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ARTICLE IN PRESSG ModelMLET-5585; No. of Pages 4
Immunology Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Immunology Letters
j ourna l ho me page: www.elsev ier .com/ locate / immlet
eview
ax D. Cooper and the delineation of two lymphoid lineages in thedaptive immune system
omenico Ribatti a,b,∗
Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, ItalyNational Cancer Institute “Giovanni Paolo II”, Bari, Italy
r t i c l e i n f o
rticle history:eceived 24 July 2014eceived in revised form 30 August 2014ccepted 4 September 2014vailable online xxx
a b s t r a c t
This article outlines the fundamental contribution of Max D. Cooper to the analysis of the role of thethymus and of the bursa of Fabricius in the development of immunologic competence both before andafter birth, placing a new scientific paradigm in the definition of the ontogeny of the lymphoid tissues.
© 2014 Elsevier B.V. All rights reserved.
eywords:ursa of Fabriciusistory of medicine
mmunologyymphocyteshymus
. Biographic notes
Max D. Cooper (Fig. 1) attended medical school at “Tulane Uni-ersity” and received doctoral degree in 1957. After a year spent athe University of San Francisco, Cooper worked to establish the dualature of the immune system with Robert A. Good as postdoctoral
ellow and Assistant Professor at the University of Minnesota from963 until 1967. He was the appointed Associate Professor at theniversity of Alabama at Birmingham (UAB) where he remained for
he next 41 years, as Professor of Immunology at the Departmentsf Pediatrics, Medicine, Microbiology and Pathology. In 1974, whilen sabbatical at the University College in London, he worked withartin Raff and John Owen to identify the bone marrow and fetal
iver precursors of B cells.He has received the Sandoz Prize in Immunology, American Col-
ege of Physicians Science Award, AAI Lifetime Achievement Award,very-Landsteiner Prize, and the Robert Koch Award.
Please cite this article in press as: Ribatti D. Max D. Cooper and the delinImmunol Lett (2014), http://dx.doi.org/10.1016/j.imlet.2014.09.005
∗ Correspondence to: Department of Basic Medical Sciences, Neurosciences andensory Organs, University of Bari Medical School, Policlinico – Piazza G. Cesare, 11,0124 Bari, Italy. Tel.: +39 080 5478326; fax: +39 080 5478310.
E-mail address: [email protected]
ttp://dx.doi.org/10.1016/j.imlet.2014.09.005165-2478/© 2014 Elsevier B.V. All rights reserved.
2. The role of the bursa of Fabricius and of the thymus inthe definition of two patterns of lymphocyte lineages
The bursa of Fabricius and the thymus are the central lymphoidorgans in the chicken essential for the ontogenetic developmentof the adaptive immunity. In the chicken embryo, the thymus isthe first lymphoid organ to develop. The epithelial component isevident before the ninth day of incubation, and the thymus is afully developed lymphoid organ by the twelfth day of incubation.Between the twelfth and the fourteenth day, budding of the epithe-lial fold of the bursa is observed, and on the fourteenth day thelymphoid structures begin to develop by direct transformation ofepithelial cells to lymphoid cells (Fig. 2).
The functional dissociation within/of the chicken immune sys-tem was firstly suggested by Szenberg and Warner in 1962 [1]. In1956, Bruce Glick and co-workers [2] demonstrated that the bursaplays an important role in antibody production, showing that anti-body responses are suppressed in the majority of bursectomizedchickens.
In 1958, Francis A.P. Miller [3] discovered the role of thymus-derived cells in cellular immunity. In 1960, Metcalf [4] studied theperipheral blood lymphocyte levels and histology of the lymphoidtissues in mice thymectomized between 4 and 6 weeks of age and
eation of two lymphoid lineages in the adaptive immune system.
demonstrated that there was a slow progressive fall in circulatinglymphocytes to a maximum of 30–40% below normal values.
Observations on the changes in the lymphoid organs after bur-sectomy and thymectomy in chickens have indicated the possible
ARTICLE ING ModelIMLET-5585; No. of Pages 4
2 D. Ribatti / Immunology Lette
esdloos
irradiation” [6]. He specified that: “I devised an alternative strat-
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Fig. 1. A port trait of Max D. Cooper.
xistence of two almost completely separate lymphocytopoieticystems (Fig. 3). The earliest scientific contribution of Max Cooperefined the basis of adaptive immunity. In 1964, as postdoctoral fel-
ow in the laboratory of Robert Good, he discovered the dual origin
Please cite this article in press as: Ribatti D. Max D. Cooper and the delinImmunol Lett (2014), http://dx.doi.org/10.1016/j.imlet.2014.09.005
f lymphoid cells in the chicken. Earlier removal of the thymus andf the bursa was needed to clarify their respective roles in immuneystem development.
Fig. 2. Time-course of the morphogenesis of ly
Fig. 3. An original model of Max D. Cooper concerning the deproduced from Ref. [17].
PRESSrs xxx (2014) xxx–xxx
As Robert A. Good has written: “Max Cooper, then an allergist-pediatrician, had just come to our laboratory to begin hisimmunology post doctorate fellowship training. He decided torevisit in laboratory studies the roles played by the thymus andbursa on lymphoid development in the chicken. Removal of thethymus from X-irradiated, newly hatched chickens, removal ofthe bursa of Fabricius from similarly sublethally irradiated newlyhatched chickens, or removal of both thymus and bursa fromsuch newly hatched chickens each produced very different results.Removal of the thymus so early in life prevented the developmentof lymphocytes in the blood and in the dense aggregates of lym-phocytes in the white pulp of chicken spleen, leaving the germinalcenter and plasma cell development impressively intact” [5].
On the other hand, in the mind of Cooper: “The plan was tocompare the immunological status of the different experimen-tal groups, after they recovered from the effects of surgery and
eation of two lymphoid lineages in the adaptive immune system.
egy that would combine posthatching thymectomy or bursectomytogether with whole body irradiation to destroy cells that mighthave seeded earlier from the thymus and bursa or that could have
mphoid follicles in the bursa of Fabricius.
ifferent development of thymus and bursal systems.
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een influenced by postulated thymic and bursal humoral factors.n these experiments I removed either the thymus or the bursa,hen subjected the newly hatched chicks to near lethal irradiationnd waited several weeks until they and their irradiated controlsecovered from the irradiated effects” [7].
Bursectomized and irradiated birds were characterized byhe absence of germinal centers, plasma cells and circulatingmmunogloblulins, or the ability to make antibodies in response tommunization. This evidence clearly shows that the bursa provides
unique microenvironment for the proliferation and differentia-ion of B cells [8].
On the other hand, thymectomized and irradiated animals wereeficient in lymphocytes that mediated inflammatory responses, asssessed by skin graft rejection, delayed-type hypersensitivity, andraft versus host reaction. Birds subjected to combined thymectomynd bursectomy and irradiation had severe cellular and humoralmmune defects [9,10].
As Good has précised: “The thymus, we had found, was relatedo the development of a population of small lymphocytes, whiche called thymus-dependent cells and were later named T cells by
van Roitt. They were located especially in blood, in splenic whiteulp aggregates, and in specific regions of the small lymph nodesnd gastrointestinal lymphoid aggregates in the chicken” [5].
Cooper has concluded that: “Our model of the development ofeparate lymphocyte lineages provide a reliable operational mapf these two differentiation pathways (. . .) This model radicallyhanges our perspective of lymphocyte differentiation defects inatients with primary or secondary immunodeficiency diseases”7].
. The immunoglobulin isotype switching
Cooper et al. [9], by means of immunofluorescence analysis withntisera specific for mu and gamma chains demonstrated that theursa is the first site where cells produce mu chains, and proba-ly IgM. The first surface IgM positive cells are detected from day2 of incubation and at hatching more than 90% of bursal cells areature B cells. Later, the bursa it is the first site where gamma
hains and probably IgG are produced. Injection of a specific anti-ody against the mu chain into the developing chick embryo athe moment of appearance of IgM-staining cells in the bursa pre-ents the development of both IgM- and IgG-producing cells inhicken. Moreover, when specific goat antiserum against mu chainsas tagged with fluorescin isothiocianate and specific antiserum
gainst gamma chains was tagged with rhodamine, it was clear thathe bursa was the first site to develop both IgM- and IgG-producingymphocytes. Bursectomy at 17–19 days of embryonic develop-
ent prevented development of a population of IgG-producinglasma cells. Chicken bursectomized and irradiated at hatching failo develop either IgM or IgG and cannot make antibodies. Such ani-
als develop into agammaglobulinemic animals lacking all cellsf the bursa-dependent lines, and they do not have lymphocyteshose receptor immunoglobulins can be identified. The infusion
f autologous bursal lymphocytes restored germinal center devel-pment, plasma cell generation and immunoglobulin productionn bursectomized and irradiated chicks [11].
. Mammalian “bursa-equivalent” organs and the role ofiver and bone marrow in lymphopoiesis
Please cite this article in press as: Ribatti D. Max D. Cooper and the delinImmunol Lett (2014), http://dx.doi.org/10.1016/j.imlet.2014.09.005
Cooper formulated the hypothesis that “gut-associated lym-hoepithelial tissues (GALT) serve as the mammalian bursaquivalent in supplying B cells to the rest of the body” [12]. “Theonsil were my first candidates for the bursa-equivalent, but their
PRESSrs xxx (2014) xxx–xxx 3
removal in newborn rabbits had no effect on antibody production”[6].
In 1964, Sutherland [13] and co-workers had shown that neona-tal appendectomy impaired antibody response in rabbits. In 1966,Cooper et al. [11] decided on the strategy of neonatal appendec-tomy followed by Peyer’s patch removal in combination with wholebody irradiation to destroy pre-existing lymphocytes. They foundthat these rabbits had immunological defects comparable to thoseobserved in older chickens subjected to bursectomy and irradiation,while the ability to reject skin allografts was maintained. Peyer’spatches may be special sites where antigen-driven proliferation canlead to great expansion of a B-cell population and to a switching ofcapacity to produce one kind of immunoglobulin, IgM or IgG, tocapacity to produce IgA immunoglobulin.
In 1974, in collaboration with John Owen in London, Cooperperformed experiments to verify that B cells were produced inhematopoietic tissues. They demonstrated that when mouse fetalliver was placed in culture before the appearance of B cells, B cellswere indeed generated [14]. In a further study, they demonstratedthat B cells were also generated ex vivo in mouse fetal long bones[15]. In subsequent experiments, Owen et al. [16] showed that largepre-B cells undergo proliferation before giving rise to small restingpre-B cells that, in turn, differentiate to become B cells.
Overall, these findings suggested that “mammalian B-cell gen-eration is a multifocal process that shifts from one hematopoieticenvironment to another during development, and B lymphopoiesiswas later shown to continue throughout life in the bone marrow”[7]. Now, it is well established that mature B cells originate pri-marily in the bone marrow in adult mammals, a process which isantigen independent, from hematopoietic stem cells.
5. Clinical correlates
The model of the development of separate lymphocyte lineagesproposed by Cooper “radically changed our perspective of lympho-cyte differentiation defects in patients with primary or secondaryimmunodeficiency diseases” [7].
As Good has emphasized: “Our experiments with irradiatedbursectomized chicken combined with our similarly extensivehistopathologic studies of patients with primary immunodefi-ciency diseases provided a clear perspective for understandingseveral of these immunodeficiency diseases and also the entirelymphoid system in both chickens and humans” [17].
Bursectomized chickens are similar to patients with Bruton’s X-linked agammaglobulinemia, while thymectomized chickens aresimilar to patients with Di George syndrome, while bursectomizedand thymectomized in the newly hatched period chickens are sim-ilar to patients with severe combined immunodeficiency disease(SCID) [18].
The absence of germinal centers, plasma cells, and antibod-ies in patients with Bruton’s-X-linked agammaglobulinemia, whohad a normal thymus and intact cell-mediated immunity, could beexplained by an arrest in differentiation of the immunoglobulin-producing lineage of lymphocytes.
As Good has pointed: “Immediately following Cooper’s presen-tation, Di George from St. Christopher’s Hospital in Philadelphiadescribed his observations on children born without thymus orparathyroid glands who often exhibited these defects together withcongenital cardiac defects and especially with abnormalities of theoutflow tracts of the heart” [17]. Patients with Di George syn-drome develop all immunoglobulins well and form antibody to
eation of two lymphoid lineages in the adaptive immune system.
many antigens very well, but fail to produce cellular immunity.They possess germinal centers and plasma cells, Peyer’s patchesand tonsils. Although this may have been the initial description ofpatients affected with Di George syndrome, it is well established by
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ow that these patients may also present variable humoral defectsanging from selective IgA deficiency to hypogammaglobulinemiaf all classes [19].
In 1971, Cooper et al. [20] showed that boys with X-linked agam-aglobulinemia have pre-B cells in their bone marrow, but very
ew B cells, findings indicative of an early arrest in B cell lineageifferentiation.
Parallel to immunodeficiency, “we began to analyze lymphoidalignancies in patients together with our hematology-oncology
olleagues” [6]. Lymphoid malignancies could be classified accord-ng to whether the neoplastic lymphoid differentiation began inhe thymus or the mammalian bursa equivalent. In 1978, Coopert al. [21], found that acute lymphocytic leukemia (ALL) of child-ood represent pre-B cell tumors. In ALL, blockade of lymphoid cellifferentiation leads to persistent proliferation, defective cell deathnd accumulation of leukemic lymphoblasts in tissues.
. Concluding remarks
The role of the thymus and of the bursa of Fabricius in the devel-pment of immunologic competence both before and after birth haslaced a new focus on the ontogeny of the lymphoid tissues. Spec-lation on the reason for immunological failure following neonatalursectomy and thymectomy has indicated the thymus as a sourcef cells or humoral factors essential to normal lymphoid develop-ent and immunologic maturation.Both clinical and experimental data are accumulated in support
f the thesis that absence of the bursa and/or thymus during theeriod of development of the peripheral lymphoid tissues results
n both abnormal lymphoid development and immunologic defi-iency.
Please cite this article in press as: Ribatti D. Max D. Cooper and the delinImmunol Lett (2014), http://dx.doi.org/10.1016/j.imlet.2014.09.005
eferences
[1] Szenberg A, Warner N. Dissociation of immunological responsiveness in fowlswith hormonally development of lymphoid tissues. Nature 1962;194:146.
[
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[2] Glick C, Chang T, Jaap R. The bursa of Fabricius and antibody production. PoultSci 1956;35:224–34.
[3] Miller JF. Immunological function of the thymus. Lancet 1961;2:748–9.[4] Metcalf D. The effect of thymectomy on the lymphoid tissues of the mouse. Br
J Haematol 1960;6:324–33.[5] Good RA. Organization and development of the immune system. Relation to its
reconstruction. Ann N Y Acad Sci 1995;770:8–33.[6] Cooper MD. A life of adventure in immunobiology. Annu Rev Immunol
2010;28:1–19.[7] Cooper MD. Exploring lymphocyte differentiation pathways. Immunol Rev
2002;185:175–85.[8] Ratcliffe MJH. Antibodies, immunoglobulin genes and the bursa of Fabricius in
chicken B cell development. Dev Comp Immunol 2006;30:101–18.[9] Cooper MD, Peterson RD, Good RA. Delineation of the thymic and bursal lym-
phoid systems in the chicken. Nature 1965;205:143–6.10] Cooper MD, Raymond DA, Peterson RD, South MA, Good RA. The functions
of the thymus system and the bursa system in the chicken. J Exp Med1966;123:75–102.
11] Cooper MD, Schwartz ML, Good RA. Restoration of gamma globulin productionin agammaglobulinemic chickens. Science 1966;151:471–3.
12] Cooper MD, Perey DY, McKneally MF, Gabrielsen AE, Sutherland DE, GoodRA. A mammalian equivalent of the avian bursa of Fabricius. Lancet 1966;1:1388–91.
13] Sutherland DE, Archer OK, Good RA. Role of the appendix in development ofimmunologic capacity. Proc Soc Exp Biol Med 1964;115:673–6.
14] Owen JJ, Cooper MD, Raff MC. In vitro generation of B lymphocytes in mousefoetal liver, a mammalian ‘bursa equivalent’. Nature 1974;249:361–3.
15] Owen JJ, Raff MC, Cooper MD. Studies on the generation of B lymphocytes inthe mouse embryo. Eur J Immunol 1976;5:468–73.
16] Owen JJ, Wright DE, Habu S, Raff MC, Cooper MD. Studies on the genera-tion of B lymphocytes in fetal liver and bone marrow. J Immunol 1977;118:2067–72.
17] Cooper M, Gabrielsen A, Good R. Central peripheral lymphoid tissues inimmunologic processes and human disease. In: Mayerson H, editor. Lymphand the lymphatic system. Springfield: Charles C. Thomas; 1968. p. 276–305.
18] Peterson RD, Cooper MD, Good RA. The pathogenesis of immunologic deficiencydiseases. Am J Med 1965;38:579–604.
19] Patel K, Akhter J, Kobrynski L, Benjamin Gathmann MA, Davis O, Sullivan KE.Immunoglobulin deficiencies: the B-lymphocyte side of Di George syndrome.J Pediatr 2012;161:950–3.
20] Cooper MD, Lawton AR, Bockman DE. Agammaglobulinaemia with B lym-
eation of two lymphoid lineages in the adaptive immune system.
phocytes. Specific defect of plasma-cell differentiation. Lancet 1971;2:791–4.
21] Vogler LB, Crist WM, Bockman DE, Pearl ER, Lawton AR, Cooper MD. Pre-B-cellleukemia. A new phenotype of childhood lymphoblastic leukemia. N Engl J Med1978;298:872–8.
