Immunology Today, voL 7, Nos. 7&8, 1986
-commen/ r
The manyfacetsof thymicinvolution The importance of the thymus for the normal development of immune function in young mammals is well known. Whether or not the thymus has a similar importance in adults has yet to be resolved. Have we, as argued by Kendall 1 grossly underestimated the role of the adult thymus or is it, as implied by Smith 2, merely a convenient bag for the maturation of lymphocytes? Work reported in the last two years suggests the thymus maintains an active role in the immune response throughout adult life. A great deal is known about the cell types that occupy the thymus, their interactions, their differentiation and their functions 3. By contrast, we know very little about the organ that produces them. A major cause of this ignorance has been the common belief that the thymus is atrophic in the adult. Support for the idea that the thymus is not important in the adult has come from the observations that most thymocytes die in situ, that the rate of emigration of cells is very low (about 1% per day) and that adult thymectomy seems to have little effect on the immune response. However, it now seems that the true picture is much more complicated. Emigration is likely to be considerably higher than 1%. The low estimates are associated with commonly used surgical operations which result in a depletion of 50-90% of cells from the thymus 4. Thymectomy has many subtle effects on the immune system s and histological studies do not support mass intrathymic cell death 6. The view that the thymus was completely absent in adult humans arose as a consequence of the organ's extraordinary sensitivity to various external stimuli which led to so much shrinkage that the thymus was inapparent at post mortem examination. Thymic involution occurs in response to stress, to the administration of sex steroids and other hormones, to pregnancy, to lactation, to infection, to surgery, to autoimmune disease, to antibiotics and other drugs, to states of malnutrition and to malignancy. Furthermore, the thymus shrinks with age. This propensity for thymic involution is not confined to mammals, but occurs also in fish and amphibia (interestingly in amphibia involution occurs during metamorphosis when a new antigenic profile is being developedT). We do not know the significance or the mechanisms of thymic involution. There is no agreement whether the cells die intrathymically, are exported, fail to arrive from the bone marrow, develop longer cell cycles or simply cease to divide. Although the single term 'involution' is used to cover all the phenomena listed above, several distinct processes are clearly present. For example, the involution associated with old age is permanent, involves the deposition of fat within the organ and occurs in the face of falling levels of sex steroids. The involution of pregnancy is transient, and does not involve fat deposition. Although it is thought to be mediated by elevated levels of sex steroids, these effects can be overridden by maternal immunity to paternal antigens8. The involution during lactation cannot be mediated by the same set of hormones present in pregnancy as the levels of chorionic
204
Department of Obstetrics and Gynaecology' and Department of Histopathology 2, Nottingham University, Queens Medical Centre, Nottingham, NG7 2UH, UK
Ann G. ClarkeI and K.A. MacLennanz gonadotrophins and the sex steroids fall dramatically after birth. Lactational involution is thought to be maintained by the suckling stimulus and is perhaps under the control of the neuroendocrine system 9. Post mortem studies of healthy individuals who die suddenly invariably
Fig.1 (a) Perivascularspace(PVS)in a young mouse(MF1 9) at 3 weeksshowing it to be small with scantyargyrophilicfibres (reticulinstain x 270); (b) PVSat 8 weeks showing expansion of the PVS and an increase in argyrophilic fibres (reticulinstain x 270); (c) PVSat 17monthsshowingmassiveincreasein sizeand argyrophilicfibre content(reticulinstain x 270). ©1986, ElsevierSciencePublishersB.V,, Arnsterdarn 0167 4919/86/502.00
ImmunologyToday,voL 7, Nos. 7 & 8. 1986
.c o ,,,,,,, ,, reveal the thymus to be a sizeable organ even in extreme old age 1°. There is considerable controversy surrounding the time scale of thymic involutional changes. Some studies in man suggest the thymus increases in size until puberty during which it sharply involutes; this is followed by a more gradual decrease in size until the age of 40 which is accompanied by fatty infiltration of the organ. Insignificant changes occur thereafter ~°. Studies in animals support a similar puberty-related decline in thymic size in rodents 11'~2 but in sheep involution commences long before puberty, around 30 days after birth 13. A recent morphometric study of the human thymus suggests a different sequence of events TM. Instead of the accepted puberty-associated thymic involution, these workers have shown that the thymus is at its maximum size by one year of age, then progressively involutes at a constant rate. They have also described two functional units within the thymus, the thymic epithelial space (TES) characterized by a network of epithelial cells and associated lymphocytes and the perivascular space (PVS) which contains a network of argyrophilic fibres (ones which can be stained with silver) enclosing lymphatic and blood vessels and an array of lymphocytes, macrophages and granulocytes. The TES is regarded as the functional unit of thymic lymphocyte processing and is situated separately but in close proximity to the PVS which is regarded as the site of T-lymphocyte trafficking. These two components of the human thymus involute at different times during life. The TES is at its largest by one year of age and progressively involutes thereafter at a constant rate which appears independent of pubertyassociated endocrine influences. In contrast, the PVS size and lymphocytic content increases between one year and puberty after which adipose tissue infiltrates this site replacing the lymphocytes. Fig. 1 shows that changes similar to those in human beings occur in the PVS in the aging mouse thymus (K. MacLennan and A. Clarke, unpublished). A large amount of evidence suggests that the residual tissue found in the thymus after involution is immunocompetent. Of thymocytes taken from aging thymus's, 50% maintain the ability to form E-rosettes. DNA synthesis is practically unaltered with age and thymic hormones continue to be produced by the aging epithelial
=
cells is. There is evidence that some immune functions may be increased during involution 16. Immunohistological analysis of the involuting human thymus with monaqlonal antibodies shows normal antigenic expression and generation of thymocyte subpopulations 17. These results suggest that thymic involution is a complex process which affects the various functional units within the organ at different times during life. The largely ignored 'highways' of the thymus have now been defined in adult humans and mice. Study of the functions and nature of these complex areas should lead to a greater understanding of the immune capacities of the involuted thymus.
References
1 Kendall, M.D. (1984) Experientia 40, 1181-1185 2 Smith, K. (1984) ImmunoL Today 5, 8344 3 Ramion, P.L. and Schlossman,S.F.(1986)Adv. Int. Med. 31, 1-16 4 Rocha,B. (1985) Eur. J. ImmunoL 15, 1131-1135 5 Taylor, R.B.(1965) Nature (London) 208, 1334-1335 6 Kendall, M.D. (1984) ImmunoL Today 5, 286-287 7 Du Pasquier,L. and Weiss, N. (1973) Eur. J. Immunol. 3, 773-777 8 Clarke,A.G. (1984) in ImmunologicalAspects of Reproduction in Mammals (Crighton, D.B. ed.) pp. 153-182, Butterworths, London 9 Gregoire, C. (1947)J. EndocrinoL 5, 68-87 11} Kendall, M.D., Johnson, H.R.M. and Singh, J. (1980) J. Anat. 131,485-499 11 Hinokawa, K. and Makinodan, T. (1975) J. Immunol. 114, 1659-1664 12 Segal,J., Troen, B. and Ingbar, S. (1985) Thymus 4, 211-220 13 Reynolds,J.D. (1976) PhD ThesisThe development and physiology of the gut-associated lymphoid system in lambs,
Australian National University,Canberra 14 Steinmann, G.G., Klaus, B. and M~ller-Hermelink, H.-K (1985) Scand. J. ImmunoL 22, 563 575 15 Kendall, M.D. (1981)in The Thymus Gland(Kendall, M.D. ed.) pp. 21-35, Academic Press,London 16 Baroni, C.D., Valtieri, M., Stoppacciaro, A. etal. (1983) Immunology 50, 519-527 17 Steinmann, G.G. (1986)in Curr. Top. PathoL 75, (MQllerHermelink, H.-K. ed.) pp. 43-88, Springer-Verlag, Berlin
205
-commen/ r
The manyfacetsof thymicinvolution The importance of the thymus for the normal development of immune function in young mammals is well known. Whether or not the thymus has a similar importance in adults has yet to be resolved. Have we, as argued by Kendall 1 grossly underestimated the role of the adult thymus or is it, as implied by Smith 2, merely a convenient bag for the maturation of lymphocytes? Work reported in the last two years suggests the thymus maintains an active role in the immune response throughout adult life. A great deal is known about the cell types that occupy the thymus, their interactions, their differentiation and their functions 3. By contrast, we know very little about the organ that produces them. A major cause of this ignorance has been the common belief that the thymus is atrophic in the adult. Support for the idea that the thymus is not important in the adult has come from the observations that most thymocytes die in situ, that the rate of emigration of cells is very low (about 1% per day) and that adult thymectomy seems to have little effect on the immune response. However, it now seems that the true picture is much more complicated. Emigration is likely to be considerably higher than 1%. The low estimates are associated with commonly used surgical operations which result in a depletion of 50-90% of cells from the thymus 4. Thymectomy has many subtle effects on the immune system s and histological studies do not support mass intrathymic cell death 6. The view that the thymus was completely absent in adult humans arose as a consequence of the organ's extraordinary sensitivity to various external stimuli which led to so much shrinkage that the thymus was inapparent at post mortem examination. Thymic involution occurs in response to stress, to the administration of sex steroids and other hormones, to pregnancy, to lactation, to infection, to surgery, to autoimmune disease, to antibiotics and other drugs, to states of malnutrition and to malignancy. Furthermore, the thymus shrinks with age. This propensity for thymic involution is not confined to mammals, but occurs also in fish and amphibia (interestingly in amphibia involution occurs during metamorphosis when a new antigenic profile is being developedT). We do not know the significance or the mechanisms of thymic involution. There is no agreement whether the cells die intrathymically, are exported, fail to arrive from the bone marrow, develop longer cell cycles or simply cease to divide. Although the single term 'involution' is used to cover all the phenomena listed above, several distinct processes are clearly present. For example, the involution associated with old age is permanent, involves the deposition of fat within the organ and occurs in the face of falling levels of sex steroids. The involution of pregnancy is transient, and does not involve fat deposition. Although it is thought to be mediated by elevated levels of sex steroids, these effects can be overridden by maternal immunity to paternal antigens8. The involution during lactation cannot be mediated by the same set of hormones present in pregnancy as the levels of chorionic
204
Department of Obstetrics and Gynaecology' and Department of Histopathology 2, Nottingham University, Queens Medical Centre, Nottingham, NG7 2UH, UK
Ann G. ClarkeI and K.A. MacLennanz gonadotrophins and the sex steroids fall dramatically after birth. Lactational involution is thought to be maintained by the suckling stimulus and is perhaps under the control of the neuroendocrine system 9. Post mortem studies of healthy individuals who die suddenly invariably
Fig.1 (a) Perivascularspace(PVS)in a young mouse(MF1 9) at 3 weeksshowing it to be small with scantyargyrophilicfibres (reticulinstain x 270); (b) PVSat 8 weeks showing expansion of the PVS and an increase in argyrophilic fibres (reticulinstain x 270); (c) PVSat 17monthsshowingmassiveincreasein sizeand argyrophilicfibre content(reticulinstain x 270). ©1986, ElsevierSciencePublishersB.V,, Arnsterdarn 0167 4919/86/502.00
ImmunologyToday,voL 7, Nos. 7 & 8. 1986
.c o ,,,,,,, ,, reveal the thymus to be a sizeable organ even in extreme old age 1°. There is considerable controversy surrounding the time scale of thymic involutional changes. Some studies in man suggest the thymus increases in size until puberty during which it sharply involutes; this is followed by a more gradual decrease in size until the age of 40 which is accompanied by fatty infiltration of the organ. Insignificant changes occur thereafter ~°. Studies in animals support a similar puberty-related decline in thymic size in rodents 11'~2 but in sheep involution commences long before puberty, around 30 days after birth 13. A recent morphometric study of the human thymus suggests a different sequence of events TM. Instead of the accepted puberty-associated thymic involution, these workers have shown that the thymus is at its maximum size by one year of age, then progressively involutes at a constant rate. They have also described two functional units within the thymus, the thymic epithelial space (TES) characterized by a network of epithelial cells and associated lymphocytes and the perivascular space (PVS) which contains a network of argyrophilic fibres (ones which can be stained with silver) enclosing lymphatic and blood vessels and an array of lymphocytes, macrophages and granulocytes. The TES is regarded as the functional unit of thymic lymphocyte processing and is situated separately but in close proximity to the PVS which is regarded as the site of T-lymphocyte trafficking. These two components of the human thymus involute at different times during life. The TES is at its largest by one year of age and progressively involutes thereafter at a constant rate which appears independent of pubertyassociated endocrine influences. In contrast, the PVS size and lymphocytic content increases between one year and puberty after which adipose tissue infiltrates this site replacing the lymphocytes. Fig. 1 shows that changes similar to those in human beings occur in the PVS in the aging mouse thymus (K. MacLennan and A. Clarke, unpublished). A large amount of evidence suggests that the residual tissue found in the thymus after involution is immunocompetent. Of thymocytes taken from aging thymus's, 50% maintain the ability to form E-rosettes. DNA synthesis is practically unaltered with age and thymic hormones continue to be produced by the aging epithelial
=
cells is. There is evidence that some immune functions may be increased during involution 16. Immunohistological analysis of the involuting human thymus with monaqlonal antibodies shows normal antigenic expression and generation of thymocyte subpopulations 17. These results suggest that thymic involution is a complex process which affects the various functional units within the organ at different times during life. The largely ignored 'highways' of the thymus have now been defined in adult humans and mice. Study of the functions and nature of these complex areas should lead to a greater understanding of the immune capacities of the involuted thymus.
References
1 Kendall, M.D. (1984) Experientia 40, 1181-1185 2 Smith, K. (1984) ImmunoL Today 5, 8344 3 Ramion, P.L. and Schlossman,S.F.(1986)Adv. Int. Med. 31, 1-16 4 Rocha,B. (1985) Eur. J. ImmunoL 15, 1131-1135 5 Taylor, R.B.(1965) Nature (London) 208, 1334-1335 6 Kendall, M.D. (1984) ImmunoL Today 5, 286-287 7 Du Pasquier,L. and Weiss, N. (1973) Eur. J. Immunol. 3, 773-777 8 Clarke,A.G. (1984) in ImmunologicalAspects of Reproduction in Mammals (Crighton, D.B. ed.) pp. 153-182, Butterworths, London 9 Gregoire, C. (1947)J. EndocrinoL 5, 68-87 11} Kendall, M.D., Johnson, H.R.M. and Singh, J. (1980) J. Anat. 131,485-499 11 Hinokawa, K. and Makinodan, T. (1975) J. Immunol. 114, 1659-1664 12 Segal,J., Troen, B. and Ingbar, S. (1985) Thymus 4, 211-220 13 Reynolds,J.D. (1976) PhD ThesisThe development and physiology of the gut-associated lymphoid system in lambs,
Australian National University,Canberra 14 Steinmann, G.G., Klaus, B. and M~ller-Hermelink, H.-K (1985) Scand. J. ImmunoL 22, 563 575 15 Kendall, M.D. (1981)in The Thymus Gland(Kendall, M.D. ed.) pp. 21-35, Academic Press,London 16 Baroni, C.D., Valtieri, M., Stoppacciaro, A. etal. (1983) Immunology 50, 519-527 17 Steinmann, G.G. (1986)in Curr. Top. PathoL 75, (MQllerHermelink, H.-K. ed.) pp. 43-88, Springer-Verlag, Berlin
205
