- Email: [email protected]
Systemic lupus erythematosus—Disease of an unusual immunologic responsiveness?
The American Journal VOL.
OCTOBER,
XXVII
of Medicine
1959
No. 4
Editorial Systemic
Lupus
an Unusual
Erythematosus-Disease
Immunologic
suggestion has often been made that a form of anaphylactic hypersensitivity is involved in the pathogenesis of systemic lupus erythematosus (SLE). This suggestion arose primarily from certain similarities between the symptoms and pathologic lesions of SLE and serum sickness, and from the experiments of Rich in which vascular lesions were induced by experimental anaphylactic reactions. However, supporting evidence derived from study of the immune reactions of the patients has been lacking. Recently it has been possible to characterize many abnormal serologic reactions which occur in this disease. Evidence suggesting the existence of an autoimmunity has been obtained. The results strengthen the view that an abnormal immunological response is present in SLE, but indicate that the abnormality may be a type which has not been previously recognized. The number of autologous tissue components to which circulating antibodies can be found in SLE is striking. y-globulins which react with the red blood cells occur frequently [7]. Leucagglutinins arise in patients with SLE without prior transfusions [2]. Platelet agglutinins may play a role in the occasional thrombocytopenic purpura [3]. A y-globulin circulates which has an antithromboplastic activity [4], and another is commonly present which gives rise to a false positive Wassermann reaction [ 71. Seemingly large amounts of y-globulin are present in the renal lesions [5j and in the fibrotic lesions of the spleen [6].
T
of
Responsiveness?
The discovery of the L.E. cell by Hargraves has led to identification of a group of serum factors which react with different constituents of the cell nucleus [7], The L.E. cell appears to result from the interaction of one such factor with nuclear nucleoprotein, for which both DNA and histone are essential. Separate factors are present which react with pure DNA, isolated histone, and with an unidentified substance extractable from the nucleus with isotonic buffers [8]. One or more y-globulins may arise which react with cytoplasmic constituents [9]. The antinuclear factors are noteworthy because of the known poor experimental antigenicity of nucleic acids and histone. The evidence that these reactions are immunological is reasonably good in all cases and very good in a few. All the serum factors are y-globulins. Most of the reactions have been shown either by identification of the r-globulin on the affected cell or tissue, or by such immunological technics as complement fixation, precipitation, hemagglutination or passive cutaneous anaphylaxis. The L.E. cell factor and the factor which precipitates with DNA have been recovered in purified form from combinations with nucleoprotein and DNA, respectively. They possess the physical and immunological characteristics of typical human antibody y-globulin. The capacity of these factors to react with the patient’s own cell materials suggests that they are autoantibodies. Evidence for hyper-reactivity to foreign antigens in SLE has also appeared. Patients with
HE
525
Editorial SLE have been found to be among the most prolific producers of antibodies to rare blood group substances [l&77]. They have been reported to produce demonstrable antibodies to antibiotics more frequently than most other patients [ 721. However, hyper-reactivity to foreign antigens remains to be established by quantitative, comparative studies with standardized antigens. There is thus considerable evidence that unusual antibodies, including autoantibodies, arise in SLE. The circumstances leading to their appearance are obscure. A spontaneous alteration in the patient’s cells rendering them autoantigenic would seem unlikely because it would require nearly simultaneous changes in the constituents of many different types of cells. An infectious agent might induce such alterations, for instance in a manner analogous to the alteration of bacterial cell composition and antigenicity by bacteriophage [ 731. However, neither altered cell constituents nor infectious agents have been identified in SLE. The ready reactivity of the serum factors with cell components from normal human and animal tissues argues against a primary change in cell antigenicity, but is not conclusive because antibodies to abnormal cells can cross react with normal cells. Thus the hypothesis that an altered cell antigenicity exists in SLE has not been excluded, but supporting evidence has not yet appeared. On the other hand, the multiplicity of cell components to which antibodies are formed, the varying patterns appearing in different serums, and the probable hyper-reactivity to foreign antigens suggest that an unusually productive antibody synthesizing system is present. In this instance, an abnormal immune system would be reacting against normal cell constituents. What is the role of the serum factors in the pathogenesis of the disease? Certainly in some instances, they may be responsible for a hemolytic anemia or a thrombocytopenic purpura. However, some of the factors are present more often than is a corresponding clinical syndrome, and these syndromes themselves are not essential features of the disease. Considerable .evidence is accumulating that the ‘antinuclear, ‘antibodies, which are capable of reacting with the nucleus of most cells, cannot gain access to the nucleus of a normal cell. Thus it appears that the mere presence of these factors is not usually sufficient
to induce tissue lesions. Furthermore, the disease can occur without any of the known serum factors being demonstrable, indicating that they are not essential in pathogenesis. It remains possible that the serum factors require some preliminary tissue injury before they can alter cells in vivo. Antigen-antibody complexes involving one or more serum factors may arise during the normal disintegration of cells and they may be injurious. It may be that current technics are inadequate to demonstrate these or other ways in which the factors are pathogenic. However, the evidence to date supports the view that the factors are by-products of a deranged immune system rather than decisively important pathogenic agents. The possibility therefore arises that the deranged system is responsible for the disease in some other way. This implies existence of an immunologic aberration which can induce autologous tissue injury and also give rise to a variety of autoantibodies. Currently recognized types of hypersensitivity have not yet been shown to possess this capacity. Thus understanding of the abnormality is likely to require a search for new types of immunologic reactions. In recent years there have been important additions to the group of biological reactions which appear to have an immunological basis. Any one of these might conceivably provide the clue to an understanding of the abnormality in SLE. Immunologic tolerance has been discovered [74]. In this phenomenon, exposure of a fetus to an antigen will prevent that individual, upon reaching adulthood, from reacting to that antigen. By inference, normal people may not form autoantibodies because they are “exposed” to their own cells in utero, and thus become tolerant. After establishment of a state of tolerance, or after paralysis of the immune response by radiation, it has been possible to populate one animal with functional bone marrow or spleen cells of another of the same or different species. A characteristic disease often results which is apparently the result of an immune reaction of the graft against the host [ 751. Thus, at least under these unusual circumstances, one type of viable cells within an individual can react immunologically against another type, with deleterious consequences. Less clearly immunological but potentially quite significant are the observations of biologists AMERICAN
JOURNAL
OF
MEDICINE
Editorial on the capacity of cells to recognize and react with one another [ 761. Isolated cells in suspension can recombine to form tissues similar to those of their origin, In doing so, they will avoid or reject cells of unlike origin. Mixtures of cells will segregate themselves according to tissues or origin. The mechanism of this behavior remains obscure; for example, it is not known whether materials secreted by the cells contribute to their compatibility or incompatibility. It is conceivable that these reactions between cells are a more general expression of the function of antibody production which is a specialized activity of the lymphatic system. Exploration of the tissues and immune systems of patients with SLE for aberrations in reactions such as these may prove fruitful. Abnormalities in the behavior of one cell or tissue toward another in cell suspensions may be demonstrable. Abnormal tolerance mechanisms may be found, in which the patient loses “tolerance” of his own cells. Perhaps cells with different somatic or genetic composition exist in the patients and react against other cells or cell products with which they normally would be compatible. This latter idea is made less unreasonable by two recent findings. Thefirstis theobservation that within certain inbred strainsof mice, homografting of skin is possible in all combinations except from male to female [17]. This suggests that tissue incompatibilities can exist which bear some relationship to the chromosome composition of the cells. The second is the demonstration of chromosome differences in certain human diseases [18], and the probable identification of the first human genetic mosaic [ 791. ,4n excellent example of the application of some of these concepts to a supposedly autoimmune disease has been provided by Paterson [ZO]. He has succeeded in transferring experimental allergic encephalomyelitis from one rat to another by means of washed lymph node cells. To accomplish this, it was necessary to make the recipient rat tolerant of the donor cells by neonatal injection of spleen cells from the prospective donor. The donor cells when administered later, after the recipient had matured, could then survive long enough to induce the disease. This induction of the disease presumably has an immunological basis but the precise mechanism remains to, be clarified. One significant aspect of this work is the lead it provides toward achievement of an experiOC’roBER,
1959
527
mental model of SLE and related diseases. A way may be found to transfer an abnormal immunologic response from man to a tolerant animal. This latter development would be facilitated if a delayed or cellular hypersensitivity to autologous tissue existed in SLE. While no clear evidence for such a phenomenon some suggestive data are achas appeared, cumulating. Intradermal injection of autologous leukocyte homogenates into patients with SLE has led to a skin reaction consisting of erythema, induration and inflammatory cell infiltration beginning at about ten hours and lasting until thirty-six hours [21]. The reaction is independent of disease activity and also of the presence of serum antibodies capable of reacting with cell constituents. Similar reactions have not occurred to any extent in normal subjects, but considerable work remains to be carried out before this reaction can be adjudged an autoimmune reaction of a delayed type. Another useful approach may lie in exploration of the relations between rheumatoid arthritis and SLE, and the genetic backgrounds of patients with these illnesses. The clinical similarities of the two, despite obvious differences, has long been recognized. However, the hallmark of rheumatoid arthritis has been the rheumatoid factor which is a y-globulin of high molecular weight, and probably is a peculiar type of antibody. The hallmark of SLE has been the L.E. cell and what now appears to be a group of antinuclear antibodies. The coexistence of these two types of unusual y-globulins in the same person is known. It now appears that relatives, often asymptomatic, of patients with classic SLE may have the rheumatoid factor in their serum [ZZ]. This suggests a familial predisposition to an abnormal immune response which in some instances may manifest itself as rheumatoid arthritis, sometimes as SLE, and sometimes as serologic reactions without clinical symptoms. These suggestions are highly speculative, and may hold little merit in themselves. However, although classic immunologic technics have provided strong evidence for an abnormality of the immunologic response in SLE, considerable doubt remains about the importance of the specific reactions identified in the initiation of the disease. If these reactions are now studied in the context of newer knowledge of immunologic responses and of the reactions of cells
Editorial and tissues to one another, hitherto unappreciated immunologic phenomena may be uncovered which lie closer to the roots of this disease. HALSTED
R.
HOLMAN,
M.D.
9.
10.
The Rockefeller Institute, New York, New York REFERENCES
11.
1. HARVEY, A., SHULMAN,L., TUMULTY, P., CONLEY, C.
2.
3.
4.
5.
6.
7.
8.
and SCHOENRICH, E. Systemic lupus erythematosus. Medicine, 33: 291, 1954. VAN LOGHAM, J., VAN DER HART, M. and BRISTEL, H. The occurrence of complete and incomplete white cell antibodies. VOX Sang&is, 2: 257, 1957 (New series). DAUSSET, J. Normal and pathological platelet agglutinins investigated by means of the shaking method. VOX Sanguinis, 4: 204, 1954. LEE, S. and SANDERS,M. A disorder of blood coagulation in systemic lupus erythematosus. J. Clin. Invest., 34: 1814, 1955. MELLORS, R. C., ORTEGA, L. G. and HOLMAN,H. R. Role of gamma globulin in pathogen& of renal lesions in systemic lupus erythematosus and chronic membranous glomerulonephritis, with an observation on the lupus erythematosus cell reaction. J. Exper. Med., 106: 191, 1957. VAZQUEZ, J. J. and DIXON, F. J. Immunohistochemical study of lesions in rheumatic fever, systemic lupus erythematosus, and rheumatoid arthritis. Lab. Invest., 6: 205, 1957. HOLMAN, H., DEICHER, H. and ROBBINS, W. Antinuclear “antibodies” in lupus erythematosus. In: Mechanisms of hypersensitivity (Proceedings of the Henry Ford Symposium, 1958) Boston, 1959. Little, Brown and Co. HOLMAN, H., DEICHER, H. and KUNKEL, H. The
12.
13.
14. 15.
16.
17.
18.
19.
L.E. cell and the L.E. serum factors. Bull. N. Y. Acad. Med., 35: 409, 1959. GAJDUSEK, D. An “autoimmune” reaction against human tissue antigens in certain acute and chronic diseases. Arch. Znt. Med., 101: 9, 1958. CALLENDER, S. and RACE, R. A serological and genetical study of multiple antibodies formed in response to blood transfusion by a patient with lupus erythematosus diffusus. Ann. Eugenics, 13: 102, 1946. WALLER, R. and RACE, R. Six blood group antibodies in the serum of a transfused patient. Brit. Med. J., 1: 225, 1951. MUELLING, R., BEVEN, T., SAMSON,R., JENEVEIN, E. and GUILLORY, J. Studies in human sensitivity to antibiotics, Am. J. Clin. Path., 29: 503, 1958. UETAKE, H., WAKAGAWA, T. and AKEBA, T. Relationship of bacteriophage to antigenic changes in group E salmonellas. J. Bacterial., 69: 571, 1955. &DEWAR, P. B. In: A discussion on immunological tolerance. Prod. Roy. Sot. B., 146: 1, 1956. BARNES, D. and LOUTIT, I. Immunological status and longevity of radiation chimeras, Proc. Roy. Sot. B., 150: 131, 1959. MOSCONA, A. Tissues from dissociated cells. Scientific American, 200: 132, 1959. BILLINGHAM, R. and SILVERS, W. Induction of tolerance of skin isografts from male donors in female mice. Science, 128: 780, 1958. FORD, C., JONES, K., MILLER, O., MITTWOCH, V., PENROSE, L., RIDLER, M. and SHAPIRO, A. The chromosomes in a patient showing both Mongolism and Klinefelter syndrome. Lancet, 1: 709, 1959. FORD, C., POLANI, P., BRIGGS, J. and BISHOP, P. A presumptive human xxy/xx mosaic, Nature, 183:
1031, 1959. 20. PATERSON, P. Transfer
of allergic encephalomyelitis in rats by means of immune lymph cells. Fed. Proc., 18: 591, 1959. 21. HOLMAN, H. and DEICHER, H. Data to be published. 22. HOLMAN, H. and KUNKEL, H. Data to be published.
AMERICAN
JOURNAL
OF
MEDICINE
OCTOBER,
XXVII
of Medicine
1959
No. 4
Editorial Systemic
Lupus
an Unusual
Erythematosus-Disease
Immunologic
suggestion has often been made that a form of anaphylactic hypersensitivity is involved in the pathogenesis of systemic lupus erythematosus (SLE). This suggestion arose primarily from certain similarities between the symptoms and pathologic lesions of SLE and serum sickness, and from the experiments of Rich in which vascular lesions were induced by experimental anaphylactic reactions. However, supporting evidence derived from study of the immune reactions of the patients has been lacking. Recently it has been possible to characterize many abnormal serologic reactions which occur in this disease. Evidence suggesting the existence of an autoimmunity has been obtained. The results strengthen the view that an abnormal immunological response is present in SLE, but indicate that the abnormality may be a type which has not been previously recognized. The number of autologous tissue components to which circulating antibodies can be found in SLE is striking. y-globulins which react with the red blood cells occur frequently [7]. Leucagglutinins arise in patients with SLE without prior transfusions [2]. Platelet agglutinins may play a role in the occasional thrombocytopenic purpura [3]. A y-globulin circulates which has an antithromboplastic activity [4], and another is commonly present which gives rise to a false positive Wassermann reaction [ 71. Seemingly large amounts of y-globulin are present in the renal lesions [5j and in the fibrotic lesions of the spleen [6].
T
of
Responsiveness?
The discovery of the L.E. cell by Hargraves has led to identification of a group of serum factors which react with different constituents of the cell nucleus [7], The L.E. cell appears to result from the interaction of one such factor with nuclear nucleoprotein, for which both DNA and histone are essential. Separate factors are present which react with pure DNA, isolated histone, and with an unidentified substance extractable from the nucleus with isotonic buffers [8]. One or more y-globulins may arise which react with cytoplasmic constituents [9]. The antinuclear factors are noteworthy because of the known poor experimental antigenicity of nucleic acids and histone. The evidence that these reactions are immunological is reasonably good in all cases and very good in a few. All the serum factors are y-globulins. Most of the reactions have been shown either by identification of the r-globulin on the affected cell or tissue, or by such immunological technics as complement fixation, precipitation, hemagglutination or passive cutaneous anaphylaxis. The L.E. cell factor and the factor which precipitates with DNA have been recovered in purified form from combinations with nucleoprotein and DNA, respectively. They possess the physical and immunological characteristics of typical human antibody y-globulin. The capacity of these factors to react with the patient’s own cell materials suggests that they are autoantibodies. Evidence for hyper-reactivity to foreign antigens in SLE has also appeared. Patients with
HE
525
Editorial SLE have been found to be among the most prolific producers of antibodies to rare blood group substances [l&77]. They have been reported to produce demonstrable antibodies to antibiotics more frequently than most other patients [ 721. However, hyper-reactivity to foreign antigens remains to be established by quantitative, comparative studies with standardized antigens. There is thus considerable evidence that unusual antibodies, including autoantibodies, arise in SLE. The circumstances leading to their appearance are obscure. A spontaneous alteration in the patient’s cells rendering them autoantigenic would seem unlikely because it would require nearly simultaneous changes in the constituents of many different types of cells. An infectious agent might induce such alterations, for instance in a manner analogous to the alteration of bacterial cell composition and antigenicity by bacteriophage [ 731. However, neither altered cell constituents nor infectious agents have been identified in SLE. The ready reactivity of the serum factors with cell components from normal human and animal tissues argues against a primary change in cell antigenicity, but is not conclusive because antibodies to abnormal cells can cross react with normal cells. Thus the hypothesis that an altered cell antigenicity exists in SLE has not been excluded, but supporting evidence has not yet appeared. On the other hand, the multiplicity of cell components to which antibodies are formed, the varying patterns appearing in different serums, and the probable hyper-reactivity to foreign antigens suggest that an unusually productive antibody synthesizing system is present. In this instance, an abnormal immune system would be reacting against normal cell constituents. What is the role of the serum factors in the pathogenesis of the disease? Certainly in some instances, they may be responsible for a hemolytic anemia or a thrombocytopenic purpura. However, some of the factors are present more often than is a corresponding clinical syndrome, and these syndromes themselves are not essential features of the disease. Considerable .evidence is accumulating that the ‘antinuclear, ‘antibodies, which are capable of reacting with the nucleus of most cells, cannot gain access to the nucleus of a normal cell. Thus it appears that the mere presence of these factors is not usually sufficient
to induce tissue lesions. Furthermore, the disease can occur without any of the known serum factors being demonstrable, indicating that they are not essential in pathogenesis. It remains possible that the serum factors require some preliminary tissue injury before they can alter cells in vivo. Antigen-antibody complexes involving one or more serum factors may arise during the normal disintegration of cells and they may be injurious. It may be that current technics are inadequate to demonstrate these or other ways in which the factors are pathogenic. However, the evidence to date supports the view that the factors are by-products of a deranged immune system rather than decisively important pathogenic agents. The possibility therefore arises that the deranged system is responsible for the disease in some other way. This implies existence of an immunologic aberration which can induce autologous tissue injury and also give rise to a variety of autoantibodies. Currently recognized types of hypersensitivity have not yet been shown to possess this capacity. Thus understanding of the abnormality is likely to require a search for new types of immunologic reactions. In recent years there have been important additions to the group of biological reactions which appear to have an immunological basis. Any one of these might conceivably provide the clue to an understanding of the abnormality in SLE. Immunologic tolerance has been discovered [74]. In this phenomenon, exposure of a fetus to an antigen will prevent that individual, upon reaching adulthood, from reacting to that antigen. By inference, normal people may not form autoantibodies because they are “exposed” to their own cells in utero, and thus become tolerant. After establishment of a state of tolerance, or after paralysis of the immune response by radiation, it has been possible to populate one animal with functional bone marrow or spleen cells of another of the same or different species. A characteristic disease often results which is apparently the result of an immune reaction of the graft against the host [ 751. Thus, at least under these unusual circumstances, one type of viable cells within an individual can react immunologically against another type, with deleterious consequences. Less clearly immunological but potentially quite significant are the observations of biologists AMERICAN
JOURNAL
OF
MEDICINE
Editorial on the capacity of cells to recognize and react with one another [ 761. Isolated cells in suspension can recombine to form tissues similar to those of their origin, In doing so, they will avoid or reject cells of unlike origin. Mixtures of cells will segregate themselves according to tissues or origin. The mechanism of this behavior remains obscure; for example, it is not known whether materials secreted by the cells contribute to their compatibility or incompatibility. It is conceivable that these reactions between cells are a more general expression of the function of antibody production which is a specialized activity of the lymphatic system. Exploration of the tissues and immune systems of patients with SLE for aberrations in reactions such as these may prove fruitful. Abnormalities in the behavior of one cell or tissue toward another in cell suspensions may be demonstrable. Abnormal tolerance mechanisms may be found, in which the patient loses “tolerance” of his own cells. Perhaps cells with different somatic or genetic composition exist in the patients and react against other cells or cell products with which they normally would be compatible. This latter idea is made less unreasonable by two recent findings. Thefirstis theobservation that within certain inbred strainsof mice, homografting of skin is possible in all combinations except from male to female [17]. This suggests that tissue incompatibilities can exist which bear some relationship to the chromosome composition of the cells. The second is the demonstration of chromosome differences in certain human diseases [18], and the probable identification of the first human genetic mosaic [ 791. ,4n excellent example of the application of some of these concepts to a supposedly autoimmune disease has been provided by Paterson [ZO]. He has succeeded in transferring experimental allergic encephalomyelitis from one rat to another by means of washed lymph node cells. To accomplish this, it was necessary to make the recipient rat tolerant of the donor cells by neonatal injection of spleen cells from the prospective donor. The donor cells when administered later, after the recipient had matured, could then survive long enough to induce the disease. This induction of the disease presumably has an immunological basis but the precise mechanism remains to, be clarified. One significant aspect of this work is the lead it provides toward achievement of an experiOC’roBER,
1959
527
mental model of SLE and related diseases. A way may be found to transfer an abnormal immunologic response from man to a tolerant animal. This latter development would be facilitated if a delayed or cellular hypersensitivity to autologous tissue existed in SLE. While no clear evidence for such a phenomenon some suggestive data are achas appeared, cumulating. Intradermal injection of autologous leukocyte homogenates into patients with SLE has led to a skin reaction consisting of erythema, induration and inflammatory cell infiltration beginning at about ten hours and lasting until thirty-six hours [21]. The reaction is independent of disease activity and also of the presence of serum antibodies capable of reacting with cell constituents. Similar reactions have not occurred to any extent in normal subjects, but considerable work remains to be carried out before this reaction can be adjudged an autoimmune reaction of a delayed type. Another useful approach may lie in exploration of the relations between rheumatoid arthritis and SLE, and the genetic backgrounds of patients with these illnesses. The clinical similarities of the two, despite obvious differences, has long been recognized. However, the hallmark of rheumatoid arthritis has been the rheumatoid factor which is a y-globulin of high molecular weight, and probably is a peculiar type of antibody. The hallmark of SLE has been the L.E. cell and what now appears to be a group of antinuclear antibodies. The coexistence of these two types of unusual y-globulins in the same person is known. It now appears that relatives, often asymptomatic, of patients with classic SLE may have the rheumatoid factor in their serum [ZZ]. This suggests a familial predisposition to an abnormal immune response which in some instances may manifest itself as rheumatoid arthritis, sometimes as SLE, and sometimes as serologic reactions without clinical symptoms. These suggestions are highly speculative, and may hold little merit in themselves. However, although classic immunologic technics have provided strong evidence for an abnormality of the immunologic response in SLE, considerable doubt remains about the importance of the specific reactions identified in the initiation of the disease. If these reactions are now studied in the context of newer knowledge of immunologic responses and of the reactions of cells
Editorial and tissues to one another, hitherto unappreciated immunologic phenomena may be uncovered which lie closer to the roots of this disease. HALSTED
R.
HOLMAN,
M.D.
9.
10.
The Rockefeller Institute, New York, New York REFERENCES
11.
1. HARVEY, A., SHULMAN,L., TUMULTY, P., CONLEY, C.
2.
3.
4.
5.
6.
7.
8.
and SCHOENRICH, E. Systemic lupus erythematosus. Medicine, 33: 291, 1954. VAN LOGHAM, J., VAN DER HART, M. and BRISTEL, H. The occurrence of complete and incomplete white cell antibodies. VOX Sang&is, 2: 257, 1957 (New series). DAUSSET, J. Normal and pathological platelet agglutinins investigated by means of the shaking method. VOX Sanguinis, 4: 204, 1954. LEE, S. and SANDERS,M. A disorder of blood coagulation in systemic lupus erythematosus. J. Clin. Invest., 34: 1814, 1955. MELLORS, R. C., ORTEGA, L. G. and HOLMAN,H. R. Role of gamma globulin in pathogen& of renal lesions in systemic lupus erythematosus and chronic membranous glomerulonephritis, with an observation on the lupus erythematosus cell reaction. J. Exper. Med., 106: 191, 1957. VAZQUEZ, J. J. and DIXON, F. J. Immunohistochemical study of lesions in rheumatic fever, systemic lupus erythematosus, and rheumatoid arthritis. Lab. Invest., 6: 205, 1957. HOLMAN, H., DEICHER, H. and ROBBINS, W. Antinuclear “antibodies” in lupus erythematosus. In: Mechanisms of hypersensitivity (Proceedings of the Henry Ford Symposium, 1958) Boston, 1959. Little, Brown and Co. HOLMAN, H., DEICHER, H. and KUNKEL, H. The
12.
13.
14. 15.
16.
17.
18.
19.
L.E. cell and the L.E. serum factors. Bull. N. Y. Acad. Med., 35: 409, 1959. GAJDUSEK, D. An “autoimmune” reaction against human tissue antigens in certain acute and chronic diseases. Arch. Znt. Med., 101: 9, 1958. CALLENDER, S. and RACE, R. A serological and genetical study of multiple antibodies formed in response to blood transfusion by a patient with lupus erythematosus diffusus. Ann. Eugenics, 13: 102, 1946. WALLER, R. and RACE, R. Six blood group antibodies in the serum of a transfused patient. Brit. Med. J., 1: 225, 1951. MUELLING, R., BEVEN, T., SAMSON,R., JENEVEIN, E. and GUILLORY, J. Studies in human sensitivity to antibiotics, Am. J. Clin. Path., 29: 503, 1958. UETAKE, H., WAKAGAWA, T. and AKEBA, T. Relationship of bacteriophage to antigenic changes in group E salmonellas. J. Bacterial., 69: 571, 1955. &DEWAR, P. B. In: A discussion on immunological tolerance. Prod. Roy. Sot. B., 146: 1, 1956. BARNES, D. and LOUTIT, I. Immunological status and longevity of radiation chimeras, Proc. Roy. Sot. B., 150: 131, 1959. MOSCONA, A. Tissues from dissociated cells. Scientific American, 200: 132, 1959. BILLINGHAM, R. and SILVERS, W. Induction of tolerance of skin isografts from male donors in female mice. Science, 128: 780, 1958. FORD, C., JONES, K., MILLER, O., MITTWOCH, V., PENROSE, L., RIDLER, M. and SHAPIRO, A. The chromosomes in a patient showing both Mongolism and Klinefelter syndrome. Lancet, 1: 709, 1959. FORD, C., POLANI, P., BRIGGS, J. and BISHOP, P. A presumptive human xxy/xx mosaic, Nature, 183:
1031, 1959. 20. PATERSON, P. Transfer
of allergic encephalomyelitis in rats by means of immune lymph cells. Fed. Proc., 18: 591, 1959. 21. HOLMAN, H. and DEICHER, H. Data to be published. 22. HOLMAN, H. and KUNKEL, H. Data to be published.
AMERICAN
JOURNAL
OF
MEDICINE