Bursa of Fabricius

Kalle‐Pekka Nera, University of Turku, Turku, Finland
Minna K Kyläniemi, University of Turku, Turku, Finland
Olli Lassila, University of Turku, Turku, Finland

Published online: November 2015

DOI: 10.1002/9780470015902.a0000506.pub4

Abstract

The bursa of Fabricius plays a central role in the development of the antibody‐producing B‐lymphocyte lineage in birds. It consists of more than 10 000 follicles surrounded by connective tissue. These follicles provide an appropriate microenvironment for generating a primary repertoire of antibodies. Immunoglobulin gene diversification is achieved by gene conversion and is antigen independent. Bursal B cells undergo very rapid cell division while expressing AID, UNG, Pax5 and Bcl6, genes that are also expressed in proliferating germinal center B cells. By the time of sexual maturity, the bursa involutes and the only source of B‐cell renewal in adult birds is the pool of postbursal B cells in the peripheral lymphoid organs. Bursal B‐cell line DT40 provides a unique model system for gene‐targeting studies clarifying the B‐cell development, function and Ig diversification.

Key Concepts

  • Bursa of Fabricius is the primary site for B‐cell development.
  • Bursa is the site of primary antibody repertoire formation in birds.
  • Bursa involutes at the time of sexual maturity.
  • Antibody diversification in the bursa of Fabricius is antigen independent and occurs mostly by Ig gene conversion.
  • Bursal‐derived DT40 B‐cell line provides a reverse genetic model to study molecular function of B cells.

Keywords: aves; B cells; Ig diversification; gene conversion; haematopoiesis; DT40; evolution

Figure 1. Anatomy and structure of the avian bursa of Fabricius. (a) Anatomical location of the chicken thymus and the bursa of Fabricius, and a cross‐section of the bursa of Fabricius. The bursa has a highly folded surface surrounding the central lumen, which is connected to the intestine by the bursal duct. The lymphoid follicles are situated within the longitudinal plicae. Altogether, the bursa contains approximately 10 000 follicles. Between the bursal medulla and lumen is the follicular‐associated epithelium (FAE). (b) Avian B‐cell development. The progenitor cells seeding the bursal primordium originate from the paraaortic mesenchyme. These prebursal ‘stem cells’ (prebursal B‐cell progenitors) are committed to the B‐cell lineage before bursal colonisation. Within the bursal follicles the surface immunoglobulin‐expressing bursal progenitors start to divide and diversify their immunoglobulin V genes. The proliferating bursal B cells are densely packed in the cortical part of the bursal follicles. The medulla (M) contains mainly loosely packed lymphocytes and stromal cells. Starting shortly before hatching, diversified B cells start to emigrate from the bursa; however, more than 95% of bursal B cells die by apoptosis. Within the peripheral lymphoid organs, postbursal B cells can further modify their immunoglobulin gene specificity by gene conversion and by somatic hypermutation. The peripheral lymphoid organs cannot, however, replace the important function of the bursa as a mutant‐generating organ.
Figure 2. Comparison of human and avian immunoglobulin (Ig) gene diversification. While humans have multiple functional Ig variable (V) regions, avians have only one. Thus, no considerable variation is generated by gene rearrangement in avians. Ig V region diversity is generated by gene conversion, which uses upstream V pseudogene segments as templates for homologous recombination generating mutations to the recombined functional V region. Further diversification is achieved by somatic hypermutation (SHM).
Figure 3. Schematic comparison of human and avian B‐cell development. In human (and mouse) B cells develop in the foetal liver and bone marrow. During pro‐B‐cell stage, Ig heavy chains (IgH) are rearranged and expressed on the cell surface with surrogate light chains as part of a pre‐BCR complex. Following Ig light (IgL), chain rearrangement leads to the expression of completed IgM on the cell surface of immature B cells. Owing to the multiple Ig V(D)J regions, multitude IgMs with variable specificity are generated. In contrast, birds recombine IgH and IgL chains simultaneously during the prebursal development, and no considerable variation in Ig specificity is generated. The Ig diversity is primarily achieved by gene conversion and to lesser extent by somatic hypermutation (SHM) at the bursal stage of the development. SHM further adds variability to Ig specificity at the stage of germinal centre (GC) B cells in both human and birds, but in avian GCs also Ig gene conversion occurs at early stages of GC development.
close

References

Alinikula J, Lassila O and Nera KP (2006) DT40 mutants: a model to study transcriptional regulation of B cell development and function. Subcellular Biochemistry 40: 189–205.

Alinikula J, Kohonen P, Nera KP and Lassila O (2010) Concerted action of Helios and Ikaros controls the expression oh inositol 5‐phosphatase SHIP. European Journal of Immunology 40: 2599–2607.

Alinikula J, Nera KP, Junttila S and Lassila O (2011) Alternate pathways for Bcl6‐mediated regulation of B cell to plasma cell differentiation. European Journal of Immunology 41: 2404–2413.

Alinikula J and Schatz DG (2014) Super‐enhancer transcription converges on AID. Cell 159: 1490–1492.

Alt FW, Zhang Y, Meng FL, Guo C and Schwer B (2013) Mechanisms of programmed DNA lesions and genomic instability in the immune system. Cell 152: 417–429.

Arakawa H, Furasawa S, Ekino S and Yamagishi H (1996) Immunoglobulin gene hyperconversion ongoing in chicken splenic germinal centers. EMBO Journal 15: 2540–2546.

Arakawa H, Hauschild J and Buerstedde JM (2002) Requirement of the activation‐induced deaminase (AID) gene for immunoglobulin gene conversion. Science 295: 1301–1306.

Buerstedde JM, Reynaud CA, Humphries EH, et al. (1990) Light chain gene conversion continues at high rate in an ALV‐induced cell line. EMBO Journal 9: 921–927.

Buerstedde JM and Takeda S (1991) Increased ratio of targeted to random integration after transfection of chicken B cell lines. Cell 67: 179–188.

Buerstedde JM, Alinikula J, Arakawa H, McDonald JJ and Schatz DG (2014) Targeting of somatic hypermutation by immunoglobulin enhancer and enhancer‐like sequences. PLoS Biology 12: e1001831.

Cobaleda C, Schebesta A, Delogu A and Busslinger M (2007) Pax5: the guardian of B cell identity and function. Nature Immunology 8: 463–470.

Cooper MD, Peterson RD and Good RA (1965) Delineation of the thymic system and bursal system in the chicken. Nature 205: 143–146.

Cooper MD (2010) A life of adventure in immunobiology. Annual Review of Immunology 28: 1–19.

Davani D, Pancer Z, Cheroutre H and Ratcliffe MJH (2014a) Negative selection of self‐reactive chicken B cells requires B cell receptor signaling and is independent of the bursal microenvironment. Journal of Immunology 192: 3207–3217.

Davani D, Pancer Z and Ratcliffe MJH (2014b) Ligation of surface Ig by gut‐derived antigen positively selects chicken bursal and peripheral B cells. Journal of Immunology 192: 3218–3227.

Flajnik MF (2002) Comparative analyses of immunoglobulin genes: surprises and portents. Nature Reviews Immunology 2: 688–698.

Glick B, Chang TS and Jaap RG (1956) The bursa of Fabricius and antibody production. Poultry Science 35: 224–225.

Harris RS, Sale JE, Petersten‐Mahrt SK and Neuberger MS (2002) AID is essential for immunoglobulin V gene conversion in a cultured B cell line. Current Biology 12: 435–438.

Kim S, Humphries EH, Tjoelker L, Carlson L and Thompson CB (1990) Ongoing diversification of the rearranged immunoglobulin light‐chain gene in a bursal lymphoma cell line. Molecular and Cellular Biology 10: 3224–3231.

Koskela K, Kohonen P, Nieminen P, Buerstedde JM and Lassila O (2003) Insight into lymphoid development by gene expression profiling of avian B cells. Immunogenetics 55: 412–422.

Lassila O, Alanen A, Lefkovits I, Cooper MD and Pink JR (1988) Immunoglobulin diversification in embryonic chicken bursa and in individual bursal follicles. European Journal of Immunology 18: 943–949.

Lassila O (1989) Emigration of B‐cells from chicken bursa of Fabricius. European Journal of Immunology 19: 955–958.

Lassila O, Eskola J and Toivanen P (1979) Prebursal stem cells in the intraembryonic mesenchyme of the chick embryo at 7 days of incubation. Journal of Immunology 123: 2091–2094.

Lassila O, Eskola J, Toivanen P, Martin C and Dieterlen‐Liévre F (1978) The origin of lymphoid stem cells studied in chicken yolk sac‐embryo chimaeras. Nature 272: 353–354.

Liippo J, Mansikka A and Lassila O (1999) The evolutionarily conserved avian Aiolos gene encodes alternative isoforms. European Journal of Immunology 29: 2651–2657.

Lin W, Kurosawa K, Murayama A, Kagaya E and Ohta K (2010) B‐cell display‐based one‐step method to generate chimeric human IgG monoclonal antibodies. Nucleic Acids Research 39: e14. DOI: 10.1093/nar/gkq1122.

Mansikka A, Sandberg M, Lassila O and Toivanen P (1990) Rearrangement of immunoglobulin light chain genes in the chicken occurs prior to colonization of the embryonic bursa of Fabricius. Proceedings of the National Academy of Sciences of the United States of America 87: 9416–9420.

Magari M, Aya T, Ikeda M, et al. (2009) Enhancement of antibody production from a chicken B cell line DT40 by reducing Pax5 expression. Journal of Bioscience and Bioengineering 107: 206–209.

Muramatsu M, Kinoshita K, Fagarasan S, et al. (2000) Class switch recombination and hypermutation require activation‐induced cytidine deaminase (AID), a potential RNA editing enzyme. Cell 102: 553–563.

Narvi E, Nera KP, Terho P, et al. (2007) Aiolos controls gene conversion and cell death in DT40 cells. Scandinavian Journal of Immunology 65: 503–513.

Nera KP, Alinikula J, Terho P, et al. (2006a) Ikaros has a crucial role in regulation of B cell receptor signalling. European Journal of Immunology 36: 516–525.

Nera KP, Kohonen P, Narvi E, et al. (2006b) Loss of Pax5 promotes plasma cell differentiation. Immunity 24: 283–293.

Nera KP, Kyläniemi MK and Lassila O (2015) Regulation of B cell to plasma cell transition within the follicular B cell response. Scandinavian Journal of Immunology. DOI: 10.1111/sji.12336.

Ratcliffe MJH (2006) Antibodies, immunoglobulin genes and the bursa of Fabricius in chicken B cell development. Developmental and Comparative Immunology 30: 101–118.

Revy P, Muto T, Levy Y, et al. (2000) Activation‐induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the hyper‐IgM syndrome. Cell 102: 565–575.

Reynaud CA, Anquez V, Grimal H and Weill JC (1987) A hyperconversion mechanism generates the chicken light chain preimmune repertoire. Cell 48: 379–388.

Saribasak H, Saribasak NN, Ipek FM, et al. (2006) Uracil DNA glycosylase disruption blocks Ig gene conversion and induces transition mutations. Journal of Immunology 176: 365–371.

Sayegh CE, Drury GL and Ratcliffe MJH (1999) Efficient antibody diversication by gene conversion in vivo in the absence of selection for V(D)J‐encoded determinants. EMBO Journal 18: 6319–6328.

Schoetz U, Cervelli M, Wang YD, Fiedler P and Buerstedde JM (2006) E2A expression stimulates Ig hypermutation. Journal of Immunology 177: 395–400.

Wang JH, Nichogiannopoulou A, Wu L, et al. (1996) Selective defects in the development of the fetal and adult lymphoid system in mice with an Ikaros null mutation. Immunity 5: 537–549.

Further Reading

Arakawa H and Buerstedde JM (2004) Immunoglobulin gene conversion: insights from bursal B cells and the DT40 cell line. Developmental Dynamics 229: 458–464.

Brown WRA, Hubbard SJ, Tickle C and Wilson SA (2003) The chicken as a model for large‐scale analysis of vertebrate gene function. Nature Reviews. Genetics 4: 87–98.

Buerstedde JM and Takeda S (eds) (2006) Reviews and Protocols in DT40 Research. Subcellular Biochemistry, vol. 40. New York: Springer. ISBN: 9781402048951.

Gitlin AD and Nussenzweig MC (2015) Fifty years of B lymphocytes. Nature 517: 139–141.

McCormack WT, Tjoelker LW and Thompson CM (1991) Avian B‐cell development: generation of an immunoglobulin repertoire by gene conversion. Annual Review of Immunology 9: 219–241.

Molnar J, Poti A, Pipek O, et al. (2014) The genome of the chickenDT40 bursal lymphoma cell line. G3: Genes, Genomes, and Genetics 4: 2231–2240. DOI: 10.1534/g3.114.013482.

Weill JC and Reynaud CA (1987) The chicken B cell compartment. Science 238: 1094–1098.

Related Sub-Topics:

Antibodies | Tissues of the Immune System | Acquired (Adaptive) Immunity | Cell Differentiation and Stem Cells | Genes, Molecules and Cellular Processes | Developmental Models | Cells of the Immune System
Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: Bursa of Fabricius
 
How to Cite close
Nera, Kalle‐Pekka, Kyläniemi, Minna K, and Lassila, Olli(Nov 2015) Bursa of Fabricius. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000506.pub4]