- Email: [email protected]
The immunologic basis of autoimmunization
Requested
manuscripts
The immunologic autoimmunization
basis of
Robert S. Schwartz, M.D. Boston, Mass.
Autoimmunization is today so readily accepted as established fact that it is easy to forget its turbulent history. There was a time when a few stubborn physicians had to insist against informed opinion that autoimmune diseases really existed. The answer they received was, “. I’ll never believe there is such a thing as an autoantibody.“’ Now the tables are turned. Today immunochemists are presenting schemes that require the formation of autoantibodies during the normal immune response.” Between these two extremes there is an evolution of thought that
AUTOlMMUNlZATlON DISEASE
VS AUTOIMMUNE
Autoimmunization is the production of antibodies against autoantigens; the autoantibodies so formed may or may not be pathogenetic. In an autoimmune disease the lesions are caused by pathogenetic autoantibodies. For instance, cold agglutinins reactive with autologous red cells are usually formed in the wake of infection by Mycoplasma pneumoniae, but hemolytic anemia is a relatively rare complication.” Thus, the presence of an autoantibody does not necessarily imply the existence of a relevant lesion. Other examples are: (1) Antibodies against nuclear antigens, smooth muscle, and mitochondria in the sera of patients with chronic liver disease.lR (2) Anti-
From the Hematology Service, New England Medical Center Hospital, and Department of Medicine, Tufts University School of Medicine. Supported by United States Public Health Service Grant No. 07937. Presented at the Postgraduate Course of the American Congress of Allergy and Immunology, New York, N. Y., March, 1977.
nuclear and anti-DNA antibodies without signs of systemic lupus erythematosus (SLE) associated with treatment by certain drugs.14 (3) Production of autoantibodies by clinically healthy relatives of patients with SLE.15 (4) Presence of autoantibodies (e.g., rheumatoid factor, antinuclear antibodies) in healthy, elderly persons. Ifi What can we make of such “orphan” autoantibodies? There are several possibilities. Perhaps they are markers of a genetic susceptibility to autoimmune disease. Family studies in SLE15 tend to support this. They may be triggered by certain infectious agents; the example of Mycoplasma pneumoniae was already cited. In experimental animals, several kinds of retroviruses” and even Schistosoma infectionlx can result in the formation of antinuclear antibodies. Drugs like alpha-methyldopa and procainamide are wellestablished promoters of autoantibody production. l4 Finally, some autoantibodies may have a physiologic function, perhaps to remove by-products of dead cells.ls None of these explanations gives us an insight; they merely warn that autoimmunization may not be a sufficient reason to diagnose autoimmune disease. Vol. 60, No. 1, pp. 69-72
70
Schwartz
J. ALLERGY
ANTIGEN
CLIN. IMMUNOL. JULY 1977
immune hemolytic anemia and immune thrombocytopenia, pernicious anemia, and Hashimoto’s disease are examples. (3) The associations between certain autoimmune diseases and either malignant lymphoproliferative diseases or immunodeficiency seem more than coincidental. They imply a fundamental disturbance of immunoregulation.
IMMUNOREGULATION
\fI(+ t
ANTIGEN FIG. 1. Immunoregulation. MO, macrophage; T,+, helper T cell; TsI suppressor T ceil; B, B cell. Feedward on the right, feedback on the left. lmmunoregulation by antibody is indicated at the bottom of the diagram.
LINKED AUTOIMMUNE DISEASE Autoimmune hemolytic anemia (AIHA) is, in reality, a syndrome. It may develop as an idiopathic, independent entity or arise in association with any of the following: drug therapy, infection, another autoimmune disease, or a malignancy. AIHA associated with immune thrombocytopenia (Evans’ syndrome)20 is well recognized, as is AIHA during the course of SLE.21 The association between AIHA and malignancies of lymphoid tissue-chronic lymphocytic leukemia, for example-is remarkable.22 Overlap, either clinical, serologic, or both, is a compelling feature of many autoimmune diseases. Indeed, even those disorders thought to be “organspecific” may show considerable linkage as, for example, in autoimmune polyendocrine deficiencies.23 The extraordinary overlapping relationships among Hashimoto’s disease, Graves’ disease, and euthyroid Graves’ ophthalmopathy24 are more recent examples. Sjiigren’s syndrome, with its numerous serologic abnormalities and its tendency toward malignant degeneration,25 is even more striking. Notably, the linkage also extends to the apparent paradox of autoimmune disease associated with immunodeficiency. 26 We may draw three conclusions from this: (1) Every autoimmune disease, no matter how “organspecific, ’ ’ can potentially or actually does involve multiple autoantibodies and autoantigens. (2) Autoimmune diseases tend to form chsters of related disorders: polyendocrinopathies, simultaneous Hashimoto’s disease and Graves’ disease, sequential auto-
This term was coined to convey the idea that the feedforward aspects of the immune response are precisely balanced by feedback mechanisms.27 There is a growing appreciation that there are two immune systems, one being the mirror image of the other. The feedforward system begins with antigen and culminates in antibody (or cytotoxic lymphocytes). The feedback system can enter the scheme at either end: by contact with antigen or antibody (Fig. 1). Furthermore, feedback may be either antigen-specific or distribute its effects among several or even numerous specificities (nonspeci$c feedback is probably more in the eye of the beholder than in Nature). The concept of immunoregulation was made central to our understanding of autoimmunization by two discoveries: (1) the existence in normal individuals of B cells with receptors for autoantigenP, 2gand (2) the role of suppressor cells in the maintenance of immunologic tolerance. 3o An equally important fact is that in immune responses to a great variety of antigens, B cells cannot be triggered to produce antibodies without an appropriate signal from T cells (helper T cells).31 All the evidence points to the idea that the entire repertoire of antigen-binding possibilities, including autoantigens, is displayed on the membranes of B cells in the form of surface immunoglobulins. Each clone of B cells expresses a unique antigen-binding structure on its membranes. B cells with receptors for autoantigens do not ordinarily secrete autoantibodies because they fail to receive an appropriate signal from helper T cells. However, if the need for helper T cells can be bypassed then the potential of autoreactive B cells is realized. Such a short circuit in the immunoregulatory system can be achieved experimentally by treatment with certain adjuvants32 and by graft vs host reactions.33 This kind of mechanism may explain the workings of experimentally induced autoimmune diseases like thyroiditis, encephalitis, and orchitis, all of which require administration of the relevant antigen together with an adjuvant. Conceivably, a short-circuit mechanism may be implicated in autoimmunity associated with infection or drug therapy. Why is there no “helper” signal for autoantigens in normal individuals? There is no rigorously proved answer to this question. However, indirect evidence
VOLUME NUMBER
Basis of autoimmunization
60 1
71
implicates a suppressor cell system, i.e., a subpopulation of cells that inhibits the functions of both helper T cells and I3 cells. In the case of immunologic tolerance of exogenous antigens, suppressor cells are, in many instances, the controlling element. We can see tantalizing evidence of how this applies to autoimmunization in the case of NZB mice. Three relevant findings have been made in these animals34: (1) the uniform development of autoimmune disease, (2) a relatively high incidence of malignant lymphomas, and (3) a profound impairment of suppressor T cell function. The latter may be only one sign of defective T cells in these mice, for as they age all their T cells; diminish in numbers and ultimately there is anergy. Thus, there is also a link with immunodeficiency. What causes this remarkable chain of events in the T cell system of NZB mice? Some claim that the thymus is the seat of the problem and propose the lack of a thymic hormone as the mechanism.35 Others suggest that it is all secondary to a virus-a type C xenotropic virus36-but recent evidence from genetic experiments demonstrated that virus production and expression of autoimmunity in NZB mice segregated as independent variables.3’ The possibility of a mixed disturbance of suppressor cells has not been excluded. Perhaps impaired function of some subsets of suppressor T cells could account for the production of autoantibodies, whereas overactivity of other subsets could account for the immunodeficiency. A precedent for the latter has already been established in certain types of immunodeficiency syndromes in human beings.“*
from somatic mutations? Studies of idiotypes have provided interesting clues. Idiotypes are individual antigenic specificities possessed by antibody molecules. An idiotype represents the structure of the antibody-combining site of the molecule and hence is located in the Fab region. Both the heavy and light chains contribute to the idiotype.“’ It is the idiotype that makes the molecule unique. The somatic mutation theory of antibody formation would be favored if different individuals never shared the same idiotype; the germ line theory would be supported if the same idiotypes were found in immunoglobulins from different individuals. In fact, both “private” and “public” (shared) idiotypes have been found in mice, rabbits, and humans.41 One of the most interesting examples of the latter is the presence of cross-reactive idiotypes on human cold agglutinins42 and rheumatoid factors. 43 Indeed, these autoantibodies seem heterogenous with regard to idiotypes: some are not shared, whereas others are, even if they are on different classes of immunoglobulin molecules.44 There is thus reason to believe: (I) the tine structure of autoantibodies resembles that of conventional antibodies and (2) some autoantibodies may be specified by genes that are encoded within germ line cells. Further analysis of the idiotypes of autoantibodies may be rewarding. If the encoding of structural genes for autoantibodies within the germ line proves to be a general attribute, we can then ask about the evolutionary pressure that maintained this apparent anomaly. What biologic function-if any-is hidden within this paradox?
AUTOIMMUNIZATION: NURTURE?
There are obvious reasons why physicians want to control immune responses. These range from the cure of atopic diseases to the arrest of malignant growth. Presently, the clinical management of immune disorders is almost entirely empirical. This is unsatisfactory because all too often what we think should work is used as the treatment of choice. In many instances, unfortunately, the should derives from an imperfect understanding (or ignorance) of the immune system. It is clear to many that the treatment of autoimmune diseases is often unsatisfactory. SLE and rheumatoid arthritis are examples. Despite advances in the serology of these diseases, we remain with relatively few therapeutic modalities. Perhaps immunosuppression is the wrong approach. In light of what we know now, will immunostimulation be a practical form of therapy? Throughout this brief review I have tried to point out how much the process of autoimmunization resembles that of normal immunization-or at least that an understanding of the one is linked to knowledge of the other. Therefore, one prospect facing us is that
NATURE OR
1 stated before that, in normal individuals, there are B cells with receptors for autoantigens. This suggests that the ability to make autoantibodies is programmed, i.e., genetically determined. Indeed, there is striking evidence that some autoimmune diseases have a genetic basis. We know this a priori in the case of NZB mice, a highly inbred strain. The same applies to spontaneous autoimmune thyroiditis in inbred chickens.3s The striking concordance of SLE in identical twins15 is another piece of evidence. This can be interpreted in several ways. Take, for example, the case of multiple sclerosis. On the one hand there is evidence of linkage to genes within the HLA system; on the other hand many suspect a viral etiology. The two findings are not necessarily incompatible: susceptibility to a virus may be specified by immune response genes linked to the HLA system.40 What about other autoantibodies? Is their structure encoded within germ line genes or do they result
IMPLICATIONS FOR THE FUTURE
72
Schwartz
J. ALLERGY
advances in autoimmune diseases will affect all of immunology. It should be clear that the reverse is also true: advances in basic immunology will influence our understanding of autoimmune diseases. Finally, the history of autoimmunization has an important lesson: do not tum down a new idea merely because it does not fit into a preconceived scheme. In short, never repeat the error embodied in the statement, “. . . I’11 never believe there is such a thing as an autoantibody.”
22.
23.
24.
25.
REFERENCES I. Witebsky,
E.: Closing remarks, Ann. N. Y. Acad. Sci.
124978, 196.5. 2. Kohler, H., Rowley, D. A., Duclos, T., et al.: Complementary idiotypy in the regulation of the immune response, Fed. Proc. 36:221, 1977. 3. Ehrlich, P., and Morgenroth, J.: Ueber haemolysene. Dritte mitthielung, Klin. Wochenschr. 37:453, 1900. 4. Metalnikoff, S.: Sur la spermatoxine et l’anti-spermatoxine, Ann. Inst. Pasteur 14:577, 1900. 5. Dameshek, W., and Schwartz, S. 0.: Acute hemolytic anemia (acquired hemolytic icterus, acute type), Medicine 19:23 I, 1940. 6. Billingham, R. E., Brent, L., and Medawar, P. B.: Actively acquired tolerance of foreign cells, Nature 172:603, 1953. 7. Bumet, F. M.: “The clonal selection theory of acquired immunity,” London, 1959, Cambridge University Press. 8. Bielschowsky, M., Helyer, B. J., and Howie, J. B.: Spontaneous hemolytic anemia in mice of NZB/BL strain, Proc. Univ. Otago Med. Sch. 379, 1959. 9. Moller, G.: Demonstration of mouse isoantigens at the cellular level by the fluorescent antibody technique, J. Exp. Med. 114:415, 1961. 10. Slater, R. J., Ward, S. M., and Kunkel, H. G.: Immunologic relationships among the myeloma proteins, J. Exp. Med. 101:85, 1955. 11. Gershon, R. K., and Kondo, K.: Infectious immunological tolerance, Immunology 21:903, 1971. 12. Jacobson, L. B.: Clinical and immunologic features of transient cold agglutinin hemolytic anemia, Am. J. Med. 54:5 14, 1973. 13. Doniach, D.: Autoimmunity in liver diseases, Prog. Clin. lmmunol. 1:45, 1972. 14. Alarcon-Segovia: Drug-induced lupus syndromes, Mayo Clin. Proc. 44~664, 1969. 15. Block, S. R., Winfield, J. B., Lockshin, M. D., et al.: Studies of twins with systemic lupus erythematosus, Am. J. Med. 59:533, 1975. 16. Cammarata, R. J., Rodnan, G. P., and Fennell, R. H.: Serum anti-gamma globulin and antinuclear factors in the aged, J. A. M. A. 199:455, 1967. 17. Schwartz, R. S.: Viruses and systemic lupus erythematosus, N. Engl. J. Med. 293:132, 1975. 18. Hillyer, G. V.: Deoxyribonucleic acid (DNA) and antibodies to DNA in the serum of hamsters and man infected with schistosomes, Proc. Sot. Exp. Biol. Med. 136:880, 1971. 19. Grabar, P.: “Self” and “not-self” in immunology, Lancet 1: 1320, 1974. 20. Evans, R. S., and Weiser, R. S.: The serology of autoimmune hemolytic disease. Observations on 41 patients, Arch. Int. Med. 100:371, 1957. 21. Budman, D. R., and Steinberg, A. D.: Hematologic aspects of
26.
CLIN. IMMUNOL. JULY 1977
systemic lupus erythematosus, Ann. Intern. Med. 86:220, 1977. Schwartz, R. S., and Co&a, N.: Autoimmune hemolytic anemia: Clinical correlations and biological implications, Semin. Hematol. 3:2, 1966. Irvine, W. J., and Barnes, E. W.: Addison’s disease, ovarian failure and hypoparathyroidism, Clin. Endocrinol. Metab. 4:379, 1975. Solomon, D. H., Chopra, I. J., Chopra, U., et al.: Identification of subgroups of euthyroid Graves’ ophthalmopathy, N. Engl. J. Med. 2%:181, 1977. Cummings, N. A., Scholl, G. L., Asofsky, R., et al.: Sjiigren’s syndrome-newer aspects of research, diagnosis and therapy, Ann. Intern. Med. 75937, 1971.
Hong, R.: Immunodeficiency:Enigmasand speculations,
Prog. Clin. Immunol. 2:1, 1974. 27. Schwartz, R. S.: Immunoregulation by antibody, in Progress in immunology,New York, 1971, AcademicPress,Inc.,
p. 1081. 28. Roberts, I. M., Whittingham, S., and Mackay, I. R.: Tolerance to an autoantigen-thyroglobulin, Lancet 2:936, 1973. 29. Bankhurst,A. D., Torrigiani, G., andAllison, A. C.: Lymphocytes binding human thyroglobulin in healthy people and its relevance to tolerance for autoantigens, Lancet 1:226, 1973. 30. Nachtegal, D., Zan-Bar, I., and Feldman, M.: The role of specific suppressor T cells in immune tolerance, Transplant. Rev. 26:87, 1975. 31. Bretscher, P. A.: The two signal model for B cell induction, Transplant. Rev. 23:37, 1975. 32. Cunningham, A. J.: Self-tolerance maintained by active suppressor mechanisms, Transplant. Rev. 31:23, 1976. 33 Gleichmann, E., Gleichmann, H., and Welke, W.: Autoimmunization and lymphomagenesis in parent + F, combinations differing at the major histocompatibility complex: Model for spontaneous disease caused by altered self-antigens?
Transplant.Rev. 31:156,1976. 34 Talal, N.: Autoimmunity and lymphoid malignancy in New Zealand Black mice, Progr. Clin. Immunol. 2101, 1974. 35 Bach, J. F., Dardenne, M., and Salomon, J. C.: Absence of serum thymic activity in adult NZB and (NZB X NZW)F, mice, Clin. Exp. Immunol. 14:247, 1973. 36 Levy, J. A.: Endogenous C-type viruses: Double agents in natural life processes, Biomedicine 24:84, 1976. 37 Datta, S. K., and Schwartz, R. S.: Autoimmunization and graft versus host reactions, Transplant. Rev. 31:44, 1976. 38 Waldmann, T., and Broder, S.: Suppressor cells, Prog. Clin.
Immunol.3:155, 1977. 39. Rose, N. R., Bacon, L. D., and Sundick, R. S.: Genetic determinants of thyroiditis in the OS chicken, Transplant. Rev. 31:264, 1976. 40. Bach, F. H., and van Rood, J. J.: The major histocompatibility complex-genetics and biology, N. Engl. J. Med. 295:927, 1976. 41. Capra, J. D.: Towards a chemical definition of idotypy, Fed. Proc. 36:204, 1977. 42. Williams, R. C., Kunkel, H. G., and Capra, J. D.: Antigenic specificities related to the cold agglutinin activity of gamma M globulins, Science 161:379, 1968. 43. Kunkel, H. G., Agnello, V., Joslin, F. G., et al.: Crossidiotypic specificity among monoclonal IgM proteins with anti-y-globulin activity, J. Exp. Med. 137:3ll, 1973. 44. Sogn, J. A., Coligan, J. E., and Kindt, T. J.: The use of idiotypes as markers for antibody variable regions in the rabbit, Fed. Proc. 36:214, 1977.
manuscripts
The immunologic autoimmunization
basis of
Robert S. Schwartz, M.D. Boston, Mass.
Autoimmunization is today so readily accepted as established fact that it is easy to forget its turbulent history. There was a time when a few stubborn physicians had to insist against informed opinion that autoimmune diseases really existed. The answer they received was, “. I’ll never believe there is such a thing as an autoantibody.“’ Now the tables are turned. Today immunochemists are presenting schemes that require the formation of autoantibodies during the normal immune response.” Between these two extremes there is an evolution of thought that
AUTOlMMUNlZATlON DISEASE
VS AUTOIMMUNE
Autoimmunization is the production of antibodies against autoantigens; the autoantibodies so formed may or may not be pathogenetic. In an autoimmune disease the lesions are caused by pathogenetic autoantibodies. For instance, cold agglutinins reactive with autologous red cells are usually formed in the wake of infection by Mycoplasma pneumoniae, but hemolytic anemia is a relatively rare complication.” Thus, the presence of an autoantibody does not necessarily imply the existence of a relevant lesion. Other examples are: (1) Antibodies against nuclear antigens, smooth muscle, and mitochondria in the sera of patients with chronic liver disease.lR (2) Anti-
From the Hematology Service, New England Medical Center Hospital, and Department of Medicine, Tufts University School of Medicine. Supported by United States Public Health Service Grant No. 07937. Presented at the Postgraduate Course of the American Congress of Allergy and Immunology, New York, N. Y., March, 1977.
nuclear and anti-DNA antibodies without signs of systemic lupus erythematosus (SLE) associated with treatment by certain drugs.14 (3) Production of autoantibodies by clinically healthy relatives of patients with SLE.15 (4) Presence of autoantibodies (e.g., rheumatoid factor, antinuclear antibodies) in healthy, elderly persons. Ifi What can we make of such “orphan” autoantibodies? There are several possibilities. Perhaps they are markers of a genetic susceptibility to autoimmune disease. Family studies in SLE15 tend to support this. They may be triggered by certain infectious agents; the example of Mycoplasma pneumoniae was already cited. In experimental animals, several kinds of retroviruses” and even Schistosoma infectionlx can result in the formation of antinuclear antibodies. Drugs like alpha-methyldopa and procainamide are wellestablished promoters of autoantibody production. l4 Finally, some autoantibodies may have a physiologic function, perhaps to remove by-products of dead cells.ls None of these explanations gives us an insight; they merely warn that autoimmunization may not be a sufficient reason to diagnose autoimmune disease. Vol. 60, No. 1, pp. 69-72
70
Schwartz
J. ALLERGY
ANTIGEN
CLIN. IMMUNOL. JULY 1977
immune hemolytic anemia and immune thrombocytopenia, pernicious anemia, and Hashimoto’s disease are examples. (3) The associations between certain autoimmune diseases and either malignant lymphoproliferative diseases or immunodeficiency seem more than coincidental. They imply a fundamental disturbance of immunoregulation.
IMMUNOREGULATION
\fI(+ t
ANTIGEN FIG. 1. Immunoregulation. MO, macrophage; T,+, helper T cell; TsI suppressor T ceil; B, B cell. Feedward on the right, feedback on the left. lmmunoregulation by antibody is indicated at the bottom of the diagram.
LINKED AUTOIMMUNE DISEASE Autoimmune hemolytic anemia (AIHA) is, in reality, a syndrome. It may develop as an idiopathic, independent entity or arise in association with any of the following: drug therapy, infection, another autoimmune disease, or a malignancy. AIHA associated with immune thrombocytopenia (Evans’ syndrome)20 is well recognized, as is AIHA during the course of SLE.21 The association between AIHA and malignancies of lymphoid tissue-chronic lymphocytic leukemia, for example-is remarkable.22 Overlap, either clinical, serologic, or both, is a compelling feature of many autoimmune diseases. Indeed, even those disorders thought to be “organspecific” may show considerable linkage as, for example, in autoimmune polyendocrine deficiencies.23 The extraordinary overlapping relationships among Hashimoto’s disease, Graves’ disease, and euthyroid Graves’ ophthalmopathy24 are more recent examples. Sjiigren’s syndrome, with its numerous serologic abnormalities and its tendency toward malignant degeneration,25 is even more striking. Notably, the linkage also extends to the apparent paradox of autoimmune disease associated with immunodeficiency. 26 We may draw three conclusions from this: (1) Every autoimmune disease, no matter how “organspecific, ’ ’ can potentially or actually does involve multiple autoantibodies and autoantigens. (2) Autoimmune diseases tend to form chsters of related disorders: polyendocrinopathies, simultaneous Hashimoto’s disease and Graves’ disease, sequential auto-
This term was coined to convey the idea that the feedforward aspects of the immune response are precisely balanced by feedback mechanisms.27 There is a growing appreciation that there are two immune systems, one being the mirror image of the other. The feedforward system begins with antigen and culminates in antibody (or cytotoxic lymphocytes). The feedback system can enter the scheme at either end: by contact with antigen or antibody (Fig. 1). Furthermore, feedback may be either antigen-specific or distribute its effects among several or even numerous specificities (nonspeci$c feedback is probably more in the eye of the beholder than in Nature). The concept of immunoregulation was made central to our understanding of autoimmunization by two discoveries: (1) the existence in normal individuals of B cells with receptors for autoantigenP, 2gand (2) the role of suppressor cells in the maintenance of immunologic tolerance. 3o An equally important fact is that in immune responses to a great variety of antigens, B cells cannot be triggered to produce antibodies without an appropriate signal from T cells (helper T cells).31 All the evidence points to the idea that the entire repertoire of antigen-binding possibilities, including autoantigens, is displayed on the membranes of B cells in the form of surface immunoglobulins. Each clone of B cells expresses a unique antigen-binding structure on its membranes. B cells with receptors for autoantigens do not ordinarily secrete autoantibodies because they fail to receive an appropriate signal from helper T cells. However, if the need for helper T cells can be bypassed then the potential of autoreactive B cells is realized. Such a short circuit in the immunoregulatory system can be achieved experimentally by treatment with certain adjuvants32 and by graft vs host reactions.33 This kind of mechanism may explain the workings of experimentally induced autoimmune diseases like thyroiditis, encephalitis, and orchitis, all of which require administration of the relevant antigen together with an adjuvant. Conceivably, a short-circuit mechanism may be implicated in autoimmunity associated with infection or drug therapy. Why is there no “helper” signal for autoantigens in normal individuals? There is no rigorously proved answer to this question. However, indirect evidence
VOLUME NUMBER
Basis of autoimmunization
60 1
71
implicates a suppressor cell system, i.e., a subpopulation of cells that inhibits the functions of both helper T cells and I3 cells. In the case of immunologic tolerance of exogenous antigens, suppressor cells are, in many instances, the controlling element. We can see tantalizing evidence of how this applies to autoimmunization in the case of NZB mice. Three relevant findings have been made in these animals34: (1) the uniform development of autoimmune disease, (2) a relatively high incidence of malignant lymphomas, and (3) a profound impairment of suppressor T cell function. The latter may be only one sign of defective T cells in these mice, for as they age all their T cells; diminish in numbers and ultimately there is anergy. Thus, there is also a link with immunodeficiency. What causes this remarkable chain of events in the T cell system of NZB mice? Some claim that the thymus is the seat of the problem and propose the lack of a thymic hormone as the mechanism.35 Others suggest that it is all secondary to a virus-a type C xenotropic virus36-but recent evidence from genetic experiments demonstrated that virus production and expression of autoimmunity in NZB mice segregated as independent variables.3’ The possibility of a mixed disturbance of suppressor cells has not been excluded. Perhaps impaired function of some subsets of suppressor T cells could account for the production of autoantibodies, whereas overactivity of other subsets could account for the immunodeficiency. A precedent for the latter has already been established in certain types of immunodeficiency syndromes in human beings.“*
from somatic mutations? Studies of idiotypes have provided interesting clues. Idiotypes are individual antigenic specificities possessed by antibody molecules. An idiotype represents the structure of the antibody-combining site of the molecule and hence is located in the Fab region. Both the heavy and light chains contribute to the idiotype.“’ It is the idiotype that makes the molecule unique. The somatic mutation theory of antibody formation would be favored if different individuals never shared the same idiotype; the germ line theory would be supported if the same idiotypes were found in immunoglobulins from different individuals. In fact, both “private” and “public” (shared) idiotypes have been found in mice, rabbits, and humans.41 One of the most interesting examples of the latter is the presence of cross-reactive idiotypes on human cold agglutinins42 and rheumatoid factors. 43 Indeed, these autoantibodies seem heterogenous with regard to idiotypes: some are not shared, whereas others are, even if they are on different classes of immunoglobulin molecules.44 There is thus reason to believe: (I) the tine structure of autoantibodies resembles that of conventional antibodies and (2) some autoantibodies may be specified by genes that are encoded within germ line cells. Further analysis of the idiotypes of autoantibodies may be rewarding. If the encoding of structural genes for autoantibodies within the germ line proves to be a general attribute, we can then ask about the evolutionary pressure that maintained this apparent anomaly. What biologic function-if any-is hidden within this paradox?
AUTOIMMUNIZATION: NURTURE?
There are obvious reasons why physicians want to control immune responses. These range from the cure of atopic diseases to the arrest of malignant growth. Presently, the clinical management of immune disorders is almost entirely empirical. This is unsatisfactory because all too often what we think should work is used as the treatment of choice. In many instances, unfortunately, the should derives from an imperfect understanding (or ignorance) of the immune system. It is clear to many that the treatment of autoimmune diseases is often unsatisfactory. SLE and rheumatoid arthritis are examples. Despite advances in the serology of these diseases, we remain with relatively few therapeutic modalities. Perhaps immunosuppression is the wrong approach. In light of what we know now, will immunostimulation be a practical form of therapy? Throughout this brief review I have tried to point out how much the process of autoimmunization resembles that of normal immunization-or at least that an understanding of the one is linked to knowledge of the other. Therefore, one prospect facing us is that
NATURE OR
1 stated before that, in normal individuals, there are B cells with receptors for autoantigens. This suggests that the ability to make autoantibodies is programmed, i.e., genetically determined. Indeed, there is striking evidence that some autoimmune diseases have a genetic basis. We know this a priori in the case of NZB mice, a highly inbred strain. The same applies to spontaneous autoimmune thyroiditis in inbred chickens.3s The striking concordance of SLE in identical twins15 is another piece of evidence. This can be interpreted in several ways. Take, for example, the case of multiple sclerosis. On the one hand there is evidence of linkage to genes within the HLA system; on the other hand many suspect a viral etiology. The two findings are not necessarily incompatible: susceptibility to a virus may be specified by immune response genes linked to the HLA system.40 What about other autoantibodies? Is their structure encoded within germ line genes or do they result
IMPLICATIONS FOR THE FUTURE
72
Schwartz
J. ALLERGY
advances in autoimmune diseases will affect all of immunology. It should be clear that the reverse is also true: advances in basic immunology will influence our understanding of autoimmune diseases. Finally, the history of autoimmunization has an important lesson: do not tum down a new idea merely because it does not fit into a preconceived scheme. In short, never repeat the error embodied in the statement, “. . . I’11 never believe there is such a thing as an autoantibody.”
22.
23.
24.
25.
REFERENCES I. Witebsky,
E.: Closing remarks, Ann. N. Y. Acad. Sci.
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