Abstract
The avian immune system provides an excellent model to track B-cell development from prebursal stem cells throughout B-cell differentiation and maturation. Bursal B cells are uniquely positioned at the crossroads of B-cell development, having properties of both stem cells and of mature B cells, as demonstrated by their ability to reconstruct the bursal B-cell compartment and to express and diversify the B-cell receptor at their cell surface. To understand avian B-cell development better, we determined the gene expression profile of different B-cell stages using a bursal expressed sequence tag array. The expression profile of bursal B cells reveals the presence of factors associated with B-cell signaling and defines novel B-cell-specific genes. Genes associated with proliferation, apoptosis, DNA repair and recombination are abundantly expressed. The expression profile of the DT40 cell line is most similar to bursal B cells rather than to other stages of B-cell development, confirming the suitability of DT40 for studies of B-cell physiology. Interestingly, prebursal stem cells express genes involved in B-cell receptor signaling, although they express only low levels of immunoglobulin genes. This suggests that B-cell receptor-mediated selection is present before bursal colonization. The gene expression signatures of germinal centers and cells of the Harderian gland indicate that evolutionarily conserved genetic programs regulate B-cell activation and terminal differentiation.
Similar content being viewed by others
References
Abdrakhmanov I, Lodygin D, Geroth P, Arakawa H, Law A, Plachy J, Korn B, Buerstedde JM (2000) A large database of chicken bursal ESTs as a resource for the analysis of vertebrate gene function. Genome Res 10:2062–2069
Alizadeh AA, Eisen MB, Davis RE, Ma C, Lossos IS, Rosenwald A, Boldrick JC, Sabet H, Tran T, Yu X, Powell JI, Yang L, Marti GE, Moore T, Hudson J, Jr, Lu L, Lewis DB, Tibshirani R, Sherlock G, Chan WC, Greiner TC, Weisenburger DD, Armitage JO, Warnke R, Staudt LM, et al (2000) Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403:503–511
Altschul SF, Madden TL, Schaffer AA, Zhang J, Zhang Z, Miller W, Lipman DJ (1997) Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res 25:3389–3402
Arakawa H, Furusawa S, Ekino S, Yamagishi H (1996) Immunoglobulin gene hyperconversion ongoing in chicken splenic germinal centers. EMBO J 15:2540–2546
Arakawa H, Hauschild J, Buerstedde JM (2002) Requirement of the activation-induced deaminase (AID) gene for immunoglobulin gene conversion. Science 295:1301–1306
Babst M, Katzmann DJ, Estepa-Sabal EJ, Meerloo T, Emr SD (2002) Escrt-III: an endosome-associated heterooligomeric protein complex required for mvb sorting. Dev Cell 3:271–282
Bang BG, Bang FB (1968) Localized lymphoid tissues and plasma cells in paraocular and paranasal organ systems in chickens. Am J Pathol 53:735–751
Bezzubova O, Silbergleit A, Yamaguchi-Iwai Y, Takeda S, Buerstedde JM (1997) Reduced X-ray resistance and homologous recombination frequencies in a RAD54−/− mutant of the chicken DT40 cell line. Cell 89:185–193
Buerstedde JM, Takeda S (1991) Increased ratio of targeted to random integration after transfection of chicken B cell lines. Cell 67:179–188
Buerstedde JM, Arakawa H, Watahiki A, Carninci PP, Hayashizaki YY, Korn B, Plachy J (2002) The DT40 web site: sampling and connecting the genes of a B cell line. Nucleic Acids Res 30:230–231
Carlisle AJ, Prabhu VV, Elkahloun A, Hudson J, Trent JM, Linehan WM, Williams ED, Emmert-Buck MR, Liotta LA, Munson PJ, Krizman DB (2000) Development of a prostate cDNA microarray and statistical gene expression analysis package. Mol Carcinog 28:12–22
Cassimeris L (2002) The oncoprotein 18/stathmin family of microtubule destabilizers. Curr Opin Cell Biol 14:18–24
Chen Y, Dougherty E, Bittner M (1997) Ratio-based decisions and the quantitative analysis of cDNA microarray images. J Biomed Opt 2:364–374
Cooper MD, Kearney JF, Gathings WE, Lawton AR (1980) Effects of anti-Ig antibodies on the development and differentiation of B cells. Immunol Rev 52:29–53
Dysvik B, Jonassen I (2001) J-Express: exploring gene expression data using Java. Bioinformatics 17:369–370
Faast R, Thonglairoam V, Schulz TC, Beall J, Wells JR, Taylor H, Matthaei K, Rathjen PD, Tremethick DJ, Lyons I (2001) Histone variant H2A.Z is required for early mammalian development. Curr Biol 11:1183–1187
Fambrough D, McClure K, Kazlauskas A, Lander ES (1999) Diverse signaling pathways activated by growth factor receptors induce broadly overlapping, rather than independent, sets of genes. Cell 97:727–741
Goitsuka R, Fujimura Y, Mamada H, Umeda A, Morimura T, Uetsuka K, Doi K, Tsuji S, Kitamura D (1998) BASH, a novel signaling molecule preferentially expressed in B cells of the bursa of Fabricius. J Immunol 161:5804–5808
Han W, Takano T, He J, Ding J, Gao S, Noda C, Yanagi S, Yamamura H (2001) Role of BLNK in oxidative stress signaling in B cells. Antioxid Redox Signal 3:1065–1073
Harding HP, Novoa I, Zhang Y, Zeng H, Wek R, Schapira M, Ron D (2000) Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell 6:1099–1108
Houssaint E, Diez E, Pink JR (1987) Ontogeny and tissue distribution of the chicken Bu-1a antigen. Immunology 62:463–470
Houssaint E, Lassila O, Vainio O (1989) Bu-1 antigen expression as a marker for B cell precursors in chicken embryos. Eur J Immunol 19:239–243
Hsu SY, Kaipia A, McGee E, Lomeli M, Hsueh AJ (1997) Bok is a pro-apoptotic Bcl-2 protein with restricted expression in reproductive tissues and heterodimerizes with selective anti-apoptotic Bcl-2 family members. Proc Natl Acad Sci USA 94:12401–12406
Jiang X, Kim HE, Shu H, Zhao Y, Zhang H, Kofron J, Donnelly J, Burns D, Ng SC, Rosenberg S, Wang X (2003) Distinctive roles of PHAP proteins and prothymosin-alpha in a death regulatory pathway. Science 299:223–226
Koskela K, Arstila T, Lassila O (1998) Costimulatory function of CD28 in avian γδ T cells is evolutionarily conserved. Scand J Immunol 48:635–641
Kovac CR, Emelyanov A, Singh M, Ashouian N, Birshtein BK (2000) BSAP (Pax5)-importin alpha 1 (Rch1) interaction identifies a nuclear localization sequence. J Biol Chem 275:16752–16757
Kurosaki T (1999) Genetic analysis of B cell antigen receptor signaling. Annu Rev Immunol 17:555–592
Kurosaki T, Tsukada S (2000) BLNK: connecting Syk and Btk to calcium signals. Immunity 12:1–5
Lahti JM (1999) Use of gene knockouts in cultured cells to study apoptosis. Methods 17:305–312
Lassila O (1989) Emigration of B cells from chicken bursa of Fabricius. Eur J Immunol 19:955–958
Lassila O, Alanen A, Lefkovits I, Cooper MD, Pink JR (1988) Immunoglobulin diversification in embryonic chicken bursae and in individual bursal follicles. Eur J Immunol 18:943–949
Liippo J, Mansikka A, Lassila O (1999) The evolutionarily conserved avian Aiolos gene encodes alternative isoforms. Eur J Immunol 29:2651–2657
Ma Q, Jones D, Springer TA (1999) The chemokine receptor CXCR4 is required for the retention of B lineage and granulocytic precursors within the bone marrow microenvironment. Immunity 10:463–471
Mansikka A, Sandberg M, Veromaa T, Vainio O, Granfors K, Toivanen P (1989) B cell maturation in the chicken Harderian gland. J Immunol 142:1826–1833
Mansikka A, Sandberg M, Lassila O, Toivanen P (1990) Rearrangement of immunoglobulin light chain genes in the chicken occurs prior to colonization of the embryonic bursa of Fabricius. Proc Natl Acad Sci USA 87:9416–9420
Masuelli L, Cutler ML (1996) Increased expression of the Ras suppressor Rsu-1 enhances Erk-2 activation and inhibits Jun kinase activation. Mol Cell Biol 16:5466–5476
Matsubae M, Kurihara T, Tachibana T, Imamoto N, Yoneda Y (2000) Characterization of the nuclear transport of a novel leucine-rich acidic nuclear protein-like protein. FEBS Lett 468:171–175
McCormack WT, Tjoelker LW, Thompson CB (1991) Avian B-cell development: generation of an immunoglobulin repertoire by gene conversion. Annu Rev Immunol 9:219–241
Neiman PE, Gehly EB, Carlson LM, Cotter RC, Thompson CB (1988) Bursal stem cells as targets for myc-induced preneoplastic proliferation and maturation arrest. Curr Top Microbiol Immunol 141:67–74
Neiman PE, Ruddell A, Jasoni C, Loring G, Thomas SJ, Brandvold KA, Lee R, Burnside J, Delrow J (2001) Analysis of gene expression during myc oncogene-induced lymphomagenesis in the bursa of Fabricius. Proc Natl Acad Sci USA 98:6378–6383
Nieminen P, Liippo J, Lassila O (2000) Pax-5 and EBF are expressed in committed B-cell progenitors prior to the colonization of the embryonic bursa of fabricius. Scand J Immunol 52:465–469
Nieminen P, Liippo J, Lassila O (2001) Bursa of Fabricius. In: Nature encyclopedia of life sciences. Nature Publishing Group, London, p 4506. http://www.els.net/ [DOI 10.1038/npg.els.0000506]
Okada T, Maeda A, Iwamatsu A, Gotoh K, Kurosaki T (2000) BCAP: the tyrosine kinase substrate that connects B cell receptor to phosphoinositide 3-kinase activation. Immunity 13:817–827
Ott VL, Cambier JC (2002) Introduction: multifaceted roles of lipids and their catabolites in immune cell signaling. Semin Immunol 14:1–6
Pifer J, Robison D, Funk PE (2002) The avian ChB6 alloantigen triggers apoptosis in a mammalian cell line. J Immunol 169:1372–1378
Pink JR, Lassila O (1987) B-cell commitment and diversification in the bursa of Fabricius. Curr Top Microbiol Immunol 135:57–64
Reimold AM, Iwakoshi NN, Manis J, Vallabhajosyula P, Szomolanyi-Tsuda E, Gravallese EM, Friend D, Grusby MJ, Alt F, Glimcher LH (2001) Plasma cell differentiation requires the transcription factor XBP-1. Nature 412:300–307
Rolink AG, Melchers F (2002) BAFFled B cells survive and thrive: roles of BAFF in B-cell development. Curr Opin Immunol 14:266–275
Sayegh CE, Demaries SL, Pike KA, Friedman JE, Ratcliffe MJ (2000) The chicken B-cell receptor complex and its role in avian B-cell development. Immunol Rev 175:187–200
Schebesta M, Heavey B, Busslinger M (2002) Transcriptional control of B-cell development. Curr Opin Immunol 14:216–223
Shaffer AL, Yu X, He Y, Boldrick J, Chan EP, Staudt LM (2000) BCL-6 represses genes that function in lymphocyte differentiation, inflammation, and cell cycle control. Immunity 13:199–212
Shaffer AL, Rosenwald A, Hurt EM, Giltnane JM, Lam LT, Pickeral OK, Staudt LM (2001) Signatures of the immune response. Immunity 15:375–385
Smithyman AM, Carr K, Forman D, White RG (1979) Separation of germinal centres from chicken spleen. Adv Exp Med Biol 114:37–41
Swanson PC (2002) Fine structure and activity of discrete RAG-HMG complexes on V(D)J recombination signals. Mol Cell Biol 22:1340–1351
Torgerson TR, Colosia AD, Donahue JP, Lin YZ, Hawiger J (1998) Regulation of NF-kappa B, AP-1, NFAT, and STAT1 nuclear import in T lymphocytes by noninvasive delivery of peptide carrying the nuclear localization sequence of NF-kappa B p50. J Immunol 161:6084–6092
Volkert MR, Elliott NA, Housman DE (2000) Functional genomics reveals a family of eukaryotic oxidation protection genes. Proc Natl Acad Sci USA 97:14530–14535
Weill JC, Reynaud CA (1987) The chicken B cell compartment. Science 238:1094–1098
Winding P, Berchtold MW (2001) The chicken B cell line DT40: a novel tool for gene disruption experiments. J Immunol Methods 249:1–16
Zhuang Y, Barndt RJ, Pan L, Kelley R, Dai M (1998) Functional replacement of the mouse E2A gene with a human HEB cDNA. Mol Cell Biol 18:3340–3349
Zicca A, Cadoni A, Leprini A, Millo R, Lydyard PM, Grossi CE (1982) Immunofluorescent and ultrastructural analysis of plasma cell degeneration in the chicken Harder's gland. Dev Comp Immunol 6:131–139
Acknowledgements
The authors wish to thank Prof. H. Arvilommi and Drs. H. Salminen, J. Liippo, K.-P. Nera, M. Möttönen, J. Heikkinen and E. Veistinen for critically reading the manuscript. Ms. A. Karvonen, M. Kuusimurto and J. Matsson are acknowledged for their excellent technical assistance. This work was financially supported by the European Union (QLK3-CT-2000-00785), Tekes (the National Technology Agency), Turku Graduate School of Biomedical Sciences, the Academy of Finland, special funds from the Research and Science Foundation of Farmos, the Finnish Cultural Foundation of Southwest Finland, the Finnish Medical Foundation, the Turku University Foundation, Emil and Blida Maunula Foundation, Emil Aaltonen foundation and the Paulo Foundation. Experiments using animals were done with the permission of the local authorities (Accredition No: 1071/00).
Author information
Authors and Affiliations
Corresponding author
Additional information
K. Koskela, P. Kohonen and P. Nieminen contributed equally to this work
Electronic Supplementary Material
Rights and permissions
About this article
Cite this article
Koskela, K., Kohonen, P., Nieminen, P. et al. Insight into lymphoid development by gene expression profiling of avian B cells. Immunogenetics 55, 412–422 (2003). https://doi.org/10.1007/s00251-003-0592-7
Received:
Revised:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00251-003-0592-7