Abstract
During B lymphocyte differentiation, immunoglobulin heavy chain constant region (CH) genes undergo a unique series of DNA recombination events culminating in the CH class switch. CH switch (S) regions are located 2 kb 5' of each CH gene except delta (i.e. mu, gamma 3, gamma 1, gamma 2b, gamma 2a, epsilon and alpha). We describe the structural features of the gamma 3 switch region. Hybridization experiments show that S gamma 3 has remarkable homology to both S mu and other S gamma regions while S mu possesses limited homology to the other S gamma sequences. However, S mu possesses extensive sequence homology with S epsilon and S alpha. The nucleotide sequence of S gamma 3 reveals higher densities of S mu repetitive sequences (GAGCT and GGGGT) and another S region common sequence (YAGGTTG) than observed for S gamma 1, S gamma 2b or S gamma 2a. In addition, the conservation of S mu like repetitive sequences in S gamma regions is correlated with the 5' leads to 3' gamma gene order (i.e. S gamma 3 greater than S gamma 1 greater than S gamma 2b greater than S gamma 2a). A model is presented which suggests that the unique features of S gamma 3 may allow for successive switches from C mu to any C gamma gene.
Full text
PDF













Images in this article
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Coleclough C., Cooper D., Perry R. P. Rearrangement of immunoglobulin heavy chain genes during B-lymphocyte development as revealed by studies of mouse plasmacytoma cells. Proc Natl Acad Sci U S A. 1980 Mar;77(3):1422–1426. doi: 10.1073/pnas.77.3.1422. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cory S., Adams J. M. Deletions are associated with somatic rearrangement of immunoglobulin heavy chain genes. Cell. 1980 Jan;19(1):37–51. doi: 10.1016/0092-8674(80)90386-4. [DOI] [PubMed] [Google Scholar]
- Cory S., Jackson J., Adams J. M. Deletions in the constant region locus can account for switches in immunoglobulin heavy chain expression. Nature. 1980 Jun 12;285(5765):450–456. doi: 10.1038/285450a0. [DOI] [PubMed] [Google Scholar]
- Davis M. M., Kim S. K., Hood L. E. DNA sequences mediating class switching in alpha-immunoglobulins. Science. 1980 Sep 19;209(4463):1360–1365. doi: 10.1126/science.6774415. [DOI] [PubMed] [Google Scholar]
- Eckhardt L. A., Tilley S. A., Lang R. B., Marcu K. B., Birshtein B. K. DNA rearrangements in MPC-11 immunoglobulin heavy chain class-switch variants. Proc Natl Acad Sci U S A. 1982 May;79(9):3006–3010. doi: 10.1073/pnas.79.9.3006. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Francus T., Birshtein B. K. An IgG2a-producing variant of an IgG2b-producing mouse myeloma cell line. Structural studies on the Fc region of parent and variant heavy chains. Biochemistry. 1978 Oct 3;17(20):4324–4331. doi: 10.1021/bi00613a033. [DOI] [PubMed] [Google Scholar]
- Gearhart P. J., Hurwitz J. L., Cebra J. J. Successive switching of antibody isotypes expressed within the lines of a B-cell clone. Proc Natl Acad Sci U S A. 1980 Sep;77(9):5424–5428. doi: 10.1073/pnas.77.9.5424. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Harris L. J., Lang R. B., Marcu K. B. Non-immunoglobulin-associated DNA rearrangements in mouse plasmacytomas. Proc Natl Acad Sci U S A. 1982 Jul;79(13):4175–4179. doi: 10.1073/pnas.79.13.4175. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Honjo T., Kataoka T. Organization of immunoglobulin heavy chain genes and allelic deletion model. Proc Natl Acad Sci U S A. 1978 May;75(5):2140–2144. doi: 10.1073/pnas.75.5.2140. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hurwitz J. L., Coleclough C., Cebra J. J. CH gene rearrangements in IgM-bearing B cells and in the normal splenic DNA component of hybridomas making different isotypes of antibody. Cell. 1980 Nov;22(2 Pt 2):349–359. doi: 10.1016/0092-8674(80)90345-1. [DOI] [PubMed] [Google Scholar]
- Kataoka T., Miyata T., Honjo T. Repetitive sequences in class-switch recombination regions of immunoglobulin heavy chain genes. Cell. 1981 Feb;23(2):357–368. doi: 10.1016/0092-8674(81)90131-8. [DOI] [PubMed] [Google Scholar]
- Lang R. B., Stanton L. W., Marcu K. B. On immunoglobulin heavy chain gene switching: two gamma 2b genes are rearranged via switch sequences in MPC-11 cells but only one is expressed. Nucleic Acids Res. 1982 Jan 22;10(2):611–630. doi: 10.1093/nar/10.2.611. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Liu C. P., Tucker P. W., Mushinski J. F., Blattner F. R. Mapping of heavy chain genes for mouse immunoglobulins M and D. Science. 1980 Sep 19;209(4463):1348–1353. doi: 10.1126/science.6774414. [DOI] [PubMed] [Google Scholar]
- Marcu K. B., Arnheim N., Banerji J., Penncavage N. A., Seperack P., Lang R., Miesfeld R., Harris L., Greenberg R. Studies on the nature and germ-line stability of DNA sequences flanking the mouse immunoglobulin heavy-chain constant-region genes. Cold Spring Harb Symp Quant Biol. 1981;45(Pt 2):899–911. doi: 10.1101/sqb.1981.045.01.107. [DOI] [PubMed] [Google Scholar]
- Marcu K. B., Banerji J., Penncavage N. A., Lang R., Arnheim N. 5' flanking region of immunoglobulin heavy chain constant region genes displays length heterogeneity in germlines of inbred mouse strains. Cell. 1980 Nov;22(1 Pt 1):187–196. doi: 10.1016/0092-8674(80)90167-1. [DOI] [PubMed] [Google Scholar]
- Marcu K. B., Lang R. B., Stanton L. W., Harris L. J. A model for the molecular requirements of immunoglobulin heavy chain class switching. Nature. 1982 Jul 1;298(5869):87–89. doi: 10.1038/298087a0. [DOI] [PubMed] [Google Scholar]
- Maxam A. M., Gilbert W. Sequencing end-labeled DNA with base-specific chemical cleavages. Methods Enzymol. 1980;65(1):499–560. doi: 10.1016/s0076-6879(80)65059-9. [DOI] [PubMed] [Google Scholar]
- Mongini P. K., Paul W. E., Metcalf E. S. T cell regulation of immunoglobulin class expression in the antibody response to trinitrophenyl-ficoll. Evidence for T cell enhancement of the immunoglobulin class switch. J Exp Med. 1982 Mar 1;155(3):884–902. doi: 10.1084/jem.155.3.884. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nikaido T., Nakai S., Honjo T. Switch region of immunoglobulin Cmu gene is composed of simple tandem repetitive sequences. Nature. 1981 Aug 27;292(5826):845–848. doi: 10.1038/292845a0. [DOI] [PubMed] [Google Scholar]
- Nikaido T., Yamawaki-Kataoka Y., Honjo T. Nucleotide sequences of switch regions of immunoglobulin C epsilon and C gamma genes and their comparison. J Biol Chem. 1982 Jul 10;257(13):7322–7329. [PubMed] [Google Scholar]
- Nossal G. J., Warner N. L., Lewis H. Incidence of cells simultaneously secreting IgM and IgG antibody to sheep erythrocytes. Cell Immunol. 1971 Feb;2(1):41–53. doi: 10.1016/0008-8749(71)90024-4. [DOI] [PubMed] [Google Scholar]
- Obata M., Kataoka T., Nakai S., Yamagishi H., Takahashi N., Yamawaki-Kataoka Y., Nikaido T., Shimizu A., Honjo T. Structure of a rearranged gamma 1 chain gene and its implication to immunoglobulin class-switch mechanism. Proc Natl Acad Sci U S A. 1981 Apr;78(4):2437–2441. doi: 10.1073/pnas.78.4.2437. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Rabbitts T. H., Forster A., Dunnick W., Bentley D. L. The role of gene deletion in the immunoglobulin heavy chain switch. Nature. 1980 Jan 24;283(5745):351–356. doi: 10.1038/283351a0. [DOI] [PubMed] [Google Scholar]
- Rabbitts T. H., Forster A., Milstein C. P. Human immunoglobulin heavy chain genes: evolutionary comparisons of C mu, C delta and C gamma genes and associated switch sequences. Nucleic Acids Res. 1981 Sep 25;9(18):4509–4524. doi: 10.1093/nar/9.18.4509. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Radbruch A., Liesegang B., Rajewsky K. Isolation of variants of mouse myeloma X63 that express changed immunoglobulin class. Proc Natl Acad Sci U S A. 1980 May;77(5):2909–2913. doi: 10.1073/pnas.77.5.2909. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Raff M. C. Development and modulation of B lymphocytes: studies on newly formed B cells and their putative precursors in the hemopoietic tissues of mice. Cold Spring Harb Symp Quant Biol. 1977;41(Pt 1):159–162. doi: 10.1101/sqb.1977.041.01.020. [DOI] [PubMed] [Google Scholar]
- Ravetch J. V., Kirsch I. R., Leder P. Evolutionary approach to the question of immunoglobulin heavy chain switching: evidence from cloned human and mouse genes. Proc Natl Acad Sci U S A. 1980 Nov;77(11):6734–6738. doi: 10.1073/pnas.77.11.6734. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sakano H., Hüppi K., Heinrich G., Tonegawa S. Sequences at the somatic recombination sites of immunoglobulin light-chain genes. Nature. 1979 Jul 26;280(5720):288–294. doi: 10.1038/280288a0. [DOI] [PubMed] [Google Scholar]
- Sakano H., Rogers J. H., Hüppi K., Brack C., Traunecker A., Maki R., Wall R., Tonegawa S. Domains and the hinge region of an immunoglobulin heavy chain are encoded in separate DNA segments. Nature. 1979 Feb 22;277(5698):627–633. doi: 10.1038/277627a0. [DOI] [PubMed] [Google Scholar]
- Shimizu A., Takahashi N., Yamawaki-Kataoka Y., Nishida Y., Kataoka T., Honjo T. Ordering of mouse immunoglobulin heavy chain genes by molecular cloning. Nature. 1981 Jan 15;289(5794):149–153. doi: 10.1038/289149a0. [DOI] [PubMed] [Google Scholar]
- Shimizu A., Takahashi N., Yaoita Y., Honjo T. Organization of the constant-region gene family of the mouse immunoglobulin heavy chain. Cell. 1982 Mar;28(3):499–506. doi: 10.1016/0092-8674(82)90204-5. [DOI] [PubMed] [Google Scholar]
- Sikorav J. L., Auffray C., Rougeon F. Structure of the constant and 3' untranslated regions of the murine Balb/c gamma 2a heavy chain messenger RNA. Nucleic Acids Res. 1980 Jul 25;8(14):3143–3155. doi: 10.1093/nar/8.14.3143. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Takahashi N., Nakai S., Honjo T. Cloning of human immunoglobulin mu gene and comparison with mouse mu gene. Nucleic Acids Res. 1980 Dec 20;8(24):5983–5991. doi: 10.1093/nar/8.24.5983. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yaoita Y., Honjo T. Deletion of immunoglobulin heavy chain genes from expressed allelic chromosome. Nature. 1980 Aug 28;286(5776):850–853. doi: 10.1038/286850a0. [DOI] [PubMed] [Google Scholar]


