
863:
859:
855:
851:
847:
843:
836:
833:
828:
822:
818:
811:
809:
805:
800:
796:
791:
786:
782:
778:
774:
770:
769:Mol Biol Evol
766:
759:
757:
755:
753:
751:
747:
742:
736:
732:
725:
723:
721:
719:
715:
710:
704:
700:
699:
691:
689:
687:
683:
678:
672:
668:
661:
659:
655:
650:
646:
642:
638:
634:
630:
623:
621:
619:
617:
613:
608:
602:
598:
591:
589:
587:
583:
578:
572:
568:
561:
558:
553:
547:
543:
536:
534:
532:
530:
528:
526:
524:
522:
520:
518:
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512:
505:
501:
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491:
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483:
481:
474:
468:
465:
461:
457:
453:
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445:
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437:
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429:
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417:
413:
409:
405:
401:
397:
393:
390:
387:
386:
385:
383:
379:
375:
371:
367:
363:
359:
355:
346:
342:
338:
334:
330:
326:
322:
319:
315:
311:
307:
303:
299:
294:
287:
285:
283:
279:
274:
269:
255:
250:
246:
243:
238:
231:
229:
224:
220:
216:
212:
208:
204:
200:
197:
193:
192:
191:
185:
181:
178:
174:
169:
165:
163:
159:
155:
146:
144:
142:
138:
134:
130:
126:
122:
118:
114:
110:
106:
101:
99:
95:
91:
87:
86:outer surface
83:
80:
79:transmembrane
76:
73:
69:
65:
61:
53:
52:phospholipids
49:
45:
41:
37:
32:
19:
1713:
1621:Co-receptors
1574:MHC class II
1454:
1217:
1213:
1203:
1170:
1166:
1159:
1116:
1112:
1102:
1075:
1071:
1061:
1036:
1032:
1026:
1009:
1005:
992:
973:
968:
936:(1): 21–27.
933:
929:
919:
894:
890:
884:
849:
845:
835:
816:
772:
768:
730:
697:
666:
632:
628:
596:
566:
560:
541:
478:
428:ion channels
388:
350:
300:, including
270:
249:Heterodimers
247:
234:
226:
189:
150:
102:
63:
59:
57:
1894:Lymphocytes
1569:MHC class I
1465:Co-receptor
1328:Epsilon (ε)
1319:Fc receptor
775:: 1147–57.
629:Mol Immunol
254:V, D, and J
223:cytoplasmic
203:heterodimer
162:bone marrow
1888:Categories
1473:stimulate:
1012:: 1151–8.
983:0815342438
930:Immunology
852:: 411–20.
846:Immunology
506:References
452:IkB kinase
282:C-terminal
90:lymphocyte
1899:Receptors
1412:Secretory
1357:Gamma (γ)
410:and DAG (
278:apoptosis
113:paratopes
96:from the
88:of these
1760:KIR2DL5B
1755:KIR2DL5A
1497:inhibit:
1380:Neonatal
1244:22715122
1195:22885698
1151:20054396
1018:13813891
960:22269039
911:23046135
876:14632637
799:26802217
649:15219998
484:See also
312:and the
109:antibody
94:antigens
75:molecule
42:and the
1805:KIR3DS1
1800:KIR3DL3
1795:KIR3DL2
1790:KIR3DL1
1785:KIR2DS5
1780:KIR2DS4
1775:KIR2DS3
1770:KIR2DS2
1765:KIR2DS1
1750:KIR2DL4
1745:KIR2DL3
1740:KIR2DL2
1735:KIR2DL1
1679:ζ-chain
1556:Ligands
1547:T cells
1440:B cells
1375:FcγRIII
1235:3418714
1175:Bibcode
1142:2845535
1121:Bibcode
1094:8548286
1053:2284498
951:3372753
867:1783068
790:4839220
460:caspase
420:cytosol
273:epitope
205:called
121:antigen
1873:LILRB5
1868:LILRB4
1863:LILRB3
1858:LILRB2
1853:LILRB1
1848:LILRA6
1843:LILRA5
1838:LILRA4
1833:LILRA3
1828:LILRA2
1823:LILRA1
1403:Fcα/μR
1370:FcγRII
1342:FcεRII
1267:(MeSH)
1242:
1232:
1193:
1167:Nature
1149:
1139:
1113:Nature
1092:
1051:
1016:
980:
958:
948:
909:
874:
864:
823:
797:
787:
737:
705:
673:
647:
603:
573:
548:
446:, and
440:CARMA1
400:c-SMAC
372:, and
343:, and
308:, and
268:gene.
173:B cell
125:B cell
105:moiety
68:B cell
46:. The
36:B cell
1398:FcαRI
1365:FcγRI
1336:FcεRI
1214:Blood
1006:Blood
1002:(PDF)
448:MALT1
444:BCL10
436:NF-κB
406:into
396:PLC-γ
341:PLCy2
1714:see
1687:TCRζ
1685:and
1683:CD3ζ
1674:CD3ε
1669:CD3δ
1664:CD3γ
1637:CD8β
1635:and
1633:CD8α
1611:TRG@
1606:TRD@
1601:TRB@
1596:TRA@
1532:CD79
1528:Ig-β
1524:Ig-α
1504:CD22
1488:CD81
1484:CD19
1480:CD21
1240:PMID
1191:PMID
1147:PMID
1090:PMID
1049:PMID
1014:PMID
978:ISBN
956:PMID
907:PMID
872:PMID
821:ISBN
795:PMID
735:ISBN
703:ISBN
671:ISBN
645:PMID
601:ISBN
571:ISBN
546:ISBN
500:IMGT
456:TAK1
432:PKCβ
404:PIP2
392:CD79
382:BLNK
337:P13K
333:CD19
331:and
329:BLNK
316:and
242:mIgM
215:CD79
211:Ig-β
207:Ig-α
158:Ig-β
154:Ig-α
139:and
131:and
58:The
40:CD79
1659:CD3
1643:CD4
1629:CD8
1592:TCR
1564:MHC
1455:BCR
1344:is
1230:PMC
1222:doi
1218:120
1183:doi
1171:489
1137:PMC
1129:doi
1117:463
1080:doi
1041:doi
1037:141
946:PMC
938:doi
934:136
899:doi
895:250
862:PMC
854:doi
850:110
785:PMC
777:doi
637:doi
464:IkB
454:),
408:IP3
378:Syk
374:Fyn
370:Lyn
366:Blk
362:Src
347:.
345:VAV
318:BTK
314:SYK
310:FYN
306:LYN
302:Blk
64:BCR
1890::
1594::
1304::
1238:.
1228:.
1216:.
1212:.
1189:.
1181:.
1169:.
1145:.
1135:.
1127:.
1115:.
1111:.
1088:.
1074:.
1070:.
1047:.
1035:.
1010:14
1008:.
1004:.
954:.
944:.
932:.
928:.
905:.
893:.
870:.
860:.
848:.
844:.
807:^
793:.
783:.
773:33
771:.
767:.
749:^
717:^
685:^
657:^
643:.
633:41
631:.
615:^
585:^
514:^
368:,
339:,
304:,
1689:)
1639:)
1534:)
1530:(
1526:/
1486:/
1482:/
1348:)
1340:(
1294:e
1287:t
1280:v
1246:.
1224::
1197:.
1185::
1177::
1153:.
1131::
1123::
1096:.
1082::
1076:5
1055:.
1043::
1020:.
986:.
962:.
940::
913:.
901::
878:.
856::
829:.
801:.
779::
743:.
711:.
679:.
651:.
639::
609:.
579:.
554:.
266:H
262:H
258:H
230:.
213:(
209:/
62:(
20:)
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