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The Gamma System, Pathology and Therapeutics Postgrad. med. J. (February 1969) 45, 116-128. Postgrad Med J: first published as 10.1136/pgmj.45.520.116 on 1 February 1969. Downloaded from The gamma system, pathology and therapeutics RICARDO HORACIO DE LELLIS M.D. Docente auturizado de Pediatriz de la facultad de Medicinz de Buenos Aires, Medico de los Hospitale del Hospital de Pediatria Pedro de Elizalde, Buenos Aires Hypothesis for the integration of childhood immunity Ford & Micklem, 1963; Harris & Ford, 1964). Thus Advances in the immunobiology of the thymus, bone-marrow cells may replace the thymus after immunological competence and immune response radiation induced atrophy of the thymus. These cells have made it necessary to attempt a provisional may acquire 'distinguishing' properties in the scheme to describe the interplay of 'germ and soil'. thymus (Metcalfe, 1964; Auerbach, 1966) and lose Good & Papermaster (1964) have emphasized the the property of repopulating the bone marrow significance of adaptive immunity which is charac- (Dustin & Gregorie, 1931; Ford, 1966). terized by an immunological memory, the second phase of the homograft reaction and the secondary immunological response. Recently the thymus has Lymphopoiesis in the thymus been ascribed a fundamental place in the phylo- In the initial stages of ontogenesis, thymic genetic and ontogenetic development ofthe lymphoid lymphopoiesis appears to be autonomous. InProtected by copyright. system of the higher vertebrates. The inheritance of succeeding stages it may derive from circulating genetic information for the development of this precursors which settle in the thymus and differen- potential is transmitted through the lymphoid tiate (Trinin & Law, 1963; Sainte Marie & Leblond, system of mammals (Fig. 1). The thymus may be 1964); Ford, 1966. Fragments of thymus in tissue involved in the differentiation and maintenance of culture becomes differentiated by the seventh day. the potential for antibody synthesis, but the mainten- The spleen and bone-marrow do not form lymphoid ance of the synthesis of antibodies takes place in tissue, whereas the thymus forms lymphoid tissue mature, immunocompetent cells (Talmage & independently (Auerbach, 1966). Thymic lympho- Claman, 1964). cytes are of entodermal origin in contrast to peri- Both lymphopoiesis and immunogenesis have pheral lymphocytes which are of mesenchymal different aspects depending upon whether they are origin (Sainte Marie & Leblond, 1964). considered in the context of the thymus or the The thymus differs from the remainder of the peripheral lymphoid system. It can be assumed that lymphoid system in the following respects: (1) the there exists a central (thymic) and peripheral mitotic index is ten times greater in the thymus http://pmj.bmj.com/ lymphopoiesis in the same way that there is thymic than in peripheral lymphoid organs; (2) it becomes and peripheral immunogenesis. The first is charac- involuted with age; (3) the mitotic indices are un- terized, at any rate in the early periods of life, by affected by antigenic stimulation; (4) the weight is increased proliferation of lymphoid cells, the extent uninfluenced by peripheral lymphoid tissue; (5) of which appears to be genetically determined and implants of thymic tissue grow in the same way in to decline with age (Metcalf, 1956). Peripheral thymectomized subjects as in controls; and (6) its would thus be and is not reduced lymphopoiesis thymus-dependent proliferative activity by extraneous on September 29, 2021 by guest. increasingly antigen-dependent with the progress of antigens, and is comparable in intensity to that of maturation. many tumour cells. Central immunogenesis would be characterized by The proliferative stimulus would not operate the production of competent (uncommitted or 'x') diffusely since the thymus is constituted by indepen- cells (Ford, Gowans & McCullagh, 1966; Sterzl, dent subunits, each with its own source of prolifera- 1966) or by the differentiation of lymphocytes, tive stimulation. It may originate in the epithelial which, once they had reached a certain degree of cells of the medulla or indirectly via the reticular differentiation, would be liberated into the blood- cells of the cortex, possibly mediated by a humoral stream (Miller, 1961). Secondly the provision of a factor (Metcalf, 1966). milieu of immunological tolerance for lymphoid cells Clark (1966) confirmed the existence of secretory would allow the differentiation of immunologically material in the epithelial cells of mouse thymus competent cells (Miller, Marshall & White, 1962; medulla, and defined three stages of maturation in The gamma system, pathology and therapeutics 117 Postgrad Med J: first published as 10.1136/pgmj.45.520.116 on 1 February 1969. Downloaded from Differentotion ond mointenance / \ of the potential I Central lymphopoiesis c / T 0 CP / h 4 of the immunologicolly / Epithliol J competent cell call m Entoerm T o I e ra nc e Blood-thymus barrier 111111111111111111111111111111111111111111111 1llllllllllllplnllllllllllll 111l 11111111111111 I n t I e ra n c e Small Iymphocy e FLS Change to periphery L Division and expression Y of the potential S M M , Peripheral lymphopoiesis Protected by copyright. Immunologicol competence H _______________L P T r N Immune response e r 0 e v y n D Macrophoge-Smoll lymphocyta e e s S ---------- Immunoblost P1Tmo cell -.-Lymphocytes - r r I rr I - --- - _____-I Secondary | Hypooctive< \ Form I e s Subclinicol response Normolly active E< y-Globul ii Form2 http://pmj.bmj.com/ Hyperactive < ^ Form3 ^*'N^_ ____,____|_ Srcondary|/ hyperactivity FIG. 1. Hypothesis for immunological integration in children. Inherited genetic information. on September 29, 2021 by guest. relation to secretory content of a mucopolu- epithelial cell, large, medium and small lymphocytes saccharide acid sulphate: (1) densely basophilic (Dustin & Gregoire, 1931). The last of these are the granules before birth, (2) clusters of vacuoles after most differentiated (thymocytes) and are the product birth, and (3) PAS-sensitive amorphous inclusion of successive reduction mitoses (Sainte Marie & material 15 days after birth. Leblond, 1964). In summary, thymic lymphoiesis would appear to be autonomous in the initial stages of ontogenesis, Fate of the thymocytes it is stimulated by the epithelial cells of the medulla The thymus produces in its cortex more lympho- acting as subunits of stimulation and developing cytes than it needs for local development. The high according to an irreversible sequence: entoderm, mitotic activity in relation to the stability of the 118 Ricardo Horacio de Lellis Postgrad Med J: first published as 10.1136/pgmj.45.520.116 on 1 February 1969. Downloaded from organ raises two possibilities, that either the small Claman & Talmage, 1963; Nossal & Mitchell, 1966). lymphocyte degenerates and is destroyed in the A series of experimental investigations have thymus or that it migrates. The first alternative is demonstrated that thymic lymphoid cells can pro- most likely since the ratio of the number of mitotic duce antibodies (Miller et al., 1962), can become cells to the number of pyknotic cells is related to the immunologically competent and can re-establish the weight of the organ and falls with involution. The immunological activity of thymectomized animals second alternative is suggested by the effects of (Yunis et al., 1964). The thymocytes of mice and rats thymectomy and of thymic extract on peripheral immunized with tetanus toxin are capable ofactivat- lymphopoiesis. A direct or humoral stimulus might ing an immune response when transferred to regulate the production and maturation of the isologous, irradiated recipients (Stoner & Bond, peripheral lymphoid system. 1963). Thymic tissue transplanted to the anterior Some authors believe that the thymocyte never chamber of the eye of an irradiated mouse, produces leaves the thymus, but that nucleoproteins accumu- a specific antibody response, and isolated thymic lated in pyknotic cells are discharged and utilised in cells are also capable of producing a reaction rapid cell division elsewhere (Ford, 1966). The between graft and host in newly born mice (Miller, thymus would thus be a reservoir for DNA which 1964). could be utilized at any time (Bryant, 1962). Despite this the potential immune response of the Transplantation of thymocytes and lymphocytes lymphoid thymic cells in the intact animal is im- labelled with 32p gives rise in the liver to both paired by the existence of a blood-thymus barrier so homologous and heterologous thymocytes (Fich- that the antigen cannot be fixed by the thymus. In telius & Bryant, 1964). Labelled chromosome contrast to other lymphoid tissue in the normal studies have demonstrated that lymphoid cells join animal neither secondary follicles nor plasma cells the peripheral lymphatic system after a period of are developed (Miller et al., 1962). residence in the thymus (Ford & Micklem, 1963). The blood-thymus barrier has, however, anProtected by copyright. The difficulty in establishing the migration of the evolving character and is not complete for all thymocyte beyond doubt resides in the difficulty of antigens. In adult rats there is a partial barrier but labelling thymic cells without simultaneously label- in the newborn it is ineffective for both soluble anti- ling lymphoid cells. Nossal injected thymidine gens (bovine serum albumin) and specific (S. directly into the thymus of the guinea-pig with adelaide) antigens. It can be shown that the barrier minimal involvement of the other organs
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