CD79A

Cluster of differentiation CD79A also known as B-cell antigen receptor complex-associated protein alpha chain and MB-1 membrane glycoprotein, is a protein that in humans is encoded by the CD79A gene.{{cite web | title = Entrez Gene: CD79A CD79a molecule, immunoglobulin-associated alpha| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=973}}

The CD79a protein together with the related CD79b protein, forms a dimer associated with membrane-bound immunoglobulin in B-cells, thus forming the B-cell antigen receptor (BCR). This occurs in a similar manner to the association of CD3 with the T-cell receptor, and enables the cell to respond to the presence of antigens on its surface.{{cite book | vauthors = Leong AS, Cooper K, Leong FJ | year = 2003 | title = Manual of Diagnostic Cytology | edition = 2nd | publisher = Greenwich Medical Media, Ltd. | pages = XX | isbn = 1-84110-100-1 }}

It is associated with agammaglobulinemia-3.{{OMIM|613501}}

Gene

The mouse CD79A gene, then called mb-1, was cloned in the late 1980s,{{cite journal | vauthors = Sakaguchi N, Kashiwamura S, Kimoto M, Thalmann P, Melchers F | title = B lymphocyte lineage-restricted expression of mb-1, a gene with CD3-like structural properties | journal = The EMBO Journal | volume = 7 | issue = 11 | pages = 3457–3464 | date = November 1988 | pmid = 2463161 | pmc = 454845 | doi = 10.1002/j.1460-2075.1988.tb03220.x }} followed by the discovery of human CD79A in the early 1990s.{{cite journal | vauthors = Ha HJ, Kubagawa H, Burrows PD | title = Molecular cloning and expression pattern of a human gene homologous to the murine mb-1 gene | journal = Journal of Immunology | volume = 148 | issue = 5 | pages = 1526–1531 | date = March 1992 | pmid = 1538135 | doi = 10.4049/jimmunol.148.5.1526 | s2cid = 22129592 | doi-access = free }}{{cite journal | vauthors = Flaswinkel H, Reth M | title = Molecular cloning of the Ig-alpha subunit of the human B-cell antigen receptor complex | journal = Immunogenetics | volume = 36 | issue = 4 | pages = 266–269 | year = 1992 | pmid = 1639443 | doi = 10.1007/bf00215058 | s2cid = 28622219 }} It is a short gene, 4.3 kb in length, with 5 exons encoding for 2 splice variants resulting in 2 isoforms.

CD79A is conserved and abundant among ray-finned fish (actinopterygii) but not in the evolutionarily more ancient chondrichthyes such as shark.{{cite journal | vauthors = Sims R, Vandergon VO, Malone CS | title = The mouse B cell-specific mb-1 gene encodes an immunoreceptor tyrosine-based activation motif (ITAM) protein that may be evolutionarily conserved in diverse species by purifying selection | journal = Molecular Biology Reports | volume = 39 | issue = 3 | pages = 3185–3196 | date = March 2012 | pmid = 21688146 | pmc = 4667979 | doi = 10.1007/s11033-011-1085-7 }} The occurrence of CD79A thus coincides with the evolution of B cell receptors with greater diversity generated by recombination of multiple V, D, and J elements in bony fish contrasting the single V, D and J elements found in shark.{{cite journal | vauthors = Flajnik MF, Kasahara M | title = Origin and evolution of the adaptive immune system: genetic events and selective pressures | journal = Nature Reviews. Genetics | volume = 11 | issue = 1 | pages = 47–59 | date = January 2010 | pmid = 19997068 | pmc = 3805090 | doi = 10.1038/nrg2703 }}

Structure

CD79a is a membrane protein with an extracellular immunoglobulin domain, a single span transmembrane region and a short cytoplasmic domain. The cytoplasmic domain contains multiple phosphorylation sites including a conserved dual phosphotyrosine binding motif, termed immunotyrosine-based activation motif (ITAM).{{cite journal | vauthors = Reth M | title = Antigen receptor tail clue | journal = Nature | volume = 338 | issue = 6214 | pages = 383–384 | date = March 1989 | pmid = 2927501 | doi = 10.1038/338383b0 | s2cid = 5213145 | bibcode = 1989Natur.338..383R }}{{cite journal | vauthors = Cambier JC | title = Antigen and Fc receptor signaling. The awesome power of the immunoreceptor tyrosine-based activation motif (ITAM) | journal = Journal of Immunology | volume = 155 | issue = 7 | pages = 3281–3285 | date = October 1995 | pmid = 7561018 | doi = 10.4049/jimmunol.155.7.3281 | s2cid = 996547 | doi-access = free }} The larger CD79a isoform contains an insert in position 88-127 of human CD79a resulting in a complete immunoglobulin domain, whereas the smaller isoform has only a truncated Ig-like domain. CD79a has several cysteine residues, one of which forms covalent bonds with CD79b.{{cite journal | vauthors = Reth M | title = Antigen receptors on B lymphocytes | journal = Annual Review of Immunology | volume = 10 | issue = 1 | pages = 97–121 | date = 1992 | pmid = 1591006 | doi = 10.1146/annurev.iy.10.040192.000525 }}

Function

CD79a plays multiple and diverse roles in B cell development and function. The CD79a/b heterodimer associates non-covalently with the immunoglobulin heavy chain through its transmembrane region, thus forming the BCR along with the immunoglobulin light chain and the pre-BCR when associated with the surrogate light chain in developing B cells. Association of the CD79a/b heterodimer with the immunoglobulin heavy chain is required for surface expression of the BCR and BCR induced calcium flux and protein tyrosine phosphorylation.{{cite journal | vauthors = Yang J, Reth M | title = Oligomeric organization of the B-cell antigen receptor on resting cells | journal = Nature | volume = 467 | issue = 7314 | pages = 465–469 | date = September 2010 | pmid = 20818374 | doi = 10.1038/nature09357 | s2cid = 3261220 | bibcode = 2010Natur.467..465Y }} Genetic deletion of the transmembrane exon of CD79A results in loss of CD79a protein and a complete block of B cell development at the pro to pre B cell transition.{{cite journal | vauthors = Pelanda R, Braun U, Hobeika E, Nussenzweig MC, Reth M | title = B cell progenitors are arrested in maturation but have intact VDJ recombination in the absence of Ig-alpha and Ig-beta | journal = Journal of Immunology | volume = 169 | issue = 2 | pages = 865–872 | date = July 2002 | pmid = 12097390 | doi = 10.4049/jimmunol.169.2.865 | doi-access = free }} Similarly, humans with homozygous splice variants in CD79A predicted to result in loss of the transmembrane region and a truncated or absent protein display agammaglobulinemia and no peripheral B cells.{{cite journal | vauthors = Minegishi Y, Coustan-Smith E, Rapalus L, Ersoy F, Campana D, Conley ME | title = Mutations in Igalpha (CD79a) result in a complete block in B-cell development | journal = The Journal of Clinical Investigation | volume = 104 | issue = 8 | pages = 1115–1121 | date = October 1999 | pmid = 10525050 | pmc = 408581 | doi = 10.1172/JCI7696 }}{{cite journal | vauthors = Wang Y, Kanegane H, Sanal O, Tezcan I, Ersoy F, Futatani T, Miyawaki T | title = Novel Igalpha (CD79a) gene mutation in a Turkish patient with B cell-deficient agammaglobulinemia | journal = American Journal of Medical Genetics | volume = 108 | issue = 4 | pages = 333–336 | date = April 2002 | pmid = 11920841 | doi = 10.1002/ajmg.10296 }}

The CD79a ITAM tyrosines (human CD79a Tyr188 and Tyr199, mouse CD79a Tyr182 and Tyr193) phosphorylated in response to BCR crosslinking are critical for binding of Src-homology 2 domain-containing kinases such as spleen tyrosine kinase (Syk) and signal transduction by CD79a.{{cite journal | vauthors = Flaswinkel H, Reth M | title = Dual role of the tyrosine activation motif of the Ig-alpha protein during signal transduction via the B cell antigen receptor | journal = The EMBO Journal | volume = 13 | issue = 1 | pages = 83–89 | date = January 1994 | pmid = 8306975 | pmc = 394781 | doi = 10.1002/j.1460-2075.1994.tb06237.x }}{{cite journal | vauthors = Reth M, Wienands J | title = Initiation and processing of signals from the B cell antigen receptor | journal = Annual Review of Immunology | volume = 15 | issue = 1 | pages = 453–479 | date = 1997 | pmid = 9143696 | doi = 10.1146/annurev.immunol.15.1.453 }} In vivo, the CD79a ITAM tyrosines synergize with the CD79b ITAM tyrosines to mediate the transition from the pro to the pre B cell stage as suggested by the analysis of mice with targeted mutations of the CD79a and CD79b ITAM.{{cite journal | vauthors = Gazumyan A, Reichlin A, Nussenzweig MC | title = Ig beta tyrosine residues contribute to the control of B cell receptor signaling by regulating receptor internalization | journal = The Journal of Experimental Medicine | volume = 203 | issue = 7 | pages = 1785–1794 | date = July 2006 | pmid = 16818674 | pmc = 2118343 | doi = 10.1084/jem.20060221 }}{{cite journal | vauthors = Patterson HC, Kraus M, Wang D, Shahsafaei A, Henderson JM, Seagal J, Otipoby KL, Thai TH, Rajewsky K | title = Cytoplasmic Ig alpha serine/threonines fine-tune Ig alpha tyrosine phosphorylation and limit bone marrow plasma cell formation | journal = Journal of Immunology | volume = 187 | issue = 6 | pages = 2853–2858 | date = September 2011 | pmid = 21841126 | pmc = 3169759 | doi = 10.4049/jimmunol.1101143 }} Loss of only one of the two functional CD79a/b ITAMs resulted in impaired B cell development but B cell functions such as the T cell independent type II response and BCR mediated calcium flux in the available B cells were intact. However, the presence of both the CD79a and CD79b ITAM tyrosines were required for normal T cell dependent antibody responses.{{cite journal | vauthors = Kraus M, Pao LI, Reichlin A, Hu Y, Canono B, Cambier JC, Nussenzweig MC, Rajewsky K | title = Interference with immunoglobulin (Ig)alpha immunoreceptor tyrosine-based activation motif (ITAM) phosphorylation modulates or blocks B cell development, depending on the availability of an Igbeta cytoplasmic tail | journal = The Journal of Experimental Medicine | volume = 194 | issue = 4 | pages = 455–469 | date = August 2001 | pmid = 11514602 | pmc = 2193498 | doi = 10.1084/jem.194.4.455 }} The CD79a cytoplasmic domain further contains a non-ITAM tyrosine distal to the CD79a ITAM (human CD79a Tyr210, mouse CD79a Tyr204) that can bind BLNK and Nck once phosphorylated,{{cite journal | vauthors = Engels N, Wollscheid B, Wienands J | title = Association of SLP-65/BLNK with the B cell antigen receptor through a non-ITAM tyrosine of Ig-alpha | journal = European Journal of Immunology | volume = 31 | issue = 7 | pages = 2126–2134 | date = July 2001 | pmid = 11449366 | doi = 10.1002/1521-4141(200107)31:7<2126::aid-immu2126>3.0.co;2-o | s2cid = 31494726 }}{{cite journal | vauthors = Kabak S, Skaggs BJ, Gold MR, Affolter M, West KL, Foster MS, Siemasko K, Chan AC, Aebersold R, Clark MR | title = The direct recruitment of BLNK to immunoglobulin alpha couples the B-cell antigen receptor to distal signaling pathways | journal = Molecular and Cellular Biology | volume = 22 | issue = 8 | pages = 2524–2535 | date = April 2002 | pmid = 11909947 | pmc = 133735 | doi = 10.1128/MCB.22.8.2524-2535.2002 }}{{cite journal | vauthors = Castello A, Gaya M, Tucholski J, Oellerich T, Lu KH, Tafuri A, Pawson T, Wienands J, Engelke M, Batista FD | title = Nck-mediated recruitment of BCAP to the BCR regulates the PI(3)K-Akt pathway in B cells | journal = Nature Immunology | volume = 14 | issue = 9 | pages = 966–975 | date = September 2013 | pmid = 23913047 | doi = 10.1038/ni.2685 | s2cid = 2532325 }} and is critical for BCR mediated B cell proliferation and B1 cell development.{{cite journal | vauthors = Patterson HC, Kraus M, Kim YM, Ploegh H, Rajewsky K | title = The B cell receptor promotes B cell activation and proliferation through a non-ITAM tyrosine in the Igalpha cytoplasmic domain | journal = Immunity | volume = 25 | issue = 1 | pages = 55–65 | date = July 2006 | pmid = 16860757 | doi = 10.1016/j.immuni.2006.04.014 | doi-access = free }} CD79a ITAM tyrosine phosphorylation and signaling is negatively regulated by serine and threonine residues in direct proximity of the ITAM (human CD79a Ser197, Ser203, Thr209; mouse CD79a Ser191, Ser197, Thr203),{{cite journal | vauthors = Müller R, Wienands J, Reth M | title = The serine and threonine residues in the Ig-alpha cytoplasmic tail negatively regulate immunoreceptor tyrosine-based activation motif-mediated signal transduction | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 15 | pages = 8451–8454 | date = July 2000 | pmid = 10900006 | pmc = 26968 | doi = 10.1073/pnas.97.15.8451 | doi-access = free | bibcode = 2000PNAS...97.8451M }}{{cite journal | vauthors = Heizmann B, Reth M, Infantino S | title = Syk is a dual-specificity kinase that self-regulates the signal output from the B-cell antigen receptor | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 107 | issue = 43 | pages = 18563–18568 | date = October 2010 | pmid = 20940318 | pmc = 2972992 | doi = 10.1073/pnas.1009048107 | doi-access = free | bibcode = 2010PNAS..10718563H }} and play a role in limiting formation of bone marrow plasma cells secreting IgG2a and IgG2b.

Diagnostic relevance

The CD79a protein is present on the surface of B-cells throughout their life cycle, and is absent on all other healthy cells, making it a highly reliable marker for B-cells in immunohistochemistry. The protein remains present when B-cells transform into active plasma cells, and is also present in virtually all B-cell neoplasms, including B-cell lymphomas, plasmacytomas, and myelomas. It is also present in abnormal lymphocytes associated with some cases of Hodgkins disease. Because even on B-cell precursors, it can be used to stain a wider range of cells than can the alternative B-cell marker CD20, but the latter is more commonly retained on mature B-cell lymphomas, so that the two are often used together in immunohistochemistry panels.

References

External links

{{MeshName|CD79A+protein,+human}}
{{UCSC gene info|CD79A}}

Category:Clusters of differentiation