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. 1998 Jul 15;17(14):3850–3857. doi: 10.1093/emboj/17.14.3850

Gain-of-function mutations in FcgammaRI of NOD mice: implications for the evolution of the Ig superfamily.

A L Gavin 1, P S Tan 1, P M Hogarth 1
PMCID: PMC1170720  PMID: 9670002

Abstract

It has been postulated that, during evolution of the Ig superfamily, modifications of the function of individual receptors might occur by acquisition of exons and their subsequent modification, though evidence of this is lacking. Here we have analysed the interaction of mouse IgG subclasses with high-affinity FcgammaRI (CD64) which contains three Ig-like domains and is important in innate and adaptive immunity. This analysis has identified a mechanism by which the postulated modification of newly acquired exons provides gains in function. Thus, the most widely distributed FcgammaRI allele in mice (e.g. BALB/c), bound only a single IgG subclass, IgG2a, with high affinity. However, non-obese diabetic (NOD) mice expressed a unique allele that exhibits broader specificity and, in addition to binding IgG2a, FcgammaRI-NOD bound monomeric IgG3 and bound IgG2b with high affinity, an IgG subclass not bound by FcgammaRI of other mouse strains, either as monomer or multivalent immune complexes. Analysis of mutants of FcgammaRI wherein segments of the interdomain junctions were exchanged between FcgammaRI-BALB and FcgammaRI-NOD identified these regions as having major influence in 'gain-of-function' by the NOD form of FcgammaRI. Nucleotide sequence analysis of intron/exon boundaries encoding the interdomain junctions of the FcgammaRI alleles showed these to have arisen by mutation to alter existing or create new mRNA splice donor/acceptor sites, resulting in generation of modified junctions.

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Selected References

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

  1. Abdelmoula M., Spertini F., Shibata T., Gyotoku Y., Luzuy S., Lambert P. H., Izui S. IgG3 is the major source of cryoglobulins in mice. J Immunol. 1989 Jul 15;143(2):526–532. [PubMed] [Google Scholar]
  2. Allen J. M., Seed B. Isolation and expression of functional high-affinity Fc receptor complementary DNAs. Science. 1989 Jan 20;243(4889):378–381. doi: 10.1126/science.2911749. [DOI] [PubMed] [Google Scholar]
  3. Fan Q. R., Mosyak L., Winter C. C., Wagtmann N., Long E. O., Wiley D. C. Structure of the inhibitory receptor for human natural killer cells resembles haematopoietic receptors. Nature. 1997 Sep 4;389(6646):96–100. doi: 10.1038/38028. [DOI] [PubMed] [Google Scholar]
  4. Gavin A. L., Barnes N., Dijstelbloem H. M., Hogarth P. M. Identification of the mouse IgG3 receptor: implications for antibody effector function at the interface between innate and adaptive immunity. J Immunol. 1998 Jan 1;160(1):20–23. [PubMed] [Google Scholar]
  5. Gavin A. L., Hamilton J. A., Hogarth P. M. Extracellular mutations of non-obese diabetic mouse FcgammaRI modify surface expression and ligand binding. J Biol Chem. 1996 Jul 19;271(29):17091–17099. doi: 10.1074/jbc.271.29.17091. [DOI] [PubMed] [Google Scholar]
  6. Hanson M. S., Cetkovic-Cvrlje M., Ramiya V. K., Atkinson M. A., Maclaren N. K., Singh B., Elliott J. F., Serreze D. V., Leiter E. H. Quantitative thresholds of MHC class II I-E expressed on hemopoietically derived antigen-presenting cells in transgenic NOD/Lt mice determine level of diabetes resistance and indicate mechanism of protection. J Immunol. 1996 Aug 1;157(3):1279–1287. [PubMed] [Google Scholar]
  7. Hibbs M. L., Tolvanen M., Carpén O. Membrane-proximal Ig-like domain of Fc gamma RIII (CD16) contains residues critical for ligand binding. J Immunol. 1994 May 1;152(9):4466–4474. [PubMed] [Google Scholar]
  8. Hogarth P. M., Potter T. A., Cornell F. N., McLachlan R., McKenzie I. F. Monoclonal antibodies to murine cell surface antigens. I. Lyt-1.1. J Immunol. 1980 Oct;125(4):1618–1624. [PubMed] [Google Scholar]
  9. Horton R. M., Hunt H. D., Ho S. N., Pullen J. K., Pease L. R. Engineering hybrid genes without the use of restriction enzymes: gene splicing by overlap extension. Gene. 1989 Apr 15;77(1):61–68. doi: 10.1016/0378-1119(89)90359-4. [DOI] [PubMed] [Google Scholar]
  10. Hulett M. D., Hogarth P. M. Molecular basis of Fc receptor function. Adv Immunol. 1994;57:1–127. doi: 10.1016/s0065-2776(08)60671-9. [DOI] [PubMed] [Google Scholar]
  11. Hulett M. D., McKenzie I. F., Hogarth P. M. Chimeric Fc receptors identify immunoglobulin-binding regions in human Fc gamma RII and Fc epsilon RI. Eur J Immunol. 1993 Mar;23(3):640–645. doi: 10.1002/eji.1830230310. [DOI] [PubMed] [Google Scholar]
  12. Hulett M. D., Osman N., McKenzie I. F., Hogarth P. M. Chimeric Fc receptors identify functional domains of the murine high affinity receptor for IgG. J Immunol. 1991 Sep 15;147(6):1863–1868. [PubMed] [Google Scholar]
  13. Hulett M. D., Witort E., Brinkworth R. I., McKenzie I. F., Hogarth P. M. Identification of the IgG binding site of the human low affinity receptor for IgG Fc gamma RII. Enhancement and ablation of binding by site-directed mutagenesis. J Biol Chem. 1994 May 27;269(21):15287–15293. [PubMed] [Google Scholar]
  14. Hulett M. D., Witort E., Brinkworth R. I., McKenzie I. F., Hogarth P. M. Multiple regions of human Fc gamma RII (CD32) contribute to the binding of IgG. J Biol Chem. 1995 Sep 8;270(36):21188–21194. doi: 10.1074/jbc.270.36.21188. [DOI] [PubMed] [Google Scholar]
  15. Jones E. Y., Davis S. J., Williams A. F., Harlos K., Stuart D. I. Crystal structure at 2.8 A resolution of a soluble form of the cell adhesion molecule CD2. Nature. 1992 Nov 19;360(6401):232–239. doi: 10.1038/360232a0. [DOI] [PubMed] [Google Scholar]
  16. Lemoine R., Berney T., Shibata T., Fulpius T., Gyotoku Y., Shimada H., Sawada S., Izui S. Induction of "wire-loop" lesions by murine monoclonal IgG3 cryoglobulins. Kidney Int. 1992 Jan;41(1):65–72. doi: 10.1038/ki.1992.9. [DOI] [PubMed] [Google Scholar]
  17. Luan J. J., Monteiro R. C., Sautès C., Fluteau G., Eloy L., Fridman W. H., Bach J. F., Garchon H. J. Defective Fc gamma RII gene expression in macrophages of NOD mice: genetic linkage with up-regulation of IgG1 and IgG2b in serum. J Immunol. 1996 Nov 15;157(10):4707–4716. [PubMed] [Google Scholar]
  18. Mallamaci M. A., Chizzonite R., Griffin M., Nettleton M., Hakimi J., Tsien W. H., Kochan J. P. Identification of sites on the human Fc epsilon RI alpha subunit which are involved in binding human and rat IgE. J Biol Chem. 1993 Oct 15;268(29):22076–22083. [PubMed] [Google Scholar]
  19. McDonnell J. M., Beavil A. J., Mackay G. A., Jameson B. A., Korngold R., Gould H. J., Sutton B. J. Structure based design and characterization of peptides that inhibit IgE binding to its high-affinity receptor. Nat Struct Biol. 1996 May;3(5):419–426. doi: 10.1038/nsb0596-419. [DOI] [PubMed] [Google Scholar]
  20. Mongini P. K., Stein K. E., Paul W. E. T cell regulation of IgG subclass antibody production in response to T-independent antigens. J Exp Med. 1981 Jan 1;153(1):1–12. doi: 10.1084/jem.153.1.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Perlmutter R. M., Hansburg D., Briles D. E., Nicolotti R. A., Davie J. M. Subclass restriction of murine anti-carbohydrate antibodies. J Immunol. 1978 Aug;121(2):566–572. [PubMed] [Google Scholar]
  22. Podolin P. L., Denny P., Lord C. J., Hill N. J., Todd J. A., Peterson L. B., Wicker L. S., Lyons P. A. Congenic mapping of the insulin-dependent diabetes (Idd) gene, Idd10, localizes two genes mediating the Idd10 effect and eliminates the candidate Fcgr1. J Immunol. 1997 Aug 15;159(4):1835–1843. [PubMed] [Google Scholar]
  23. Porges A. J., Redecha P. B., Doebele R., Pan L. C., Salmon J. E., Kimberly R. P. Novel Fc gamma receptor I family gene products in human mononuclear cells. J Clin Invest. 1992 Nov;90(5):2102–2109. doi: 10.1172/JCI116094. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Prins J. B., Todd J. A., Rodrigues N. R., Ghosh S., Hogarth P. M., Wicker L. S., Gaffney E., Podolin P. L., Fischer P. A., Sirotina A. Linkage on chromosome 3 of autoimmune diabetes and defective Fc receptor for IgG in NOD mice. Science. 1993 Apr 30;260(5108):695–698. doi: 10.1126/science.8480181. [DOI] [PubMed] [Google Scholar]
  25. Sears D. W., Osman N., Tate B., McKenzie I. F., Hogarth P. M. Molecular cloning and expression of the mouse high affinity Fc receptor for IgG. J Immunol. 1990 Jan 1;144(1):371–378. [PubMed] [Google Scholar]
  26. Serreze D. V., Leiter E. H., Kuff E. L., Jardieu P., Ishizaka K. Molecular mimicry between insulin and retroviral antigen p73. Development of cross-reactive autoantibodies in sera of NOD and C57BL/KsJ db/db mice. Diabetes. 1988 Mar;37(3):351–358. doi: 10.2337/diab.37.3.351. [DOI] [PubMed] [Google Scholar]
  27. Slack J., Der-Balian G. P., Nahm M., Davie J. M. Subclass restriction of murine antibodies. II. The IgG plaque-forming cell response to thymus-independent type 1 and type 2 antigens in normal mice and mice expressing an X-linked immunodeficiency. J Exp Med. 1980 Apr 1;151(4):853–862. doi: 10.1084/jem.151.4.853. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Tate B. J., Witort E., McKenzie I. F., Hogarth P. M. Expression of the high responder/non-responder human Fc gamma RII. Analysis by PCR and transfection into FcR-COS cells. Immunol Cell Biol. 1992 Apr;70(Pt 2):79–87. doi: 10.1038/icb.1992.12. [DOI] [PubMed] [Google Scholar]
  29. Tsujimura K., Park Y. H., Miyama-Inaba M., Meguro T., Ohno T., Ueda M., Masuda T. Comparative studies on FcR (FcRII, FcRIII, and FcR alpha) functions of murine B cells. J Immunol. 1990 Jun 15;144(12):4571–4578. [PubMed] [Google Scholar]
  30. Wang J. H., Yan Y. W., Garrett T. P., Liu J. H., Rodgers D. W., Garlick R. L., Tarr G. E., Husain Y., Reinherz E. L., Harrison S. C. Atomic structure of a fragment of human CD4 containing two immunoglobulin-like domains. Nature. 1990 Nov 29;348(6300):411–418. doi: 10.1038/348411a0. [DOI] [PubMed] [Google Scholar]
  31. Warmerdam P. A., van de Winkel J. G., Vlug A., Westerdaal N. A., Capel P. J. A single amino acid in the second Ig-like domain of the human Fc gamma receptor II is critical for human IgG2 binding. J Immunol. 1991 Aug 15;147(4):1338–1343. [PubMed] [Google Scholar]
  32. Williams A. F., Barclay A. N. The immunoglobulin superfamily--domains for cell surface recognition. Annu Rev Immunol. 1988;6:381–405. doi: 10.1146/annurev.iy.06.040188.002121. [DOI] [PubMed] [Google Scholar]

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