Indian Ji Pediat. 36 : 252, 1969

REVIEW ARTICLE

THE TH'YMUS--A BRIEF REVIEW*

SUSHMA SINGH AND O. P. GHAI

New Delhi

The last decade has been the golden age of immunology. Its highlights were the recognition of the functions of lymphocytes and the role of the thymus in immunogenesis.

The thymus is a bilobed organ which develops as an outgrowth of the epithelium of the 3~d and 4th bran- chial clefts in the 2nd month of intrauterine life (Bevelander 1965). Shortly afterwards lymphoid cells infiltrate the epithelial gcound work. It is now believed that these lymphoid cells are extrinsically derived and flourish in the inductive environment furnished by the interaction between the epithelial component and the surrounding mesenchyme (.Moore and Owen 1967). The thymus consists of a loosely cellular medulla containing epithelial cells, scattered lymphocytes, Hassall's corpuscles (concentric whorls of epithelial cells containing a hyaline substance in the centre), occasional cystic structures ? (degenerated Hassall's corpuscles). Surrounding it is the densely packed cortex in which lymphoid cells outnumber epithelial cells and there are no Hassall's corpuscles (Bevelander 1965). The lymphoid tissue of the thymus differs from the lymphoid tissue elsewhere in

*From the Department of Pediatrics. All ~[ndia Institute of Medical Sciences, New Delhi-16.

its response to antigenic stimuli. There are no morphological features of immune response such as germinal centres or plasma cells (Miller and Osoba 1967). Electron microscopy of the medullary epithelial cells has revealed that they possess the nucleus and the cytoplasmic structure of the eells'that secrete mucoid or protein- aceous material (Sam 1966).

The size and weight of the gland varies with age and general health. It enlarges from 10 G. at birth to 20-30 G. during adolescence (.Mackay and Goldstein 1966). Thereafter it undergoes involution due to increasing loss of the cortex and infllteration with fat. The involution is enhanced by stress, starvation, debilitating illnesses, pregnancy, lactation, steroid therapy and radiotherapy. However, even in elderly patients some func- tional tissue does remain (Mackay and Goldstein 1966). It has been shown experimentally that the fetal pituitary-adrenal axis exercises an inhibitory control on th~ developmmt of the thymus ; a good example is the small adrenals and large thymus in anencephalic monsters (Beam 1967).

Role of the thymus in immunogenesis

Phylogenetic studies have shown that the immune response has its

SINGH AND GHAI--THE THYMUS--A BRIEF REVIEW 253

origin in the lymphoid tissue which is intimately associated with the gut epithelium. The lymphoid tissue connected with the gut and located in the tonsils, the thymus, Peyers' patches and the appendix is called central, as opposed to that in the spleen and the lymphnodes, termed as peripheral (Good et al. 1966). Two types of peripheral lymphoid tissues are described in higher vertebrates. (1) A collar of lymphocytes around the germinal centres, influenced by the thymus and concelned with mediation of cellular immunity, and (2) plasma cells and large pyrininophilic cells responsible for the production of immunoglobulins. Its central ~oun- terpart is not known in man ; th~ ton- sils and or appendix are probable sus- pects (Good et al. 1966).

Immunocompetence There is a lot of controversy about

the origin and the fate of the lympho- cytes of the thymus. Dukor et al. (1966) and Ford et al. (1963) believe that these cells are stem ceils probably originating from the bone-marrow. The thymus traps these lymphoid precursors from the circulation and induces intense mitosis and unique differentiation resulting in self-per- petuating immunocompetent Iympho- cytes. Whether the stem cells are pluripotential prior to their entry in the thymus where one particular gene or genes are activated is uncertain. (Good et al. 1966). These immune- competent ceils then leave the thymus and seed out in the lymphnodes and the spleen (Burnet 1962). Their inherent instinct to seed out is des- troyed by trypsin treatment (Woodruff 1968). Ninety-five I~er cent of th'. lymphocytes produced as a result of

3

intense lymphopoiesis in the thymus disintegrate in the thymus, the cause of which is not known (Miller and Osoba 1967).

The thymus is also responsible for the normal development of the peri- pheral lymphoid tissue during the earlier years. There is evidence that the thymus gland secretes a certain substance or substances vital for the proper development of lymphoid tissue. A low-molecular-weight pro- tein 'thymosin' has been isolated which causes remarkable effect in thymectomised animals. It has been experimentally proved that most of the functions of the thymus are mediated by inducers which can pass through cell-tight filters (Gold- stein et al. 1966).

The blood-thymus barrier is a parti- al one and is much less developed in the fetus and the newborn. Under certain abnormal situations, such as, a large dose of an antigen or the conti- nued presence of an antigen in the cortex, the barrier may be broken. The antigen, if it is capable of react- ing with the surface antibody of the cell, may fix the compliment and cause lysis of the immunocompetent cells. Presistence of the tolerance depends upon the dose of antigen. When the dose exceeds the mean level of one molecule per cell, the clone capable of reacting with the antigen is destroyed and the animal is render- ed immunotolerant (Nossal and Mit- chell 1966).

Effect of Thymectomy

Thymectomy in neonatal mice causes deficiency of the small lympho- cytes in the paracorticalpart of the lymphnodes, spleen and the circula-

254 INDIAN JOURNAL OF PEDIATRICS VOL. 36 NO. 258

ting pool of lymphocytes. The cir- culating lymphocytes are also rendered deficient in antigen responsiveness ( Miller et al. 1967 ). They cannot re- ject an allograft or manifest delayed hypersensitivity, ultimately may be- come ill, waste away and die ( Howeii and Heyler 1966 ). Thymectomised mice are more susceptible to carcino- genesis possibly because of their inability to eliminate oncogenic anti- gens normally dealt wi~h by the thymus. Minor benefits of thymectomy are, that it prevents lymphatic leukae- mia in the leukaemia-prone mice and also reduces the severity of autoaller- gic encephalomyelitis in chicken. However, there is no suggestion that thymectomy is beneficial in human leukaemia or immune encephalitides ( Mackay and Goldstein 1966 ).

The Thymus and Immunopathology

Congenital abnormalities I. Congenital aplasia of the thymus.

(Di-George's syndrome). Aplasia of both the thymus and parathyroid glands, both originating from the III and IV branchial pouches, is charac- terised by neonatal tetany, small jaw, lowset malformed ears, hypertelorism

and abnormalities of the great vessels. Humeral immunity is intact. Delayed hypersensitivity cannot be induced in them. Immunological deficiencies re- se ruble those of thymectomised animals (Feingold and Parris 1968). II. Hereditary t'hyrrats dysplasias.

Four types of thymic dysplasias are described :

1. ReticUlar dysgenesis. It is cha- racterised by Iymphopenia, aleuko- cytosis and rudimentary thymus. The reticular analage of lymphocytes or other leukocytes fail to develop in these patients. Its inheritance is autosomal recessive (Nossal and Mitchell 1966).

2. Lymphopenic agammaglobulinae- mia (Swiss type). It is an autosomal recessive disorder characterised by a complete absence of immunological capacity. Both humeral and cellular immunity is impaired. The thymus is small and rudimentary with no Hassall's corpuscles and few lymphocytes (Feingold and Parris 1968).

3. Sex-linked lymphopenic agamma- globulinaemia. It is similar to the above mentioned Swiss type except for its inheritance and near normal humeral immunity. The thymus is poorly developed and mainly epithelial (Fein- gold and Parris 1968).

Table 1. The effects of thymectomy in the neonatal period in mice

Neonatal tbymectomy

Lymphopenia

Loss of thymic hormone

Immunological Circulating antibody. deficiency. Delayed hypersensitivity.

Graft rejection.

Runtiug (except if germ-free). Increased susceptibility to carcinoma. Decreased susceptibility to lymphoid leukaemia. Decreased severity--Autoallergic encephalitis. Retards onset of autoimmune disease in mice.

Adopted from Mackay and Goldstein (1966).

SiNGH AND GHAI--THE THYMUS~A BRIEF REVIEW 255

4. Ataxia telengiectasia. It is cha- racterised by oculocutaneous telen- giectasis, progressive cerebeUar ataxia, deficiency of IgA, impaired delayed hypersensitivity and iaomograft rejec- tion. The thymus is small with sparse lymphocytes and no Hassall's corpus- cles. The postulation is that some abnormality lies in the mesenchymal tissue resulting in generalised vascular abnormality and defective epithelial- mesenchymal interaction in the thymus (Petersen et al. 1965). III. Autoimmune diseases

Normal thymic ceils recognise self antigens and prevent development of forbidden clones. Due to some in- fluence (viral or humoral), the thymic epithelial cells may undergo dysfunction and induce development of clones which produce autoantibodies.

(a) Myasthenia gravis. Patients with myasthenia gravis can be divided into two groups,those with thymoma and others without thymoma. Thymoma occurs in 10-30 ~ of cases. It consists of large pale epithelial, ceils which have distinct antigenic properties, similar to the myoid antigen of muscle A bands. The thymus initiates an autoimmune response to this antigen. The resultant antibodies react with the muscle and the thymus. As a result, an auto- immune type of inflammation similar to Hashimoto's thyroiditis is set up in the thymus. It is characterised by lymphopoie.sis, plasma cell infiltration and germinal centers mostly around the thymoma. The autoimmune reac- tion causes release of a humoral sub- stance which produces the characteristic neuromuscular block. Patients with myasthenia gravis without thymoma have a higher incidence of other auto- immune diseases and high titre of aut0hntibodies including those to nuclei

and thyroglobulin. In these patients a genetically altered immune mechan- ism forms the basis of pathogenesis (Goldstein 1966).

Neonatal myasthenia gravis in infants born to myasthenic mothers is due to the placental transmission of the neuromuscular-blocking substance which can be removed by dialysis. It is not an antibody as it is also seen in infants whose mothers have no auto- antibodies. Thymectomy in myas- thenia gravis is useful especially in female patients with no thymoma. Results are better with the shortest duration of symptoms at the time of operation irrespective of the severity of the disease. Thymectomy, however, is not beneficial in all cases. This could be due to permanent changes in the motor-end plate or muscle fibres as a result of long-standing disease or due to the presence of ectopic thymic tissue which continues to produce the block- ing substance (Golds�88 1966).

(b) Systemic lupus erythematos~ts. The thymus is relatively small and is characterised by the absence of the cortex, epithelial dysplasia or a spindle cell thymoma, scanty epithelial and numerous cystic HassaU's corpuscles. There are typical germinal centres and numerous plasma cells specially in patients who have not received steroids (Mackay and Goldstein 1966).

(c) Bone marrow aplasia with thy- morea. At least 50 cases of this syn- drome have been reported in the literature. The thymoma is spindle- cell in type, undefined, lymphoepithelial or lymphoid. It may be associated with myasthenia gravis and hypo- gammaglobulinaemia (Mackay and Goldstein 1966).

(d) Primary acquired agammaglo- bulinaemia. Ten per cent of cases of

256 INDIAN JOURNAL OF PEDIATRICS VOL. 36 No. 258

this disease have spindle cell thymoma. Several patients have associated illnesses such as Coomb's positive haemolytie anaemia, rheumatoid arthritis and dermatomyositis (Mackay and Gold- stein 1966). IV. Thyrotoxicosis

Enlargement of the thymus is seen in a number of patients with thyrotoxi- cosis. The mean weight of all thymic components is considerably greater in thyrotoxicosis, particularly in younger subjects. Histologically, there is epi- thelial hyperplasia in the medulla and increased thickness of the cortex (Mackay 1966). G u n n e t al. (1964) found germinal centres in 16 of the 50 thymus biopsies obtained during thyroidectomy in thyrotoxicosis. Thy- roxine is supposed to be a potent sti- mulus to epithelial cells of the thymus, which in turn gives rise to intense lym- phopoiesis in the cortex of the gland and also in peripheral lymphoid tissue {Warner 1964). V. The thymus and oncogenesis

The frequent occurrence of lympho- reticular malignancies in thymic dys- plasia, e.g., fataxia telengiectasia), and immunological abnormalities in certain lymphoproliferative disorders, e .g. , Hodgkin's disease, suggest that the pathology may have its origin in the thymus (Petersen et al. 1965). In a high-leukaemia strain of mice, the neoplasm often originates in the thymus and the thymectomised mice become tolerant to leukaemogens. It ispostu- lated that the mouse thymus possesses a leukaemogenic factor, which operates at a time of intense lymphopoiesis when leukaemogens can easily perpetuate the process (Furth et al. 1960). However, the role of the thymus in human leukaemia is not well understood. An increased incidence of malignancies in

elderly people may be due to a dimi- nished activity of the thymus gland which normally recognises oncogenic antigens and eliminates them.

References

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Bearn, J. G. (1967). Role of the fetal pituitary and adrenal glands in the development of fetal thymus of the rabbit. Endocrinology, 80, 979.

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Dukor, P., Miller, J. F. A., House, W. and Allman, V. (1966). Regeneration of thymus grafts. Histological and cytological aspects. Transplantation, 3, 639.

Feingold, D. S. and Parris, E. E. (1968). The lymphocyte and the thymus gland-congenital and hereditary abnormalities. New Engl. J. Med. 38, 579.

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SINGH AND GHAI--THE THYMUS~A BRIEF REVIEW 257

Miller, J. F. A. P. and Osoba, D. (1967). Current concepts of immunological functions of the thymus. Physiol. Rev. 47, 437.

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