Molecular Characterization of J558 Genes Encoding Tight-skin Mouse Autoantibodies: Identical Heavy-chain Variable Genes Code for Antibodies with Different Specificities

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 1994 Aug 16

PMID 8058758

Authors

K N Kasturi

X Y Yio

C A Bona

Affiliations

Soon will be listed here.

Abstract

Tight-skin mouse, a mutant strain with a single gene defect, develops cutaneous hyperplasia and specific autoantibodies, like humans affected by scleroderma. The autoantibodies produced in the tight-skin mouse are encoded primarily by heavy-chain variable (VH) genes from the J558 family. To understand the genetic basis of production of autoantibodies, we have analyzed the structure of J558 genes encoding these autoantibodies. The results showed that J558 genes encoding these antibodies were not derived from a selected germ-line gene(s) or a single subfamily but were derived from genes belonging to diverse J558 subfamilies. However, two prototype VH genes representing two new subfamilies were found to be repeatedly expressed in their germ-line form in eight independent clones. Autoantibodies with distinct specificities appear to be generated by pairing of similar/identical VH genes with different V kappa genes derived from the same or different families. Fourteen of 18 autoantibodies shared a conserved heptapeptide sequence motif, YNEKFKG, in the second complementarity-determining region of heavy chains. Usage of germ-line genes from diverse J558 subfamilies bearing a common motif to encode autoantibodies suggests a regulatory role for this motif. Thus, selection and expansion of the autoreactive B-cell repertoire in the tight-skin mouse appear to be VH-gene mediated. The frequency of N nucleotide addition at diversity-joining (D-JH) junctions was lower, whereas the frequency of usage of the DFL16 segment was higher. Finally, in contrast to normal and other autoimmune mouse strains, the frequencies of D-D fusions and D inversions were higher in tight-skin mouse total immunoglobulin as well as autoantibody repertoires.

References

Viale A, Coutinho A, HEYMAN R, Freitas A . V region dependent selection of persistent resting peripheral B cells in normal mice. Int Immunol. 1993; 5(6):599-605. DOI: 10.1093/intimm/5.6.599. View

Bloom D, Davignon J, Retter M, Shlomchik M, Pisetsky D, Cohen P . V region gene analysis of anti-Sm hybridomas from MRL/Mp-lpr/lpr mice. J Immunol. 1993; 150(4):1591-610. View

Kasturi K, Daian C, Saitoh Y, Muryoi T, Bona C . Tight-skin mouse autoantibody repertoire: analysis of VH and VK gene usage. Mol Immunol. 1993; 30(11):969-78. DOI: 10.1016/0161-5890(93)90122-r. View

Mo J, Bona C, Holmdahl R . Variable region gene selection of immunoglobulin G-expressing B cells with specificity for a defined epitope on type II collagen. Eur J Immunol. 1993; 23(10):2503-10. DOI: 10.1002/eji.1830231019. View

Chukwuocha R, Feeney A . Role of homology-directed recombination: predominantly productive rearrangements of Vh81X in newborns but not in adults. Mol Immunol. 1993; 30(16):1473-9. DOI: 10.1016/0161-5890(93)90109-o. View

Clarke S, McCray S . VH CDR3-dependent positive selection of murine VH12-expressing B cells in the neonate. Eur J Immunol. 1993; 23(12):3327-34. DOI: 10.1002/eji.1830231240. View

Green M, Sweet H, Bunker L . Tight-skin, a new mutation of the mouse causing excessive growth of connective tissue and skeleton. Am J Pathol. 1976; 82(3):493-512. PMC: 2032428. View

Early P, Huang H, Davis M, Calame K, Hood L . An immunoglobulin heavy chain variable region gene is generated from three segments of DNA: VH, D and JH. Cell. 1980; 19(4):981-92. DOI: 10.1016/0092-8674(80)90089-6. View

Sakano H, Maki R, Kurosawa Y, Roeder W, Tonegawa S . Two types of somatic recombination are necessary for the generation of complete immunoglobulin heavy-chain genes. Nature. 1980; 286(5774):676-83. DOI: 10.1038/286676a0. View

10.

Bothwell A, Paskind M, Reth M, Rajewsky K, Baltimore D . Heavy chain variable region contribution to the NPb family of antibodies: somatic mutation evident in a gamma 2a variable region. Cell. 1981; 24(3):625-37. DOI: 10.1016/0092-8674(81)90089-1. View

11.

Kurosawa Y, Tonegawa S . Organization, structure, and assembly of immunoglobulin heavy chain diversity DNA segments. J Exp Med. 1982; 155(1):201-18. PMC: 2186579. DOI: 10.1084/jem.155.1.201. View

12.

Gleason K, Kohler H . Regulatory idiotypes. T helper cells recognize a shared VH idiotope on phosphorylcholine-specific antibodies. J Exp Med. 1982; 156(2):539-49. PMC: 2186772. DOI: 10.1084/jem.156.2.539. View

13.

Alt F, Baltimore D . Joining of immunoglobulin heavy chain gene segments: implications from a chromosome with evidence of three D-JH fusions. Proc Natl Acad Sci U S A. 1982; 79(13):4118-22. PMC: 346588. DOI: 10.1073/pnas.79.13.4118. View

14.

Tonegawa S . Somatic generation of antibody diversity. Nature. 1983; 302(5909):575-81. DOI: 10.1038/302575a0. View

15.

Brodeur P, Riblet R . The immunoglobulin heavy chain variable region (Igh-V) locus in the mouse. I. One hundred Igh-V genes comprise seven families of homologous genes. Eur J Immunol. 1984; 14(10):922-30. DOI: 10.1002/eji.1830141012. View

16.

Perlmutter R, Kearney J, Chang S, HOOD L . Developmentally controlled expression of immunoglobulin VH genes. Science. 1985; 227(4694):1597-601. DOI: 10.1126/science.3975629. View

17.

Agarwal S, White-Scharf M . Heavy chain variable region. Multiple gene segments encode anti-4-(hydroxy-3-nitro-phenyl)acetyl idiotypic antibodies. J Exp Med. 1985; 161(6):1272-92. PMC: 2187640. DOI: 10.1084/jem.161.6.1272. View

18.

Maizels N, Bothwell A . The T-cell-independent immune response to the hapten NP uses a large repertoire of heavy chain genes. Cell. 1985; 43(3 Pt 2):715-20. DOI: 10.1016/0092-8674(85)90244-2. View

19.

Jimenez S, Williams C, Myers J, BASHEY R . Increased collagen biosynthesis and increased expression of type I and type III procollagen genes in tight skin (TSK) mouse fibroblasts. J Biol Chem. 1986; 261(2):657-62. View

20.

Painter C, Monestier M, Chew A, Kasturi K, Bailey C, Scott V . Specificities and V genes encoding monoclonal autoantibodies from viable motheaten mice. J Exp Med. 1988; 167(3):1137-53. PMC: 2188884. DOI: 10.1084/jem.167.3.1137. View