Lymphoid Malignancy and Development, Differentiation, andFunction of the Lymphoreticular System1
MAX D. COOPER,2 RAYMOND D. A. PETERSON,3 ANN E. GABRIELSEN,* AND ROBERT A. GOOD5
Department of Pediatrics, University of Minnesota School of Medicine, Minneapolis, Minnesota
Summary
There are 2 pathways of normal lymphoid differentiation. Thethymus is responsible for initiation and control of cellular differentiation directed toward the small lymphocyte and cellularimmunity. The avian bursa of Fabricius, and perhaps Peyer's
patches of man, initiates and controls another lymphoid differentiation pathway directed toward the plasma cell and immuno-globulin production. Thymus-dependent and bursa-dependentlymphocytic malignancies have been defined in the mouse andchicken, respectively, and are featured by abnormal Lymphoiddifferentiation beginning in one or the other central lymphoidorgan. It is proposed that clinical lymphoid malignancies mayalso be usefully classified as either thymus system or immuno-globulin-producing system malignancies. In this view Hodgkin's
disease appears to be a thymus system disease, and more focusedstudy of its central organ seems indicated.
Introduction
In a discussion of the immunologie defects in patients withHodgkin's disease and other lymphoreticular malignancies, it
seems appropriate to attempt to relate them to some of the current thinking on the normal development, differentiation, andfunction of the lymphoreticular system.
Clinical and experimental observations have long suggesteda dissociation of the immune system, a split phrased most conventionally as cellular versus humoral immunity. Immunologiedeficiencies were classified in this way, sex-linked recessiveagammaglobulinemia constituting a virtually complete failureof the humoral type with relatively intact cellular immunity;and Hodgkin's disease, in many patients, coming close to aclinical loss of cellular immunity with relatively intact immuno-globulin production (2, 27).
Warner and Szenberg (65, 67, 68), on the basis of immunologie study of chickens treated with testosterone during incubation, proposed dissociation of the lymphoid system and of immunologie function based on thymic versus bursal influence.Least consistent with the conventional functional division of
1Aided by grants from the USPHS (HE-02085, AI-00798, NB-02042), the American Cancer Society, the American Heart Association, and the National Foundation.
2Postdoctoral Research Fellow, USPHS.3Established Investigator, American Heart Association.«Research Fellow, USPHS. Grant 9T1-AI292.6American Legion Memorial Heart Research Professor of Pedi
atrics and Microbiology.
immunity was the classification of delayed hypersensitivitywith antibody responses as bursa-dependent, and its separationfrom homograft immunity classified as thymus-dependent, andcertain graft versus host capabilities viewed as not clearly dependent on either thymus or bursa. Although the concept ofdissociation has been amply confirmed (5, 13-16, 33-35), it nowseems clear that the functional division in the chicken is moreconsistent with clinical evidence and with the immunologie defects produced in rodents by neonatal thymectomy (26, 37, 46).It has also been possible to identify the components of the twosystems morphologically.
Thymus-Dependent System
Thus, we have recently proposed that the lymphoid system ofboth mammals and birds has two major components or cellsystems (13-16, 56). In this view, the tkymus-dependent system
is composed of the thymus as the central or source organ, and oflymphoid cells in the periphery largely classified as small lymphocytes. Observations on the development of the lymphoid systemsin many species have long suggested that this cell system beginsits differentiation in the thymus (10, 31), a thesis most convincingly supported by the studies of Auerbach (6, 8) in which theearly lymphoid differentiation of epithelial thymus explants wasshown to dejjend on an as yet undefined mesenchymal inductiveinfluence. Evidence of both a direct and indirect nature indicatesthat thymic lymphoid cells may populate the ]>eripheral lymphoid tissues by a seeding process (7,50, 53,62), and that a humoralthymus factor is apparently necessary for at least functionalcompletion of thymus system differentiation (42, 54).
The functional role of the thymus system of cells has beenapproached from 2 main directions. One has involved the definition of immunologie defects in animals with gross deficiency ofthe thymus system following thymectomy early in life or thymusremoval coupled with various means of peripheral small lymphocyte depletion, e.g. X-irradiation or anti-lymphocyte serumadministration (25, 26, 37, 38, 46, 47, 49). The 2nd approach hasinvolved assessment of immunologie function in patients (23, 27)and experimental animals (13-16) with an intact thymus systembut an extreme deficiency of the immunoglobulin-producingsystem. Such studies have indicated that the thymus system ofcells is the effector of graft versus host reactivity and delayedhypersensitivity, plays a major role in homograft rejection, andprobbly provides the recognition-s|>ecificity component of antibody responses. Immunologie memory may also be a functionof this cell system.
The bursa of Fabricius of chickens appears to be the centralor source organ for the immunoglobulin-production system, represented in peripheral lymphoid tissue by the lymphoid cells of thegerminal centers, hemocytoblasts, and plasma cells. Chickensirradiated and bursectomized in the newly hatched period areentirely lacking this system of cells, are agammaglobulinemic,and are incapable of specific antibody production. This experimental model is a striking parallel to the Bruton type of agamma-globulinemia (11, 15, 16).
Ackerman and Knouff's developmental studies of the bursa
suggest that gut epithelial cells differentiate into bursal lymphoidcells (1), and our own work suggests a continuum of differentiation of these cells to mature plasma cells (Refs. 16, 17 andClawson, Cooper, and Good, unpublished observations). Abursal humoral factor is apparently required for functionalmaturation of this cell system (24, 36, 64).
This system of cells has not yet been experimentally manipulated in mammals, and a mammalian equivalent of the bursa hasnot been demonstrated. However, the immunoglobulin-producingsystem seems to be relatively intact in neonatally thymectomizedrodents (4,19, 32) and in patients with certain extreme congenitallymphopenias associated with failure of thymus development(3, 52). Thus, it appears that in mammals as well as in birds,germinal center cells and plasma cells represent a separate pathway of differentiation beginning in a site other than the thymus.
Reticuloendothelial System
The reticuloendothelial system, necessary for the clearing andprocessing of foreign substances (20-22), shows no definable
morphologic or functional deficiency following manipulation ofeither the thymus or immunoglobulin-production system (16).This is not to say that this system is normal under these circumstances, since there is some evidence of enhanced reactivity andhypercellularity when the thymus-dependent development isdeficient (46, 60). This evidence does indicate that the reticuloendothelial system is separate from the 2 lymphoid cell systems.
Thymus System Malignancies
As Aisenberg (2) has pointed out, there is no experimentalmodel of Hodgkin's disease. It is apparent, however, that the
lymphocyte depletion, defective delayed hypersensitivity, abnormal homograft rejection pattern, poor response to phyto-hemagglutinin stimulation, and mild abnormality in antibody-producing capacity manifested in many patients with Hodgkin's
disease all point to a defect of the thymus system.There are several parallels between Hodgkin's disease and
mouse lymphocytic malignancies. The lymphocytic malignanciesof mice, whether spontaneous or induced by X-ray, chemicalagents, or viruses, appear to involve primarily the thymus-dependent system (Peterson et al.6). In each of these models,thymectomy during the pre-lymphoma period reduces the in-
«R. D. A. Peterson, Cooper, M. D., Gabrielsen, A. E., and R.A. Good. The Pathogenesis of Lymphoid Malignancies. Submittedfor publication.
cidence of subsequent lymphoma (28, 39, 41, 43-45). Thesemalignancies often begin in the thymus or they appear to arisein the thymus-dependent small lymphocyte population inperipheral tissues. During the incubation period of the leukemiainduced by Gross' passage A virus, C3H mice show immunologie
defects similar to those defined in neonatally thymectomizedmice, although these defects appear less exaggerated in the pre-lymphoma mice (18, 59).
The role of the thymus in the development of lymphocyticmalignancies appears to relate closely to current concepts of itsrole in the normal differentiation and development of the thymussystem of cells and cellular immunity. Kaplan (40) first focusedattention to the relationship between the presence of abundantundifferentiated cells in the thymus and the susceptibility tolymphomagenesis. It appears from these and other investigations (9, 51) that thymus cells in a critical early phase of differentiation are necessary for susceptibility to some lymphomagenicviruses. It has been proposed on the basis of these observationsthat lymphomagenic viruses alter thymic cells in such a waythat differentiation might be slowed or that these cells are deviated from their normal differentiation pathway, thus gaininginheritable independence from normal environmental growthcontrols (9).
There is clinical support for the thesis that lymphocytic malignancies primarily involve only 1 of the lymphoid tissue components as we have defined them: at least 3 boys with sex-linkedrecessive agammaglobulinemia have developed a malignancy,apparently of the thymus system, in 1 instance presenting initially as a huge thymoma (55, 61). This patient group has infinitesimal amounts of 7-globulin, usually below 10 mg/100 ml,and in our present view represents the clinical counterpart ofbursectomized-irradiated chickens. They appear to be entirelylacking in germinal centers and plasma cells, and we believethat they represent virtually complete failure of developmentof the immunoglobulin-production system as we have definedit experimentally (23, 27, 58). It is provocative that these lymphocytic malignancies not only develop in these patients but thatthey develop in what appears to be increased frequency.
converted to large mononuclear cells with a vesicular nucleusand prominent nucleolus, progressing to the "owl's-eye" appearance of the "mirror-image" type of double nucleated giant
cell, then to giant cells with many nuclei, and finally to fullyformed Hassall's corpuscles. He stated that with an admixture of
these cells, lymphocytes, and polymorphonuclear leukocytesencased in a fibrous stroma, the histologie picture of Hodgkin's
disease is produced. It is of considerable interest that of 5 Hodgkin's patients thymectomized on the basis of Thomson's concept,
1 subsequently developed myeloid leukemia (56). This is highlyreminiscent of the experience with thymectomy in mice previously inoculated with Gross' passage A virus (29).
It may be useful at this point to contrast the avian leukosismodel, visceral lymphomatosis, with the "thymus system malignancies" of mice and men. This virus-induced lymphoid ma
lignancy of chickens appears to represent primary involvementof the immunoglobulin-producing system. Young chickens aremost susceptible to the oncogenic influence of the RPL12 virus(12), and bursectomy early in life prevents progress of the diseasewhich normally kills the birds (57, 60). Serial histologie study ofchickens infected at birth with RPL-12 virus reveals malignanttransformation of bursal follicles well before evidence of malignancy in other tissues. At this early stage 1 malignant bursalfollicle may be surrounded by over 500 morphologically normalbursal follicles. Later malignant cells may be seen in germinalcenter distribution in the spleen and other organs. In contrast tonormal bursa-derived germinal center cells, the malignant cellsfail to show organization of cytoplasmic ribosomes and formationof endoplasmic reticulum. These malignant cells also contain no•y-globulin.These observations (Cooper et al., unpublished ob
servations) indicate that visceral lymphomatosis begins in thebursa of Fabricius and is featured by abnormal differentiation ofbursal lymphoid cells. Interesting also in this light is the fact thatthe thymus is almost never involved (28).
The lymph nodes of patients with giant follicular lympho-blastoma exhibit remarkable morphologic similarities to thespleens of chickens with visceral lymphomatosis. Some patientswith this malignancy become agammaglobulinemic (58). Hemo-cytoblast accumulation but no plasma cells are seen in suchpatients.
Discussion
On the basis of these views we have postulated that it may beuseful to attempt classification of experimental and humanlymphocytic malignancies by site of initial involvement, eitherthe thymus-dependent system or the immunoglobulin productionsystem (14, and Peterson et al.6).
Among the elements we must encompass in any over-all hypothesis are a degree of specificity of the virus oncogenic effecton a given cell line and what appears to be the controlling influence of the thymus or bursa on development of the lymphomain its early stages. Oncogenic virus particles find geneticallyspecific receptor sites on certain cells, and penetrance occurs.Some selectivity on the basis of cell type could also occur at thislevel. This event need not immediately arrest cell differentiation,migration, and multiplication. When, however, sufficient numbers of oncogenic virus particles attack sufficient numbers of acell type in a critical early phase of differentiation—a phase
characteristic of central or source lymphoid tissues such as thethymus and bursa representing the sites of the initial lymphoiddifferentiation—cellular biosynthetic mechanisms are predominantly occupied with virus production or otherwise altered, eventually producing, in effect, a differentiation arrest.Even though protein synthesis may continue, in the case of atleast some of the "immunoglobulin production system malignancies," specific synthesis of 7-globulin and its functional cor
relate, circulating antibody, is deficient. It would appear thatin the "thymus system malignancies" the production of "cellularantibody" may also be deficient.
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