CD79A explained

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.[1]

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.[2]

It is associated with agammaglobulinemia-3.

Gene

The mouse CD79A gene, then called mb-1, was cloned in the late 1980s,[3] followed by the discovery of human CD79A in the early 1990s.[4] [5] 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.[6] 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.[7]

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).[8] [9] 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.[10]

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.[11] 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.[12] 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.[13] [14]

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.[15] [16] 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.[17] [18] 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.[17] [19] The CD79a cytoplasmic domain further contains a non-ITAM tyrosine distal of the CD79a ITAM (human CD79a Tyr210, mouse CD79a Tyr204) that can bind BLNK and Nck once phosphorylated,[20] [21] [22] and is critical for BCR mediated B cell proliferation and B1 cell development.[23] 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),[24] [25] and play a role in limiting formation of bone marrow plasma cells secreting IgG2a and IgG2b.[18]

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.[2]

See also

Further reading

Notes and References

  1. Web site: Entrez Gene: CD79A CD79a molecule, immunoglobulin-associated alpha.
  2. Book: Leong . Anthony S-Y . Cooper . Kumarason . Leong . F Joel W-M . vanc . 2003 . Manual of Diagnostic Cytology . 2 . Greenwich Medical Media, Ltd. . XX . 1-84110-100-1 .
  3. Sakaguchi N, Kashiwamura S, Kimoto M, Thalmann P, Melchers F . B lymphocyte lineage-restricted expression of mb-1, a gene with CD3-like structural properties . The EMBO Journal . 7 . 11 . 3457–64 . Nov 1988 . 454845 . 2463161 . 10.1002/j.1460-2075.1988.tb03220.x .
  4. Ha HJ, Kubagawa H, Burrows PD . Molecular cloning and expression pattern of a human gene homologous to the murine mb-1 gene . Journal of Immunology . 148 . 5 . 1526–31 . Mar 1992 . 10.4049/jimmunol.148.5.1526 . 1538135 . 22129592 . free .
  5. Flaswinkel H, Reth M . Molecular cloning of the Ig-alpha subunit of the human B-cell antigen receptor complex . Immunogenetics . 36 . 4 . 266–9 . 1992 . 1639443 . 10.1007/bf00215058 . 28622219 .
  6. Sims R, Vandergon VO, Malone CS . 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 . Molecular Biology Reports . 39 . 3 . 3185–96 . Mar 2012 . 21688146 . 10.1007/s11033-011-1085-7 . 4667979.
  7. Flajnik MF, Kasahara M . Origin and evolution of the adaptive immune system: genetic events and selective pressures . Nature Reviews Genetics . 11 . 1 . 47–59 . Jan 2010 . 19997068 . 3805090 . 10.1038/nrg2703 .
  8. Reth M . Antigen receptor tail clue . Nature . 338 . 6214 . 383–4 . Mar 1989 . 2927501 . 10.1038/338383b0 . 1989Natur.338..383R . 5213145 .
  9. Cambier JC . Antigen and Fc receptor signaling. The awesome power of the immunoreceptor tyrosine-based activation motif (ITAM) . Journal of Immunology . 155 . 7 . 3281–5 . Oct 1995 . 10.4049/jimmunol.155.7.3281 . 7561018 . 996547 . free .
  10. Reth M . Antigen receptors on B lymphocytes . Annual Review of Immunology . 10 . 1 . 97–121 . 1992 . 1591006 . 10.1146/annurev.iy.10.040192.000525 .
  11. Yang. Jianying. Reth. Michael. September 2010. Oligomeric organization of the B-cell antigen receptor on resting cells. Nature. en. 467. 7314. 465–469. 10.1038/nature09357. 20818374. 2010Natur.467..465Y. 3261220. 1476-4687.
  12. Pelanda R, Braun U, Hobeika E, Nussenzweig MC, Reth M . B cell progenitors are arrested in maturation but have intact VDJ recombination in the absence of Ig-alpha and Ig-beta . Journal of Immunology . 169 . 2 . 865–72 . Jul 2002 . 12097390 . 10.4049/jimmunol.169.2.865. free .
  13. Minegishi Y, Coustan-Smith E, Rapalus L, Ersoy F, Campana D, Conley ME . Mutations in Igalpha (CD79a) result in a complete block in B-cell development . The Journal of Clinical Investigation . 104 . 8 . 1115–21 . Oct 1999 . 10525050 . 10.1172/JCI7696 . 408581.
  14. Wang Y, Kanegane H, Sanal O, Tezcan I, Ersoy F, Futatani T, Miyawaki T . Novel Igalpha (CD79a) gene mutation in a Turkish patient with B cell-deficient agammaglobulinemia . American Journal of Medical Genetics . 108 . 4 . 333–6 . Apr 2002 . 11920841 . 10.1002/ajmg.10296 .
  15. Flaswinkel H, Reth M . Dual role of the tyrosine activation motif of the Ig-alpha protein during signal transduction via the B cell antigen receptor . The EMBO Journal . 13 . 1 . 83–9 . Jan 1994 . 8306975 . 394781 . 10.1002/j.1460-2075.1994.tb06237.x.
  16. Reth M, Wienands J . Initiation and processing of signals from the B cell antigen receptor . Annual Review of Immunology . 15 . 1 . 453–79 . 1997 . 9143696 . 10.1146/annurev.immunol.15.1.453 .
  17. Gazumyan A, Reichlin A, Nussenzweig MC . Ig beta tyrosine residues contribute to the control of B cell receptor signaling by regulating receptor internalization . The Journal of Experimental Medicine . 203 . 7 . 1785–94 . Jul 2006 . 16818674 . 10.1084/jem.20060221 . 2118343.
  18. Patterson HC, Kraus M, Wang D, Shahsafaei A, Henderson JM, Seagal J, Otipoby KL, Thai TH, Rajewsky K . Cytoplasmic Ig alpha serine/threonines fine-tune Ig alpha tyrosine phosphorylation and limit bone marrow plasma cell formation . Journal of Immunology . 187 . 6 . 2853–8 . Sep 2011 . 21841126 . 10.4049/jimmunol.1101143 . 3169759.
  19. Kraus M, Pao LI, Reichlin A, Hu Y, Canono B, Cambier JC, Nussenzweig MC, Rajewsky K . 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 . The Journal of Experimental Medicine . 194 . 4 . 455–69 . Aug 2001 . 11514602 . 2193498 . 10.1084/jem.194.4.455 .
  20. Engels N, Wollscheid B, Wienands J . Association of SLP-65/BLNK with the B cell antigen receptor through a non-ITAM tyrosine of Ig-alpha . European Journal of Immunology . 31 . 7 . 2126–34 . Jul 2001 . 11449366 . 10.1002/1521-4141(200107)31:7<2126::aid-immu2126>3.0.co;2-o . 31494726 .
  21. Kabak S, Skaggs BJ, Gold MR, Affolter M, West KL, Foster MS, Siemasko K, Chan AC, Aebersold R, Clark MR . The direct recruitment of BLNK to immunoglobulin alpha couples the B-cell antigen receptor to distal signaling pathways . Molecular and Cellular Biology . 22 . 8 . 2524–35 . Apr 2002 . 11909947 . 133735 . 10.1128/MCB.22.8.2524-2535.2002 .
  22. Castello A, Gaya M, Tucholski J, Oellerich T, Lu KH, Tafuri A, Pawson T, Wienands J, Engelke M, Batista FD . Nck-mediated recruitment of BCAP to the BCR regulates the PI(3)K-Akt pathway in B cells . Nature Immunology . 14 . 9 . 966–75 . Sep 2013 . 23913047 . 10.1038/ni.2685 . 2532325 .
  23. Patterson HC, Kraus M, Kim YM, Ploegh H, Rajewsky K . The B cell receptor promotes B cell activation and proliferation through a non-ITAM tyrosine in the Igalpha cytoplasmic domain . Immunity . 25 . 1 . 55–65 . Jul 2006 . 16860757 . 10.1016/j.immuni.2006.04.014 . free .
  24. Müller R, Wienands J, Reth M . The serine and threonine residues in the Ig-alpha cytoplasmic tail negatively regulate immunoreceptor tyrosine-based activation motif-mediated signal transduction . Proceedings of the National Academy of Sciences of the United States of America . 97 . 15 . 8451–4 . Jul 2000 . 10900006 . 26968 . 10.1073/pnas.97.15.8451 . 2000PNAS...97.8451M . free .
  25. Heizmann B, Reth M, Infantino S . Syk is a dual-specificity kinase that self-regulates the signal output from the B-cell antigen receptor . Proceedings of the National Academy of Sciences of the United States of America . 107 . 43 . 18563–8 . Oct 2010 . 20940318 . 2972992 . 10.1073/pnas.1009048107 . 2010PNAS..10718563H . free .

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