Skip to main content
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1991 Jan 1;173(1):55–64. doi: 10.1084/jem.173.1.55

Intersection of the complement and immune systems: a signal transduction complex of the B lymphocyte-containing complement receptor type 2 and CD19

PMCID: PMC2118751  PMID: 1702139

Abstract

The complement system augments the humoral immune response, possibly by a mechanism that involves the B lymphocyte membrane receptor, CR2, which binds the C3dg fragment of C3 and triggers several B cell responses in vitro. The present study demonstrates that CR2 associates with a complex of membrane proteins that may mediate signal transduction by ligated CR2. Monoclonal antibodies to CR2 immunoprecipitated from digitonin lysates of Raji B lymphoblastoid cells a membrane complex containing CR2, approximately equimolar amounts of CD19, which is a member of the immunoglobulin superfamily, and three unidentified components: p130, p50, and p20. The complex, which was immunoprecipitated also with anti-CD19, could be dissociated by Nonidet P-40, accounting for its absence in previous studies of CR2. Expression of recombinant CR2 and CD19 in K562 erythroleukemia cells led to formation of a complex that contained not only these two proteins but also p130, p50, and p20, and another component, p14. These unidentified components of the CR2/CD19 complex coimmunoprecipitated with CD19 and not with CR2 from singly transfected cells, indicating primary association with the former. CD19 replicated the capacity of CR2 to interact synergistically with mIgM for increasing free intracellular Ca2+, suggesting that the complex mediates this function of CR2. Therefore, CR2 associates directly with CD19 to become a ligand- binding subunit of a pre-existing signal transduction complex of the B cell that may be representative of a family of membrane protein complexes. This interaction between the complement and immune systems differs from that between immunoglobulin and Clq by involving membrane rather than plasma proteins, and by having complement involved in the afferent phase of the immune response.

Full Text

The Full Text of this article is available as a PDF (1.1 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Anderson P., Caligiuri M., O'Brien C., Manley T., Ritz J., Schlossman S. F. Fc gamma receptor type III (CD16) is included in the zeta NK receptor complex expressed by human natural killer cells. Proc Natl Acad Sci U S A. 1990 Mar;87(6):2274–2278. doi: 10.1073/pnas.87.6.2274. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bijsterbosch M. K., Meade C. J., Turner G. A., Klaus G. G. B lymphocyte receptors and polyphosphoinositide degradation. Cell. 1985 Jul;41(3):999–1006. doi: 10.1016/s0092-8674(85)80080-5. [DOI] [PubMed] [Google Scholar]
  3. Bird P., Lachmann P. J. The regulation of IgG subclass production in man: low serum IgG4 in inherited deficiencies of the classical pathway of C3 activation. Eur J Immunol. 1988 Aug;18(8):1217–1222. doi: 10.1002/eji.1830180811. [DOI] [PubMed] [Google Scholar]
  4. Blank U., Ra C., Miller L., White K., Metzger H., Kinet J. P. Complete structure and expression in transfected cells of high affinity IgE receptor. Nature. 1989 Jan 12;337(6203):187–189. doi: 10.1038/337187a0. [DOI] [PubMed] [Google Scholar]
  5. Bohnsack J. F., Cooper N. R. CR2 ligands modulate human B cell activation. J Immunol. 1988 Oct 15;141(8):2569–2576. [PubMed] [Google Scholar]
  6. Böttger E. C., Hoffmann T., Hadding U., Bitter-Suermann D. Influence of genetically inherited complement deficiencies on humoral immune response in guinea pigs. J Immunol. 1985 Dec;135(6):4100–4107. [PubMed] [Google Scholar]
  7. Cambier J. C., Lehmann K. R. Ia-mediated signal transduction leads to proliferation of primed B lymphocytes. J Exp Med. 1989 Sep 1;170(3):877–886. doi: 10.1084/jem.170.3.877. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cambier J. C., Newell M. K., Justement L. B., McGuire J. C., Leach K. L., Chen Z. Z. Ia binding ligands and cAMP stimulate nuclear translocation of PKC in B lymphocytes. Nature. 1987 Jun 18;327(6123):629–632. doi: 10.1038/327629a0. [DOI] [PubMed] [Google Scholar]
  9. Campbell K. S., Cambier J. C. B lymphocyte antigen receptors (mIg) are non-covalently associated with a disulfide linked, inducibly phosphorylated glycoprotein complex. EMBO J. 1990 Feb;9(2):441–448. doi: 10.1002/j.1460-2075.1990.tb08129.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Carroll M. C., Alicot E. M., Katzman P. J., Klickstein L. B., Smith J. A., Fearon D. T. Organization of the genes encoding complement receptors type 1 and 2, decay-accelerating factor, and C4-binding protein in the RCA locus on human chromosome 1. J Exp Med. 1988 Apr 1;167(4):1271–1280. doi: 10.1084/jem.167.4.1271. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Carter R. H., Fearon D. T. Polymeric C3dg primes human B lymphocytes for proliferation induced by anti-IgM. J Immunol. 1989 Sep 15;143(6):1755–1760. [PubMed] [Google Scholar]
  12. Carter R. H., Spycher M. O., Ng Y. C., Hoffman R., Fearon D. T. Synergistic interaction between complement receptor type 2 and membrane IgM on B lymphocytes. J Immunol. 1988 Jul 15;141(2):457–463. [PubMed] [Google Scholar]
  13. Changelian P. S., Fearon D. T. Tissue-specific phosphorylation of complement receptors CR1 and CR2. J Exp Med. 1986 Jan 1;163(1):101–115. doi: 10.1084/jem.163.1.101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Frade R., Crevon M. C., Barel M., Vazquez A., Krikorian L., Charriaut C., Galanaud P. Enhancement of human B cell proliferation by an antibody to the C3d receptor, the gp 140 molecule. Eur J Immunol. 1985 Jan;15(1):73–76. doi: 10.1002/eji.1830150114. [DOI] [PubMed] [Google Scholar]
  15. Gold M. R., Jakway J. P., DeFranco A. L. Involvement of a guanine-nucleotide-binding component in membrane IgM-stimulated phosphoinositide breakdown. J Immunol. 1987 Dec 1;139(11):3604–3613. [PubMed] [Google Scholar]
  16. Gold M. R., Law D. A., DeFranco A. L. Stimulation of protein tyrosine phosphorylation by the B-lymphocyte antigen receptor. Nature. 1990 Jun 28;345(6278):810–813. doi: 10.1038/345810a0. [DOI] [PubMed] [Google Scholar]
  17. Hatzfeld A., Fischer E., Levesque J. P., Perrin R., Hatzfeld J., Kazatchkine M. D. Binding of C3 and C3dg to the CR2 complement receptor induces growth of an Epstein-Barr virus-positive human B cell line. J Immunol. 1988 Jan 1;140(1):170–175. [PubMed] [Google Scholar]
  18. Hibbs M. L., Selvaraj P., Carpén O., Springer T. A., Kuster H., Jouvin M. H., Kinet J. P. Mechanisms for regulating expression of membrane isoforms of Fc gamma RIII (CD16). Science. 1989 Dec 22;246(4937):1608–1611. doi: 10.1126/science.2531918. [DOI] [PubMed] [Google Scholar]
  19. Hombach J., Tsubata T., Leclercq L., Stappert H., Reth M. Molecular components of the B-cell antigen receptor complex of the IgM class. Nature. 1990 Feb 22;343(6260):760–762. doi: 10.1038/343760a0. [DOI] [PubMed] [Google Scholar]
  20. Iida K., Nadler L., Nussenzweig V. Identification of the membrane receptor for the complement fragment C3d by means of a monoclonal antibody. J Exp Med. 1983 Oct 1;158(4):1021–1033. doi: 10.1084/jem.158.4.1021. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Jackson C. G., Ochs H. D., Wedgwood R. J. Immune response of a patient with deficiency of the fourth component of complement and systemic lupus erythematosus. N Engl J Med. 1979 May 17;300(20):1124–1129. doi: 10.1056/NEJM197905173002002. [DOI] [PubMed] [Google Scholar]
  22. Klaus G. G., Humphrey J. H. The generation of memory cells. I. The role of C3 in the generation of B memory cells. Immunology. 1977 Jul;33(1):31–40. [PMC free article] [PubMed] [Google Scholar]
  23. Klickstein L. B., Bartow T. J., Miletic V., Rabson L. D., Smith J. A., Fearon D. T. Identification of distinct C3b and C4b recognition sites in the human C3b/C4b receptor (CR1, CD35) by deletion mutagenesis. J Exp Med. 1988 Nov 1;168(5):1699–1717. doi: 10.1084/jem.168.5.1699. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Lowell C. A., Klickstein L. B., Carter R. H., Mitchell J. A., Fearon D. T., Ahearn J. M. Mapping of the Epstein-Barr virus and C3dg binding sites to a common domain on complement receptor type 2. J Exp Med. 1989 Dec 1;170(6):1931–1946. doi: 10.1084/jem.170.6.1931. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Martinelli G. P., Matsuda T., Osler A. G. Studies of immunosuppression by cobra venom factor. I. On early IgG and IgM responses to sheep erythrocytes and DNP-protein conjugates. J Immunol. 1978 Nov;121(5):2043–2047. [PubMed] [Google Scholar]
  26. Matsuda T., Martinelli G. P., Osler A. G. Studies on immunosuppression by cobra venom factor. II. On responses to DNP-Ficoll and DNP-Polyacrylamide. J Immunol. 1978 Nov;121(5):2048–2051. [PubMed] [Google Scholar]
  27. Melchers F., Erdei A., Schulz T., Dierich M. P. Growth control of activated, synchronized murine B cells by the C3d fragment of human complement. Nature. 1985 Sep 19;317(6034):264–267. doi: 10.1038/317264a0. [DOI] [PubMed] [Google Scholar]
  28. Moore M. D., Cooper N. R., Tack B. F., Nemerow G. R. Molecular cloning of the cDNA encoding the Epstein-Barr virus/C3d receptor (complement receptor type 2) of human B lymphocytes. Proc Natl Acad Sci U S A. 1987 Dec;84(24):9194–9198. doi: 10.1073/pnas.84.24.9194. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Moore M. D., DiScipio R. G., Cooper N. R., Nemerow G. R. Hydrodynamic, electron microscopic, and ligand-binding analysis of the Epstein-Barr virus/C3dg receptor (CR2). J Biol Chem. 1989 Dec 5;264(34):20576–20582. [PubMed] [Google Scholar]
  30. Nadler L. M., Anderson K. C., Marti G., Bates M., Park E., Daley J. F., Schlossman S. F. B4, a human B lymphocyte-associated antigen expressed on normal, mitogen-activated, and malignant B lymphocytes. J Immunol. 1983 Jul;131(1):244–250. [PubMed] [Google Scholar]
  31. O'Farrell P. H. High resolution two-dimensional electrophoresis of proteins. J Biol Chem. 1975 May 25;250(10):4007–4021. [PMC free article] [PubMed] [Google Scholar]
  32. Oettgen H. C., Pettey C. L., Maloy W. L., Terhorst C. A T3-like protein complex associated with the antigen receptor on murine T cells. Nature. 1986 Mar 20;320(6059):272–275. doi: 10.1038/320272a0. [DOI] [PubMed] [Google Scholar]
  33. Pernegger G., Schulz T. F., Hosp M., Myones B. L., Petzer A. L., Eigentler A., Böck G., Wick G., Dierich M. P. Cell cycle control of a Burkitt lymphoma cell line: responsiveness to growth signals engaging the C3D/EBV receptor. Immunology. 1988 Oct;65(2):237–241. [PMC free article] [PubMed] [Google Scholar]
  34. Pesando J. M., Bouchard L. S., McMaster B. E. CD19 is functionally and physically associated with surface immunoglobulin. J Exp Med. 1989 Dec 1;170(6):2159–2164. doi: 10.1084/jem.170.6.2159. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Pezzutto A., Dörken B., Rabinovitch P. S., Ledbetter J. A., Moldenhauer G., Clark E. A. CD19 monoclonal antibody HD37 inhibits anti-immunoglobulin-induced B cell activation and proliferation. J Immunol. 1987 May 1;138(9):2793–2799. [PubMed] [Google Scholar]
  36. Ra C., Jouvin M. H., Blank U., Kinet J. P. A macrophage Fc gamma receptor and the mast cell receptor for IgE share an identical subunit. Nature. 1989 Oct 26;341(6244):752–754. doi: 10.1038/341752a0. [DOI] [PubMed] [Google Scholar]
  37. Rabinovitch P. S., June C. H., Grossmann A., Ledbetter J. A. Heterogeneity among T cells in intracellular free calcium responses after mitogen stimulation with PHA or anti-CD3. Simultaneous use of indo-1 and immunofluorescence with flow cytometry. J Immunol. 1986 Aug 1;137(3):952–961. [PubMed] [Google Scholar]
  38. Rey-Campos J., Rubinstein P., Rodriguez de Cordoba S. A physical map of the human regulator of complement activation gene cluster linking the complement genes CR1, CR2, DAF, and C4BP. J Exp Med. 1988 Feb 1;167(2):664–669. doi: 10.1084/jem.167.2.664. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Schifferli J. A., Ng Y. C., Peters D. K. The role of complement and its receptor in the elimination of immune complexes. N Engl J Med. 1986 Aug 21;315(8):488–495. doi: 10.1056/NEJM198608213150805. [DOI] [PubMed] [Google Scholar]
  40. Stamenkovic I., Seed B. CD19, the earliest differentiation antigen of the B cell lineage, bears three extracellular immunoglobulin-like domains and an Epstein-Barr virus-related cytoplasmic tail. J Exp Med. 1988 Sep 1;168(3):1205–1210. doi: 10.1084/jem.168.3.1205. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Tedder T. F., Clement L. T., Cooper M. D. Expression of C3d receptors during human B cell differentiation: immunofluorescence analysis with the HB-5 monoclonal antibody. J Immunol. 1984 Aug;133(2):678–683. [PubMed] [Google Scholar]
  42. Tedder T. F., Fearon D. T., Gartland G. L., Cooper M. D. Expression of C3b receptors on human be cells and myelomonocytic cells but not natural killer cells. J Immunol. 1983 Apr;130(4):1668–1673. [PubMed] [Google Scholar]
  43. Tedder T. F., Isaacs C. M. Isolation of cDNAs encoding the CD19 antigen of human and mouse B lymphocytes. A new member of the immunoglobulin superfamily. J Immunol. 1989 Jul 15;143(2):712–717. [PubMed] [Google Scholar]
  44. Thompson J. A., Lau A. L., Cunningham D. D. Selective radiolabeling of cell surface proteins to a high specific activity. Biochemistry. 1987 Feb 10;26(3):743–750. doi: 10.1021/bi00377a014. [DOI] [PubMed] [Google Scholar]
  45. Tsokos G. C., Lambris J. D., Finkelman F. D., Anastassiou E. D., June C. H. Monovalent ligands of complement receptor 2 inhibit whereas polyvalent ligands enhance anti-Ig-induced human B cell intracytoplasmic free calcium concentration. J Immunol. 1990 Mar 1;144(5):1640–1645. [PubMed] [Google Scholar]
  46. Weis J. H., Morton C. C., Bruns G. A., Weis J. J., Klickstein L. B., Wong W. W., Fearon D. T. A complement receptor locus: genes encoding C3b/C4b receptor and C3d/Epstein-Barr virus receptor map to 1q32. J Immunol. 1987 Jan 1;138(1):312–315. [PubMed] [Google Scholar]
  47. Weis J. J., Fearon D. T. The identification of N-linked oligosaccharides on the human CR2/Epstein-Barr virus receptor and their function in receptor metabolism, plasma membrane expression, and ligand binding. J Biol Chem. 1985 Nov 5;260(25):13824–13830. [PubMed] [Google Scholar]
  48. Weis J. J., Tedder T. F., Fearon D. T. Identification of a 145,000 Mr membrane protein as the C3d receptor (CR2) of human B lymphocytes. Proc Natl Acad Sci U S A. 1984 Feb;81(3):881–885. doi: 10.1073/pnas.81.3.881. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Weis J. J., Toothaker L. E., Smith J. A., Weis J. H., Fearon D. T. Structure of the human B lymphocyte receptor for C3d and the Epstein-Barr virus and relatedness to other members of the family of C3/C4 binding proteins. J Exp Med. 1988 Mar 1;167(3):1047–1066. doi: 10.1084/jem.167.3.1047. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Weisman H. F., Bartow T., Leppo M. K., Marsh H. C., Jr, Carson G. R., Concino M. F., Boyle M. P., Roux K. H., Weisfeldt M. L., Fearon D. T. Soluble human complement receptor type 1: in vivo inhibitor of complement suppressing post-ischemic myocardial inflammation and necrosis. Science. 1990 Jul 13;249(4965):146–151. doi: 10.1126/science.2371562. [DOI] [PubMed] [Google Scholar]
  51. Wienands J., Hombach J., Radbruch A., Riesterer C., Reth M. Molecular components of the B cell antigen receptor complex of class IgD differ partly from those of IgM. EMBO J. 1990 Feb;9(2):449–455. doi: 10.1002/j.1460-2075.1990.tb08130.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES