294
Immunology 7"oday,vol. 3, No. /1, 1982
11 Sherr, C. J., Lieber, M. M. and Todaro, G. J. (1974) Cell 1, 55-58 12 Levy, J. A., Datta, S. K. and Schwartz, R. S. (1977) Clin. Immunol. Immunopathol. 7,262-268 13 Moroni, C. and Schumann, G. (1977) 3&lure (London) 269, 600-601 14 Weiss, R. (1975) Nature (London) 255,445-447 15 Cooper, N. R., Jensen, F. C., Welsh, R. M. and Oldstonc, M. B. A. (1976)J. Exp. Med. 144, 970-984 16 Poiesz, B. J., Ruscetti, F. W., Gazdar, A. F., Bunn, P. A., Minna, J. D. and Gallo, R. C. (1980) Proc. Nail Acad. Sci. U.S.A.
77, 7415-7419 17 Miyoshi, I., Kubonishi, I., Yoshimoto, S., Akagi, T., Ohtsuki, Y., Shiraishi, Y., Nagata, K. and Hinuma, Y. (1981) Nature (London) 294, 770-771 18 Catovsky, D~, Greaves, M. F., Rose, M., Galton, D. A. G., Goolden, A. W. C,., McCluskey, D. R., White, J. M., Lampert, I., Bourikas, G., ireland, R., Bridges, J. M., Blattner, W. A. and Gallo, R. C. (1982) Lancet i, 639-643 19 Miyoshi, 1., Fujishita, M., Taguchi, H., Ohtsuki, Y., Akagi, T., Morimoto, Y. M. and Nagasaki, A. (1982) Lancet i, 683 684 20 Saxinger, W. C. and Gallo, R. C. (1982) Lar~ceIi, 1074
W h e r e do autoantibodies come from? A few years ago, the story of the origin of a u t o i m m u n e thyroiditis seemed to be settledk Roitt and Torrigiani 2 showed that thyroglobulin (Tg) normally circulates in concentrations of 10 to 50 ng ml ~, so maintaining low zone tolerance, i.e. tolerance at the T-cell (but not the B-cell) level. To initiate autoantibody production, it was necessary to replace the deleted T cells; this could be done by giving a polyclonal B-cell activator, or a cross-reactive or altered Tg antigen. Antibodyforming cells accumulated in the thyroid where they caused damage directly or indirectly. But now there is experimental evidence which challenges the view that T-cell deletion is necessarily the basis of self-tolerance to Tg. A recent publication by W e e t m a n et al. 3 describes the distribution of cells engaged in producing antibodies to Tg in rats with a u t o i m m u n e thyroiditis. W e e t m a n el al. induced thyroiditis in the rats in two different ways. Some were injected with rat Tg in Freund's complete adjuvant; these rats developed a transient disease that remitted unless periodic booster injections were given. O t h e r rats were thymectomized (Tx) a n d treated several times with whole-body irradiation (X); these ' T x plus X ' animals developed a sustained severe form of thyroiditis with hypothyroidism. In both forms of the a u t o i m m u n e disease, the major site of autoantibody production was the bone marrow. The majority of ' T x plus X ' animals also h a d anti-Tg plaque-forming cells in the thyroid at the time of examination. The latter finding must be taken with some reservation, however, because timing may be all-important. Antibody-forming cells may be present in the thyroid earlier or later in the course of the disease. Nevertheless, these findings are in stark contrast with the reports of Clinton and Weigle 4, and Boyd a n d Wick 5 which show numerous antibody-forming cells in the thyroids of rabbits with experimentally induced thyroiditis, a n d chickens with spontaneous thyroiditis, respectively. In fact, W e e t m a n el al/' also showed that anti-T c plaque-forming cells could be found in the thyroids of h u m a n s with Hashimoto's thyroiditis. T h e ' T x plus X ' model of a u t o i m m u n e thyroiditis is also particularly instructive in re-evaluating the T-cell deletion concept of self-tolerance to Tg. T h e most logical explanation for the development of autoimmunity in the ' T x plus X ' rats is that thymectomy
and irradiation reduces a population of thymusderived suppressor ceils, and permits Tg-specific helper T ceils to express themselves. Evidence supporting this view was given by A. M. McGregor, one of the W e c t m a n ' s collaborators, at a recent Thyroid Workshop in Edmonton, Alberta, held on 24-25 July 1982. He showed t h a t ' T x plus X ' rats treated with cyclosporin A show a decrease in the helper:suppressor T-cell ratio, a n d do not develop autoimmune thyroiditis. At the same meeting in Edmonton, W. Weigle proffered new findings that point directly to the presence of Tg-reactive T cells in good responder strains of mice. He found that mouse Tg stimulated the lymphnode cells of animals with experimental thyroiditis. These results confirm the earlier publication of Okayasu el al. ('. Furthermore, Weigle showed that the responding cells were Lyt 1+,2-,3 . O f course, the stimulation indices were quite low compared with those obtained with foreign antigens like ovalbumin or heterologous Tg. But we must realize that only two to six of the forty to sixty antigenic determinants on Tg act as autoantigens. Another similar line of evidence has emerged from the studies of K0jima et al. 7 in J a p a n . They found that thyroiditis develops spontaneously in certain strains of mice if the animals are thymectomized on the third day after birth. It seems that neonatal thymectomy preferentially reduces suppressor T cells and permits Tg-specific helper T cells to predominate. It remains to identify and characterize the putative suppressor-cell populations a n d determine whether they are Tg-specific or idiotype-specific. The existence of such populations may well explain why rats given rat Tg in adjuvant recover from thyroiditis spontaneously, as the balance between helper and suppressor function returns to normal. A u t o i m m u n e diseases in h u m a n s often remit spontaneously too. More important, if we can find conditions that favor suppressor-cell proliferation, we will have a new and specific way of treating a u t o i m m u n e disorders. N O E L R. R O S E
D@artment of Immunology and lnjectious Diseases, 7tze Johns Hopkins University Sehool of Hygiene and Public Health, l?,allimore, MD 27205, U.S.A.
Immunotogy To@, vol. 3, No. I I, 1982
295
References 1 Allison, A. (1976)N. EnglJ. Med. 295,821-827 2 Roitt, 1. M. and Torrigiani, G. (l 967) Endocrinology8 I, 421 3 Weetman, A. P., McGregor, A. M., Rennie, D. P. and Hall, R. (1982) lmraunology46,465-472 4 Clinton, B. A. and Weigle, W. O. (1972)ff. Exp. Med. 136, 1605 5 Boyd, R. and Wick, G. (1980) in Autoimmune Asped~ of Endocrir~e
E] (,..,.-,
Disease (Pinchera, A., Doniach, D., Fenzi, G. F. and Baschieri, L., eds), Academic Press, London 5 Weetman, A. P., McGregor, A. M. and Lazarus, J. H. (1981) Clin. Sci. 61, 17P 70kayasu, I., Kong, Y., David, C. and Rose, N. R. (1981) Cell. lmmunoL 61, 32 39 8 Kojima, A., Tanaka-Kojima, Y., Sakakura, T. and Nishizuka, Y. (1976) Lab. Invest. 34, 550-557
)
Cellular interactions involved in T-dependent Bcell activation Michael H. Julius Basel Institute for Immunology, Grenzacherstrasse 487, Posttach, CH-4005 Basel, Switzerland. In this article, Michael Julius provides a framework within which to consider the activation requirements of B cells limited @ T-helper cell activation and recognitive properties associated with effector function, focusing mainly on the requirement for an MHC-restrided T - B interaction. M a n y experimental systems have been employed to study how B lymphocytes are activated by T cells. Comparisons between them reveal clear differences which may account for the discrepant results that have been obtained. Conflicting data can be reconciled if one considers the state of B-cell activation prior to assay as well as the type of response assessed. In so doing, a general scheme of T - d e p e n d e n t B-cell activation which governs specific, polyspecific and bystander i m m u n e responses can be formulated. The outstanding feature of T-helper cell (Th) physiology is that induction/recognition is mediated by antigen (Ag) in association with I-A determinants encoded by the major histocompatibility complex ( M H C ) 1-7. The involvement of an antigen-presenting cell (APC), in this process appears critical. This p h e n o m e n o n has led to a question about Thdependent B-cell activation which is m u c h disputed whether or not the Th-APC interaction is the only MHC-restricted event involved in B-cell induction 8-~$. The major problem in attempts to analyse the requirements for MHC-restricted Th-B interaction is the high frequency of allo-reactive T cells, which prohibits the straightforward admixture of allogeneic populations of T h and B cells because the ensuing induction of either positive or negative allogeneic effects could mask or bypass the requirements for M H C restricted cellular interactions ~6. This problem has been overcome in several ways: the use of longterm T-cell lines or clones; the use of hybrid F~ T cells selected for antigen specificity in association with either parental APC; or the use of T h populations negatively selected for the allo-MHC to be tested. This
technology allows us to put the problem of allogeneic effect to rest. T h e r e q u i r e m e n t for M H C r e s t r i c t e d T h - B interactions The first suggestion that the activation of antigenspecific B cells requires a direct interaction with Th came from studies which defined a requirement for linked recognition ~7. Carrier-specific Th cells activated hapten-specific B cells only in the presence of" covalently-linked h a p t e n a n d carrier. T h e inference drawn from these experiments is that hapten-specific B cells, having b o u n d hapten, also indirectly acquire carrier determinants which allow the focusing of Th. If one assumes that as for induction, recognition by T h after activation is also limited by antigen in association with I-A products, the prediction follows that the requirement for linked recognition will correlate with the requirement for an I-A restricted Th-B interaction. A n u m b e r of studies demonstrate that induction of antigen-specific B cells is limited by an M H C restricted interaction with Th 12-15. T h e recurring principle in these experiments is that conditions which satisfy T h activation do not lead to the subsequent activation of just any B cell, but only those B cells bearing the appropriate /-A-encoded determinants which, in conjunction with antigen, satisfy Th specificity requirements. Hence, two levels of M H C restricted cellular interaction appear to limit the acti-. vation of some B cells: T h - A P C followed by Th-B. This interpretation, however, is not always applicable. Studies of parallel design suggest that fulfilment Glsevier Biomedical Press 1982 O167~,919/82/0fl00~000/$1.00
Immunology 7"oday,vol. 3, No. /1, 1982
11 Sherr, C. J., Lieber, M. M. and Todaro, G. J. (1974) Cell 1, 55-58 12 Levy, J. A., Datta, S. K. and Schwartz, R. S. (1977) Clin. Immunol. Immunopathol. 7,262-268 13 Moroni, C. and Schumann, G. (1977) 3&lure (London) 269, 600-601 14 Weiss, R. (1975) Nature (London) 255,445-447 15 Cooper, N. R., Jensen, F. C., Welsh, R. M. and Oldstonc, M. B. A. (1976)J. Exp. Med. 144, 970-984 16 Poiesz, B. J., Ruscetti, F. W., Gazdar, A. F., Bunn, P. A., Minna, J. D. and Gallo, R. C. (1980) Proc. Nail Acad. Sci. U.S.A.
77, 7415-7419 17 Miyoshi, I., Kubonishi, I., Yoshimoto, S., Akagi, T., Ohtsuki, Y., Shiraishi, Y., Nagata, K. and Hinuma, Y. (1981) Nature (London) 294, 770-771 18 Catovsky, D~, Greaves, M. F., Rose, M., Galton, D. A. G., Goolden, A. W. C,., McCluskey, D. R., White, J. M., Lampert, I., Bourikas, G., ireland, R., Bridges, J. M., Blattner, W. A. and Gallo, R. C. (1982) Lancet i, 639-643 19 Miyoshi, 1., Fujishita, M., Taguchi, H., Ohtsuki, Y., Akagi, T., Morimoto, Y. M. and Nagasaki, A. (1982) Lancet i, 683 684 20 Saxinger, W. C. and Gallo, R. C. (1982) Lar~ceIi, 1074
W h e r e do autoantibodies come from? A few years ago, the story of the origin of a u t o i m m u n e thyroiditis seemed to be settledk Roitt and Torrigiani 2 showed that thyroglobulin (Tg) normally circulates in concentrations of 10 to 50 ng ml ~, so maintaining low zone tolerance, i.e. tolerance at the T-cell (but not the B-cell) level. To initiate autoantibody production, it was necessary to replace the deleted T cells; this could be done by giving a polyclonal B-cell activator, or a cross-reactive or altered Tg antigen. Antibodyforming cells accumulated in the thyroid where they caused damage directly or indirectly. But now there is experimental evidence which challenges the view that T-cell deletion is necessarily the basis of self-tolerance to Tg. A recent publication by W e e t m a n et al. 3 describes the distribution of cells engaged in producing antibodies to Tg in rats with a u t o i m m u n e thyroiditis. W e e t m a n el al. induced thyroiditis in the rats in two different ways. Some were injected with rat Tg in Freund's complete adjuvant; these rats developed a transient disease that remitted unless periodic booster injections were given. O t h e r rats were thymectomized (Tx) a n d treated several times with whole-body irradiation (X); these ' T x plus X ' animals developed a sustained severe form of thyroiditis with hypothyroidism. In both forms of the a u t o i m m u n e disease, the major site of autoantibody production was the bone marrow. The majority of ' T x plus X ' animals also h a d anti-Tg plaque-forming cells in the thyroid at the time of examination. The latter finding must be taken with some reservation, however, because timing may be all-important. Antibody-forming cells may be present in the thyroid earlier or later in the course of the disease. Nevertheless, these findings are in stark contrast with the reports of Clinton and Weigle 4, and Boyd a n d Wick 5 which show numerous antibody-forming cells in the thyroids of rabbits with experimentally induced thyroiditis, a n d chickens with spontaneous thyroiditis, respectively. In fact, W e e t m a n el al/' also showed that anti-T c plaque-forming cells could be found in the thyroids of h u m a n s with Hashimoto's thyroiditis. T h e ' T x plus X ' model of a u t o i m m u n e thyroiditis is also particularly instructive in re-evaluating the T-cell deletion concept of self-tolerance to Tg. T h e most logical explanation for the development of autoimmunity in the ' T x plus X ' rats is that thymectomy
and irradiation reduces a population of thymusderived suppressor ceils, and permits Tg-specific helper T ceils to express themselves. Evidence supporting this view was given by A. M. McGregor, one of the W e c t m a n ' s collaborators, at a recent Thyroid Workshop in Edmonton, Alberta, held on 24-25 July 1982. He showed t h a t ' T x plus X ' rats treated with cyclosporin A show a decrease in the helper:suppressor T-cell ratio, a n d do not develop autoimmune thyroiditis. At the same meeting in Edmonton, W. Weigle proffered new findings that point directly to the presence of Tg-reactive T cells in good responder strains of mice. He found that mouse Tg stimulated the lymphnode cells of animals with experimental thyroiditis. These results confirm the earlier publication of Okayasu el al. ('. Furthermore, Weigle showed that the responding cells were Lyt 1+,2-,3 . O f course, the stimulation indices were quite low compared with those obtained with foreign antigens like ovalbumin or heterologous Tg. But we must realize that only two to six of the forty to sixty antigenic determinants on Tg act as autoantigens. Another similar line of evidence has emerged from the studies of K0jima et al. 7 in J a p a n . They found that thyroiditis develops spontaneously in certain strains of mice if the animals are thymectomized on the third day after birth. It seems that neonatal thymectomy preferentially reduces suppressor T cells and permits Tg-specific helper T cells to predominate. It remains to identify and characterize the putative suppressor-cell populations a n d determine whether they are Tg-specific or idiotype-specific. The existence of such populations may well explain why rats given rat Tg in adjuvant recover from thyroiditis spontaneously, as the balance between helper and suppressor function returns to normal. A u t o i m m u n e diseases in h u m a n s often remit spontaneously too. More important, if we can find conditions that favor suppressor-cell proliferation, we will have a new and specific way of treating a u t o i m m u n e disorders. N O E L R. R O S E
D@artment of Immunology and lnjectious Diseases, 7tze Johns Hopkins University Sehool of Hygiene and Public Health, l?,allimore, MD 27205, U.S.A.
Immunotogy To@, vol. 3, No. I I, 1982
295
References 1 Allison, A. (1976)N. EnglJ. Med. 295,821-827 2 Roitt, 1. M. and Torrigiani, G. (l 967) Endocrinology8 I, 421 3 Weetman, A. P., McGregor, A. M., Rennie, D. P. and Hall, R. (1982) lmraunology46,465-472 4 Clinton, B. A. and Weigle, W. O. (1972)ff. Exp. Med. 136, 1605 5 Boyd, R. and Wick, G. (1980) in Autoimmune Asped~ of Endocrir~e
E] (,..,.-,
Disease (Pinchera, A., Doniach, D., Fenzi, G. F. and Baschieri, L., eds), Academic Press, London 5 Weetman, A. P., McGregor, A. M. and Lazarus, J. H. (1981) Clin. Sci. 61, 17P 70kayasu, I., Kong, Y., David, C. and Rose, N. R. (1981) Cell. lmmunoL 61, 32 39 8 Kojima, A., Tanaka-Kojima, Y., Sakakura, T. and Nishizuka, Y. (1976) Lab. Invest. 34, 550-557
)
Cellular interactions involved in T-dependent Bcell activation Michael H. Julius Basel Institute for Immunology, Grenzacherstrasse 487, Posttach, CH-4005 Basel, Switzerland. In this article, Michael Julius provides a framework within which to consider the activation requirements of B cells limited @ T-helper cell activation and recognitive properties associated with effector function, focusing mainly on the requirement for an MHC-restrided T - B interaction. M a n y experimental systems have been employed to study how B lymphocytes are activated by T cells. Comparisons between them reveal clear differences which may account for the discrepant results that have been obtained. Conflicting data can be reconciled if one considers the state of B-cell activation prior to assay as well as the type of response assessed. In so doing, a general scheme of T - d e p e n d e n t B-cell activation which governs specific, polyspecific and bystander i m m u n e responses can be formulated. The outstanding feature of T-helper cell (Th) physiology is that induction/recognition is mediated by antigen (Ag) in association with I-A determinants encoded by the major histocompatibility complex ( M H C ) 1-7. The involvement of an antigen-presenting cell (APC), in this process appears critical. This p h e n o m e n o n has led to a question about Thdependent B-cell activation which is m u c h disputed whether or not the Th-APC interaction is the only MHC-restricted event involved in B-cell induction 8-~$. The major problem in attempts to analyse the requirements for MHC-restricted Th-B interaction is the high frequency of allo-reactive T cells, which prohibits the straightforward admixture of allogeneic populations of T h and B cells because the ensuing induction of either positive or negative allogeneic effects could mask or bypass the requirements for M H C restricted cellular interactions ~6. This problem has been overcome in several ways: the use of longterm T-cell lines or clones; the use of hybrid F~ T cells selected for antigen specificity in association with either parental APC; or the use of T h populations negatively selected for the allo-MHC to be tested. This
technology allows us to put the problem of allogeneic effect to rest. T h e r e q u i r e m e n t for M H C r e s t r i c t e d T h - B interactions The first suggestion that the activation of antigenspecific B cells requires a direct interaction with Th came from studies which defined a requirement for linked recognition ~7. Carrier-specific Th cells activated hapten-specific B cells only in the presence of" covalently-linked h a p t e n a n d carrier. T h e inference drawn from these experiments is that hapten-specific B cells, having b o u n d hapten, also indirectly acquire carrier determinants which allow the focusing of Th. If one assumes that as for induction, recognition by T h after activation is also limited by antigen in association with I-A products, the prediction follows that the requirement for linked recognition will correlate with the requirement for an I-A restricted Th-B interaction. A n u m b e r of studies demonstrate that induction of antigen-specific B cells is limited by an M H C restricted interaction with Th 12-15. T h e recurring principle in these experiments is that conditions which satisfy T h activation do not lead to the subsequent activation of just any B cell, but only those B cells bearing the appropriate /-A-encoded determinants which, in conjunction with antigen, satisfy Th specificity requirements. Hence, two levels of M H C restricted cellular interaction appear to limit the acti-. vation of some B cells: T h - A P C followed by Th-B. This interpretation, however, is not always applicable. Studies of parallel design suggest that fulfilment Glsevier Biomedical Press 1982 O167~,919/82/0fl00~000/$1.00
