research activities of the unit. It is a remarkable fact that far from inhibiting the academic development of the IDRL, the insertion of a small industrial base has resulted in the formation of an important new research group within the department whose activities extend far beyond originally conceived objectives. Substantial progress has been made, for instance, in the imaging of solid tumours using affinity-purified antibodies against carcinoembryonic antigen and
fn(&i&ii-) A new beginning Autoimmune phenomena are widespread in human disease and it is probable that different mechanisms may contribute to their appearance in different clinical groups of disease. The spectrum of self-antigens against which reactive autoantibodies have been described is ever increasing, although there is still little insight as to the inciting causes for the production of these autoantibodies. Nevertheless, a pathogenic aetiology is relatively easily accommodated in several cases of organ-specific autoimmunity, and likewise WC assume that the opportunity for action of inciting causes may be limited to the local milieu. On the other hand, in non-organ-specific autoimmunity, a primary pathogenic role of corresponding autoantibody may be less clear although there is widespread suspicion of basic imbalances affecting the immune system that result in the production of these autoantibodies. Although non-organ-specific autoimmunity is manifest by antibodies reactive with a bizarre set of self-antigens (e.g. IgG, cell nuclear components, cytoskeletal elements etc.), cellular mechanisms are probably central to explaining why non-organ-specific autoimmunity may occur. There is much current interest and controversy in elucidating these mechanisms, via either experimental models or investigation of immunological components in human autoimmune disease, and these have been debated in two recent compilations of short review articles’J. It is now clear that a number of B lymphocytes capable of producing autoantibodies exist normally and may be age-related, increasing in number with increasing age?. Thus, it is likely that the proliferation of autoreactive B lymphocytes to response to the corresponding autoantigen is held in check by the presence of immunoregulatory T lymphocytes. This is perhaps best illustrated by anti-IgG autoantibodies (rheumatoid factors, RF): B lymphocytes capable of producing IgM-RF are present in both rheumatoid arthritis patients and healthy individuals, and may be induced to proliferate in uilm with either Epstein-Barr virus or pokeweed mitogen4,5. There is no convincing
alpha-fete-protein. Other work is concerned with the development of assays of bronchial and intestinal immunity including studies of IgA heterogeneity. Attention is now being turned to the development of reagents for use in developing countries and this is linked with the new role of training technical staff to use and produce these reagents at distant stations but with the IDRL remaining as the reference and quality control centre for such activities.
~~~
New directions in research
in autoimmunity? evidence for the existence of corresponding ‘1’ lymphocytes autoreactive with IgG and capable of mediating cellular immunity to the autoantigen, as is also the case with other examples of non-organ-specific autoimmunity. This is not, however, to deny the possible all-important presence of immunoregulatory T lymphocytes controlling the outgrowth of autoreactive B lymphocytes in uivo. However, the nature of such cells is unclear and is likely to be a complex issue to unravel. Nevertheless, this approach has substantially widened the scope for consideration of inciting causes for autoimmunity. Previously much attention has been paid to ideas based on the immunological response to ‘altered’self antigens. However, the description of preexisting autoreactive B lymphocytes means that autoimmune responses may be expected should the action of immunoregulatory T lymphocytes be subverted in any way. In most cases, it is likely that the relevant autoantigen would not be required for this process and that we need not involve autoantigen in the construction of mechanisms for the onset of autoimmunity. There is thus increasing interest in the possible role of polyclonal B-cell activators’,” or cross-reactive antigenic epitopes/-” in autoimmune disease. Cross-reactive antigenic epitopes could arise by chance from within the intricate relationships of antigen-idiotype - anti-idiotype networks”’ and represent a route for supplying T-cell help via other non-crossreactive determinants on the (‘carrier’) cross-reactive antigen molecule. These views are compatible with the suspicion that autoimmune disease can arise as a result of unusual host reactions to a wide variety of exogeneous infections. Into this arena has now been thrown data from Van Snick” who has studied the anatomical distribution of murine IgM and IgA anti-IgG autoantibody-secreting cells. In the 129/Sv mouse colony in Brussels, but not in germ-free mice of the same strain, an age-related occurrence of serum anti-IgG autoantibody had been noted. This autoantibody has now been shown to be
produced earliest in lymph nodes draining the intestinal tract, and before its occurrence in the spleen or bone marrow”. The autoantibody response was prevented in mice that had had neonatal thymectomy, indicating a compulsory role for T lymphocytes in this process and counting against a role for the direct action of any exogeneous polyclonal B-cell activator taken into the gut. The clear implication is that perpetuated systemic anti-IgG autoantibody production in these mice originates initially from part of the local immune response to stimuli in the intestine, presumably infectious or environmental antigens. The analogy to human RF may not be strictly correct in that the range of infectious or dietary components met by the laboratory mouse will differ from that in man. Nevertheless, both the 129/Sv and human RF antiIgG autoantibody specificities are directed towards restricted antigenic determinants in the Fc region of IgG ‘).‘I. There is much evidence linking autoimmunity with a wide variety of infectious episodes; thus, for example, there is often an association of KF production with some bacterial infections and anti-nuclear antibody production with some viral infections. It is also clear that a range of autoreactive antibody responses of restricted heterogeneity may result from spontaneous infection or immunization with bacterial coccii2. It has long been held by some that persistent infection is most compatible with many of the clinical, pathological and serological features of the human autoimmune disease. The recent description of preexisting autoreactive B lymphocytes whose occurrence is age-related now opens the possibility that infective agents may sometimes be able to provide the
Is idiotypic
regulation
The mechanisms underlying the ability of the immune system to achieve self-regulation upon antigenic stimulation have long been the subject of detailed investigation. How may one account for homeostasis of each member of the staggering diversity of antibodies? Jerne’s ‘network’ hypothesis’ provided a model system in which homeostasis is preserved through a functional assembly of idiotype-anti-idiotype interactions. This system has also come comfortably to embrace the problem of conservation of apparently ‘idle’ genes in germ-line theories of diversity (see the recent article by Heinz Kiihler et nl. in this journa12). As a result a considerable number of expcriments have since been devised in order to test the validity of such a model. Much of this work has involved the observation of the effects of the administration of anti-idiotypic (anti-id) antibodies or sera on the expression of that idiotype (id). Typical among the most studied systems are the arsanil hapten’ and the streptococcal carbohydrate antigen” in A strain mice and the phosphorylcholine-specific ‘I’1 5 idiotype in
necessary interaction with the host immune system to annul T-lymphocyte immunoregulation of autoreactive B lymphocytes without the direct participation of autoantigen in triggering this response. The question now is where might this process start? The intestinal tract may yet hold a few secrets related to initial processes in the development of several examples of autoimmunity.
References I Autoimmunity Clzni~,~ vl Z~nvunolugy and Allergy, uol. 1, (1981) (E. J. Holborow, ed.) p. l-216, W. K. Saunders and Co. 2 Models of Autoimmune Diseases (1981) Irrrrrrurrr~l. Reu. 55, 5-314 3 Fang, S., Tsoukas, C. D., Frincke, L. A., Lawrance, S. K., Holbrook, T. L., Vaughan, J. H. and Carson, D. A. (198l)J. Irrm~unoi. 126, 910-914 4 Koopman, W. J. and Schrohenloher, P. E. (1980) Arlhrzlz~ Rheum. 23, 985-992
5 Slaughter, L., Carson, D. A., Jensen, F. C., Holbrook, T. L. and Vaughan, J. H. (1978)J. Exp. Mrd. 148, 1429-1434 6 Izui, S., Eisenbcrg, R. A. and Dixon, F. J. (1979) 3. Immunol. 122,2096-2102 7 Williams, R. C. Jr. (1979) Amer.]. Med. 67, 179-181 8 Rekvig, O.P. and Hannestad, K. (1980) 3. l&p. Med. 152, 1720-1733 9 Johnson, P. M. (1981) L‘lvzu~ ln Immuncilogy and Allergy, I, 103-115 10 Roitt, I. M., Cooke, A., Male, D. K., Hay, F. C., Guamotta, G., Lydyard, P. M., De Carvallo, L. P., Thanavala, Y. and Ivanyi, J. (1981) Lancet, i, 1041-1045 II Van Snick, J. L. (198I):j. Immunol. 126, 815-818 12 Grooten, J., De Baetseher, P., Vercautercn, E. and Hamers, R. (1980)
Nature
(London),
285, 401-403
the real thing? Balb/c mice”. In all of these systems it was demonstrated that the injection of anti-idiotype sera had profound suppressive or enhancing effects on the subsequent expression of that idiotype depending on the conditions employed. Eichman’s work, for example, showed that with anti-idiotypes raised in guinea pigs v, antibodies enhanced, while v2 suppressed”. Of course, these results are highly interesting but an interpretation of them in favour of the network hypothesis arouses the following objections: (1) The anti-idiotypes were raised either in another species or in strains of mice bearing a different allotype. This complicates the issue because the antibodies themselves are then foreign antigens and their Fc regions may produce abnormal functional effects in the heterologous species. (2) The anti-idiotypes were raised in animals which do not naturally carry the idiotype in question. There is no proof that an idiotype-bearing animal could necessarily synthesize its own anti-idiotype.
fn(&i&ii-) A new beginning Autoimmune phenomena are widespread in human disease and it is probable that different mechanisms may contribute to their appearance in different clinical groups of disease. The spectrum of self-antigens against which reactive autoantibodies have been described is ever increasing, although there is still little insight as to the inciting causes for the production of these autoantibodies. Nevertheless, a pathogenic aetiology is relatively easily accommodated in several cases of organ-specific autoimmunity, and likewise WC assume that the opportunity for action of inciting causes may be limited to the local milieu. On the other hand, in non-organ-specific autoimmunity, a primary pathogenic role of corresponding autoantibody may be less clear although there is widespread suspicion of basic imbalances affecting the immune system that result in the production of these autoantibodies. Although non-organ-specific autoimmunity is manifest by antibodies reactive with a bizarre set of self-antigens (e.g. IgG, cell nuclear components, cytoskeletal elements etc.), cellular mechanisms are probably central to explaining why non-organ-specific autoimmunity may occur. There is much current interest and controversy in elucidating these mechanisms, via either experimental models or investigation of immunological components in human autoimmune disease, and these have been debated in two recent compilations of short review articles’J. It is now clear that a number of B lymphocytes capable of producing autoantibodies exist normally and may be age-related, increasing in number with increasing age?. Thus, it is likely that the proliferation of autoreactive B lymphocytes to response to the corresponding autoantigen is held in check by the presence of immunoregulatory T lymphocytes. This is perhaps best illustrated by anti-IgG autoantibodies (rheumatoid factors, RF): B lymphocytes capable of producing IgM-RF are present in both rheumatoid arthritis patients and healthy individuals, and may be induced to proliferate in uilm with either Epstein-Barr virus or pokeweed mitogen4,5. There is no convincing
alpha-fete-protein. Other work is concerned with the development of assays of bronchial and intestinal immunity including studies of IgA heterogeneity. Attention is now being turned to the development of reagents for use in developing countries and this is linked with the new role of training technical staff to use and produce these reagents at distant stations but with the IDRL remaining as the reference and quality control centre for such activities.
~~~
New directions in research
in autoimmunity? evidence for the existence of corresponding ‘1’ lymphocytes autoreactive with IgG and capable of mediating cellular immunity to the autoantigen, as is also the case with other examples of non-organ-specific autoimmunity. This is not, however, to deny the possible all-important presence of immunoregulatory T lymphocytes controlling the outgrowth of autoreactive B lymphocytes in uivo. However, the nature of such cells is unclear and is likely to be a complex issue to unravel. Nevertheless, this approach has substantially widened the scope for consideration of inciting causes for autoimmunity. Previously much attention has been paid to ideas based on the immunological response to ‘altered’self antigens. However, the description of preexisting autoreactive B lymphocytes means that autoimmune responses may be expected should the action of immunoregulatory T lymphocytes be subverted in any way. In most cases, it is likely that the relevant autoantigen would not be required for this process and that we need not involve autoantigen in the construction of mechanisms for the onset of autoimmunity. There is thus increasing interest in the possible role of polyclonal B-cell activators’,” or cross-reactive antigenic epitopes/-” in autoimmune disease. Cross-reactive antigenic epitopes could arise by chance from within the intricate relationships of antigen-idiotype - anti-idiotype networks”’ and represent a route for supplying T-cell help via other non-crossreactive determinants on the (‘carrier’) cross-reactive antigen molecule. These views are compatible with the suspicion that autoimmune disease can arise as a result of unusual host reactions to a wide variety of exogeneous infections. Into this arena has now been thrown data from Van Snick” who has studied the anatomical distribution of murine IgM and IgA anti-IgG autoantibody-secreting cells. In the 129/Sv mouse colony in Brussels, but not in germ-free mice of the same strain, an age-related occurrence of serum anti-IgG autoantibody had been noted. This autoantibody has now been shown to be
produced earliest in lymph nodes draining the intestinal tract, and before its occurrence in the spleen or bone marrow”. The autoantibody response was prevented in mice that had had neonatal thymectomy, indicating a compulsory role for T lymphocytes in this process and counting against a role for the direct action of any exogeneous polyclonal B-cell activator taken into the gut. The clear implication is that perpetuated systemic anti-IgG autoantibody production in these mice originates initially from part of the local immune response to stimuli in the intestine, presumably infectious or environmental antigens. The analogy to human RF may not be strictly correct in that the range of infectious or dietary components met by the laboratory mouse will differ from that in man. Nevertheless, both the 129/Sv and human RF antiIgG autoantibody specificities are directed towards restricted antigenic determinants in the Fc region of IgG ‘).‘I. There is much evidence linking autoimmunity with a wide variety of infectious episodes; thus, for example, there is often an association of KF production with some bacterial infections and anti-nuclear antibody production with some viral infections. It is also clear that a range of autoreactive antibody responses of restricted heterogeneity may result from spontaneous infection or immunization with bacterial coccii2. It has long been held by some that persistent infection is most compatible with many of the clinical, pathological and serological features of the human autoimmune disease. The recent description of preexisting autoreactive B lymphocytes whose occurrence is age-related now opens the possibility that infective agents may sometimes be able to provide the
Is idiotypic
regulation
The mechanisms underlying the ability of the immune system to achieve self-regulation upon antigenic stimulation have long been the subject of detailed investigation. How may one account for homeostasis of each member of the staggering diversity of antibodies? Jerne’s ‘network’ hypothesis’ provided a model system in which homeostasis is preserved through a functional assembly of idiotype-anti-idiotype interactions. This system has also come comfortably to embrace the problem of conservation of apparently ‘idle’ genes in germ-line theories of diversity (see the recent article by Heinz Kiihler et nl. in this journa12). As a result a considerable number of expcriments have since been devised in order to test the validity of such a model. Much of this work has involved the observation of the effects of the administration of anti-idiotypic (anti-id) antibodies or sera on the expression of that idiotype (id). Typical among the most studied systems are the arsanil hapten’ and the streptococcal carbohydrate antigen” in A strain mice and the phosphorylcholine-specific ‘I’1 5 idiotype in
necessary interaction with the host immune system to annul T-lymphocyte immunoregulation of autoreactive B lymphocytes without the direct participation of autoantigen in triggering this response. The question now is where might this process start? The intestinal tract may yet hold a few secrets related to initial processes in the development of several examples of autoimmunity.
References I Autoimmunity Clzni~,~ vl Z~nvunolugy and Allergy, uol. 1, (1981) (E. J. Holborow, ed.) p. l-216, W. K. Saunders and Co. 2 Models of Autoimmune Diseases (1981) Irrrrrrurrr~l. Reu. 55, 5-314 3 Fang, S., Tsoukas, C. D., Frincke, L. A., Lawrance, S. K., Holbrook, T. L., Vaughan, J. H. and Carson, D. A. (198l)J. Irrm~unoi. 126, 910-914 4 Koopman, W. J. and Schrohenloher, P. E. (1980) Arlhrzlz~ Rheum. 23, 985-992
5 Slaughter, L., Carson, D. A., Jensen, F. C., Holbrook, T. L. and Vaughan, J. H. (1978)J. Exp. Mrd. 148, 1429-1434 6 Izui, S., Eisenbcrg, R. A. and Dixon, F. J. (1979) 3. Immunol. 122,2096-2102 7 Williams, R. C. Jr. (1979) Amer.]. Med. 67, 179-181 8 Rekvig, O.P. and Hannestad, K. (1980) 3. l&p. Med. 152, 1720-1733 9 Johnson, P. M. (1981) L‘lvzu~ ln Immuncilogy and Allergy, I, 103-115 10 Roitt, I. M., Cooke, A., Male, D. K., Hay, F. C., Guamotta, G., Lydyard, P. M., De Carvallo, L. P., Thanavala, Y. and Ivanyi, J. (1981) Lancet, i, 1041-1045 II Van Snick, J. L. (198I):j. Immunol. 126, 815-818 12 Grooten, J., De Baetseher, P., Vercautercn, E. and Hamers, R. (1980)
Nature
(London),
285, 401-403
the real thing? Balb/c mice”. In all of these systems it was demonstrated that the injection of anti-idiotype sera had profound suppressive or enhancing effects on the subsequent expression of that idiotype depending on the conditions employed. Eichman’s work, for example, showed that with anti-idiotypes raised in guinea pigs v, antibodies enhanced, while v2 suppressed”. Of course, these results are highly interesting but an interpretation of them in favour of the network hypothesis arouses the following objections: (1) The anti-idiotypes were raised either in another species or in strains of mice bearing a different allotype. This complicates the issue because the antibodies themselves are then foreign antigens and their Fc regions may produce abnormal functional effects in the heterologous species. (2) The anti-idiotypes were raised in animals which do not naturally carry the idiotype in question. There is no proof that an idiotype-bearing animal could necessarily synthesize its own anti-idiotype.
