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Genetically determined immune deficiency as the predisposing cause of “autoimmunity” and lymphoid neoplasia
SEPTEMBER
The
American
Journal
1971
of Medicine VOLUME
51
NUMBER
3
EDITORIAL
Genetically Determined Immune Deficiency as the Predisposing Cause of “Autoimmunity” and Lymphoid Neoplasia
H. HUGH FUDENBERG, San Francisco,
M.D.
California
From the Section of Hematology and Immunology, Department of Medicine, University of California, San Francisco, California 94122. This work was supported in part by research grants from the Office of Naval Research (NONR-3656) American Cancer Society (T-386C), Jane Coffin Childs Memorial Fund and U.S. Public Health Service (AM-08527, Al-09145 and Al-08188). Requests for reprints should be addressed to Dr. H. Hugh Fudenberg, Editorial Office, 983-M, Department of Medicine, University of California School of Medicine, San Francisco, California 94122.
Volume
51, September
1971
In 1956 we encountered a patient with long-standing “adultonset” hypogammaglobulinemia. After having this disease for many years Coomb’s-positive hemolytic anemia developed (proved by elution studies to be due to autoantibodies to red cells) and, subsequently, lymphoma. We postulated that an immune deficiency was the primamry event in predisposition to “autoimmune” diseases and lymphoma [l]. Further, our five year survey [2] of patients with “adult-onset” agammaglobulinemia showed a high incidence of certain “autoimmune” diseases despite absence of serum antibody, a higher than normal incidence of “autoimmune” diseases in family members than in normal age-matched control subjects and a very high incidence of autoantibodies without disease in first degree relatives of such patients. These findings have been confirmed by several laboratories. We later studied lymphocyte metabolism in patients and parents, and established that the “adult-onset” agammaglobulinemias are genetically determined [3]; cellular immunity, although often normal early in the course of the disease, eventually becomes defective as measured by skin tests and migration inhibition factor [4-61. A greater than normal incidence of malignant diseases is then seen in these patients. Patients with genetically determined T cell defects,* if they survive long enough, also have a high incidence of malignant diseases, at least ten times that of the general population [6]. * Terminology is that of Fudenberg et al. [6]. T cell (thymus-dependent cell), responsible for cellular immunity; B cell (bone marrow cell), responsible for humoral immunity.
295
IMMUNE
DEFICIENCY
AS CAUSE OF AUTOIMMUNITY
AND LYMPHOID
Burnet [7] has postulated that “autoimmunity” arises from emergence of “forbidden clones” which make autoantibody. Our hypothesis, in contradistinction, is that autoantibody-producing cells are always present, producing enough autoantibody to remove damaged or aged tissues [8,9]. In the normal population, the number of such cells is kept in check by normal T cells. When T cell fvnction is or becomes defective, the “governing system” controlling autoantibody-producing clones fails, and “autoimmune” disease, mediiated in most diseases by cellular immunity, emerges. (Although serum “autoanbbodies” as assayed by current technics provide a valuable diagnostic or prognostic test, tissue damage is probably via cellmediated immunity, at least in most “autoimmune” diseases.) The mechanism preventing undue proliferation ‘in the normal population of such “autoantibody” clones, which are capable of producing tissue damage, may be analogous to that which limits the amount of serum antibody produced to a given antigen and keeps the antibody (and immunoglobulin) concentrations from continuously rising in normal subjects [lo]. We further postulate that the increased frequency of mitosis of the “autoantibody”-producing cells leads to increased chances of chromosomal aberrations. Some mutants thus produced will be antigenically negative with respect to the host and incapable of control by the host immunologist defenses. This process then leads to an increased incidence of malignant diseases in such patients, who do not have overt T cell deficiency. Finally, we suggest that in overt genetic or acquired T cell defioiency, cells responsible for removing mutant cells, which contain antigens not present in host tissue, are quantitatively or qualitatively deficient so that mutant cells persist and multiply [8,9]. Experimental data for these concepts are provided by several lines of evidence from both human subjects and animals: (1) Normal subjects have low concentrations of rheumatoid factor and other “autoantibodies” in their serum [ll]. (2) In neonatally thymectomized mice (strains other than Balb/c and NZB) whose kidneys have been radiated, renal disease develops at six months. By immunofluorescence we have found gamma globulin deposition in their kidneys [12]; the pattern of fluorescence observed is indtistinguishable from that seen in the NZB and other NZ strains in which such lesions develop spontaneously. Treatment with agents which result in interferon production markedly retards the appearance of this disease in
296
NEOPLASIA -
FUDENBERG
these thymectomized and radiated animals [13]. Presumably, the “autoimmune” disease is due to activation of latent viruses in the presence of compromised T cell function.‘: (3) In NZB mice that recover from Coombs’-positive hemolytic anemia the rate of malignancy is high [16]. (4) Antilymphocyte serum apparently acts selectively by suppression of T cells [17]; patients given antilymphocyte serum appear to have a greater incidence of malignant diseases than normal [18]. (5) We have described a subject with normal or high immunoglobulin concentrations, a positive Coombs’ test, hemolytic anemia and anergy as measured by six skin test antigens [19]. A genetically determined defect may not be universal for all antigens; specific unresponsiveness to a single synthetic polypeptide antigen has been demonstrated in terms of humoral antibody by McDevitt and Sela [20], Levine and Benacerraf [21] and others; this defect has been shown to be genetically determined. We have seen one sumbject with specific unresponsiveness to staphylococcal antigens (both humoral [22] and cellular [23]), who had repeated staphylococcal infections; Hobbs has observed a similar patient [24]. It is probable that selective T cell defects for one or another antigen, genetically determined, exist in man and mouse; such selective defects may exist for T cells monitoring one given type of “autoantibody”-producing cells. For accurate assessment one must differentiate between true “autoantibody” and antibody to viral, bacterial or other antigens; it seems not unlikely that systemic lupus erythematosus in man, the disease of NZB mice and other “autoimmune” dliseases are antigen-antibody complex diseases with viral antigens as the antigen. These extrapolations in mice seem justified on the basis of data of Schur and Monroe [25], Steinberg, Baron and Talal [26] and others, since the antibodies to DNA and RNA found in such serum may well be antibodies to an exogenous virus. Aleutian mink disease is probably another example of an immune complex disease due to abnormal response to a viral antigen in a genetically predisposed host. At least in the NZB mouse, T cell functlion seems defective [27]. We have previously postulated that “autoimmune” disease is due to selective immune deficiency permit* Neonatally thymectomized mice also have a high incidence of other “autoimmune” phenomena, including Coombs’-positive hemolytic anemia [14]; similar phenomena are observed in neonatally thymectomized rabbits v51.
The American Journal of Medicine
IMMUNE
DEFICIENCY
AS
CAUSE
proliferation of one or another slow virus [13]. Perhaps germ-free synthetic diets, which would preclude viral contamination of dietary nutrients, might prevent the “autoimmune” phenomena in mice. Several groups have found large numbers of viruses in the tissues of both NZB mice and of patients with systemic lupus erythematosus; viruses have also been found widely distributed in tissues of neonatally thymectomized mice in which “autoimmune” manifestations ultimately develop [28]. In addition to virus-antibody complexes, other situations may produ,ce “autoimmune” disease. We have previously documented that at least some cases of “autoimmune” hemolytic anemia, i.e., hemolyti,c anemia with positive direct Coombs’ bystander” diseases. The test, are “innocent mechanism appears to be that antigens are absorbed to red cells in vivo, and serum antibody to the exogenous antigen reacts in vivo (and in vitro) with the antigen--the killed red cells being “innocent bystanders.” This phenomenon has been proved for Coombs’-positive hemolytic anemias caused by both penicillin [29] and insulin [19]. We have also documented keflin-induced granulocytopenia caused by a similar process: keflin ab. sorbed to granulocytes in vivo, high titers (1:60,000) of anti-keflin antibodies and binding of the patient’s serum to keflin-coated granulocytes [30]. Thus, our definitions of “autoimmune” disease must be redefined and minimal criteria set for call-
ting
OF
AUTOIMMUNITY
AND
LYMPHOID
NEOPI
ASIA
-
FUDENBERG
mg an antibomdy “autoantibody.” We do not know whether T cell function in those suffering “innocent bystander” disease is abnormal; this is now being tested. Further, we believe that T cell, B cell and granulocyte function cannot be as sharply separated as one might infer from the literature. As stated earlier, we have seen one experiment of nature in which a patient had defective cellular and humoral immunity only to staphylococci and who had a defect in neutrophil bactericidal activity specific for staphylococci [22]. We also believe that there is more than one type of T cell, since at least with certain antigens a dissociation exists between skin test and migration inhibition factor on the one hand, and lymphocyte response in vitro on the other, in both animals [31] and children with immune deficiency [32]. Whether one specific subtype of T cell controls proliferation of autoantibodyproducing clones warrants further experimentation; such experiments are now in progress. Obviously, additional test systems for the various kinds of T cells must be established, and their function, B cell function and granulocyte function must be measured in both selective and general immune deficiency before genetically determined defects in T cell function can be proved to be the cause (1) of “autoimmunity” and (2) of the defective immunologic surveillance that results in malignancy.
REFERENCES 1.
2.
3.
4.
5. 6.
7.
8.
Fudenberg H, Solomon A: “Acquired agammaglobulinemia” with auto-immune hemolytic disease: graft-versus-host reaction? VOX Sang 6: 68, 1961. Fudenberg H, German JL III, Kunkel HG: The occurrence of rheumatoid factor and other abnormalities in families of patients with agammaglobulinemia. Arthritis Rheum 5: 565, 1962. Kamin RM, Fudenberg HH, Douglas SD: A genetic agammaglobulinemia. Proc defect in “acquired” Nat Acad Sci USA 60: 881,1968. Douglas SD, Goldberg LS, Fudenberg HH: Clinical, serologic and leukocyte function studies on patients with idiopathic “acquired” agammaglobu;y7;ia and their families. Amer J Med 48: 48, Spitler L, Fudenberg HH: In preparation. Fudenberg HH, Good RA, Hitzig W, Kunkel HG, Roitt IM, Rosen FS, Rowe DS, Seligmann M, Soothill JR: Immune deficiency states: report of a WHO expert committee. Pediatrics (in press). Burnet FM: The Clonal Selection Theory of Acquired Immunity, Nashville, Tenn, Vanderbilt University Press, 1959. Fudenberg HH: Immunologic deficiency, autoimmune disease, and lymphoma: observations, implications, and speculations. Arthritis Rheum 9: 464, 1966.
Volume 51. September
1971
9. 10. 11. 12.
13.
14.
15.
16.
17.
Fudenberg HH: Are autoimmune disease immunologic deficiency states? Hasp Pratt 3: 43, 1968. Waldmann TA, Strober W: Metabolism of immunoglobulins. Progr Allerg 13: 1, 1969. Fudenberg HH: Unpublished observations. Guttman PH, Wuepper KD, Fudenberg HH: On the presence of rG and glC globulins in renal glomeruli of aging and neonatally x-irradiated mice. VOX Sang 12: 329, 1967. Guttman PH, Davis WC, Fudenberg HH, Merigan TC: Effect of interferon on the course of spontaneous and radiation-induced renal lesions in the RF/Un mouse. VOX Sang 17: 279,1969. Miller JFAP, Howard JG: Some similarities between the neonatal thymectomy syndrome and graftversus-host disease. J Reticuloendothel Sot 1: 369, 1964. Sutherland DER, Archer OK, Peterson RDA, Eckert E, Good RA: Development of “autoimmune processes” in rabbits after neonatal removal of central lymphoid tissue. Lancet 1: 130, 1965. Mellors RC: Autoimmune disease in NZB/Bl mice. II. Autoimmunity and malignant lymphoma. Blood 27: 435, 1966. Stewart PB, Bell R: Selective suppression of cell mediated immunity by equine anti-rabbit lymphocyte serum. Nature (London) 227: 279, 1970.
297
IMMUNE
18.
19.
20.
21.
22.
23. 24. 25.
298
DEFICIENCY
AS CAUSE OF AUTOIMMUNITY
AND LYMPHOID
Starzl TE, Porter KA, Andres G, Halgrimson CG, Hurwitz R, Giles G, Terasaki PI, Penn I, Schroter GT, Lilly J, Starkie SJ, Putnam CW: Long-term survival after renal transplantation in humans (with special reference to histocompatibility matching, thymectomy, homograft glomerulonephritis, heterologous ALG, and recipient malignancy). Ann Surg 172: 437,197O. Faulk WP, Tomsovic EJ, Fudenberg HH: Insulin resistance in juvenile diabetes mellitus: immunologic studies. Amer J Med 49: 133, 1970. McDevitt HO, Sela M: Genetic control of the antibody response. I. Demonstration of determinant-specific differences in response to synthetic polypep tide antigens in two strains of inbred mice. J Exp Med 122: 517, 1965. Levine BB, Benacerraf B: Genetic control in guinea pigs of immune response to conjugates of haptens and oolv L-lvsine. Science 147: 517. 1965. Davis WC: Douglas SD, Fudenberg HH: A selective neutrophil dysfunction syndrome: impaired killing of staphylococci. Ann Intern Med 69: 1237, 1968. Spitler L, Fudenberg HH: Unpublished observations. Hobbs J: Personal communication. Schur PH. Monroe M: Antibodies to ribonucleic acid in systemic lupus erythematosus. Proc Nat Acad Sci USA 63: 1108, 1969.
NEOPLASIA -
26.
27.
28.
29.
30.
31.
32.
FUDENBERG
Steinberg AD, Baron S, Talal N: The pathogenesis of autoimmunity in New Zealand mice. I. Induction of antinucleic acid antibodies by polyinosinicpolycytidylic acid. Proc Nat Acad Sci USA 63: 1102, 1969. Leventhal BG, Talal N: Response of NZB and NZB/ NZW spleen cells to mitogenic agents. J lmmun 104: 918,197O. Wilson R, Sjodin K, Bealmear M: The absence of wasting h-r thymectomized germ-free (axenic) mice. Proc Sot EXD Biol Med 117: 237. 1964. Petz LD, Fudenberg HH: Coombs-positive hemolytic anemia caused by penicillin administration. New Eng J Med 274: 171,1966. Levin AS, Weiner RS, Fudenberg HH, Spath P, Petz L: Granulocytopenia caused by anticephalothin antibodies (abstract). Clin Res 19: 424, 1971. Spitler L, Benjamini E, Young JD, Kaplan H, Fudenberg HH: Studies on the immune response to a characterized antigenic determinant of the tobacco mosaic virus protein. J Exp Med 131: 133, 1970. Levin AS, Spitler LE, Stites DP, Fudenberg HH: Wiskott-Aldrich syndrome, a genetically determined cellular immunologic deficiency: clinical and laboratory response to therapy with transfer factor. Proc Nat Acad Sci USA 67: 821, 1970.
The American
Journal of Madiclna
The
American
Journal
1971
of Medicine VOLUME
51
NUMBER
3
EDITORIAL
Genetically Determined Immune Deficiency as the Predisposing Cause of “Autoimmunity” and Lymphoid Neoplasia
H. HUGH FUDENBERG, San Francisco,
M.D.
California
From the Section of Hematology and Immunology, Department of Medicine, University of California, San Francisco, California 94122. This work was supported in part by research grants from the Office of Naval Research (NONR-3656) American Cancer Society (T-386C), Jane Coffin Childs Memorial Fund and U.S. Public Health Service (AM-08527, Al-09145 and Al-08188). Requests for reprints should be addressed to Dr. H. Hugh Fudenberg, Editorial Office, 983-M, Department of Medicine, University of California School of Medicine, San Francisco, California 94122.
Volume
51, September
1971
In 1956 we encountered a patient with long-standing “adultonset” hypogammaglobulinemia. After having this disease for many years Coomb’s-positive hemolytic anemia developed (proved by elution studies to be due to autoantibodies to red cells) and, subsequently, lymphoma. We postulated that an immune deficiency was the primamry event in predisposition to “autoimmune” diseases and lymphoma [l]. Further, our five year survey [2] of patients with “adult-onset” agammaglobulinemia showed a high incidence of certain “autoimmune” diseases despite absence of serum antibody, a higher than normal incidence of “autoimmune” diseases in family members than in normal age-matched control subjects and a very high incidence of autoantibodies without disease in first degree relatives of such patients. These findings have been confirmed by several laboratories. We later studied lymphocyte metabolism in patients and parents, and established that the “adult-onset” agammaglobulinemias are genetically determined [3]; cellular immunity, although often normal early in the course of the disease, eventually becomes defective as measured by skin tests and migration inhibition factor [4-61. A greater than normal incidence of malignant diseases is then seen in these patients. Patients with genetically determined T cell defects,* if they survive long enough, also have a high incidence of malignant diseases, at least ten times that of the general population [6]. * Terminology is that of Fudenberg et al. [6]. T cell (thymus-dependent cell), responsible for cellular immunity; B cell (bone marrow cell), responsible for humoral immunity.
295
IMMUNE
DEFICIENCY
AS CAUSE OF AUTOIMMUNITY
AND LYMPHOID
Burnet [7] has postulated that “autoimmunity” arises from emergence of “forbidden clones” which make autoantibody. Our hypothesis, in contradistinction, is that autoantibody-producing cells are always present, producing enough autoantibody to remove damaged or aged tissues [8,9]. In the normal population, the number of such cells is kept in check by normal T cells. When T cell fvnction is or becomes defective, the “governing system” controlling autoantibody-producing clones fails, and “autoimmune” disease, mediiated in most diseases by cellular immunity, emerges. (Although serum “autoanbbodies” as assayed by current technics provide a valuable diagnostic or prognostic test, tissue damage is probably via cellmediated immunity, at least in most “autoimmune” diseases.) The mechanism preventing undue proliferation ‘in the normal population of such “autoantibody” clones, which are capable of producing tissue damage, may be analogous to that which limits the amount of serum antibody produced to a given antigen and keeps the antibody (and immunoglobulin) concentrations from continuously rising in normal subjects [lo]. We further postulate that the increased frequency of mitosis of the “autoantibody”-producing cells leads to increased chances of chromosomal aberrations. Some mutants thus produced will be antigenically negative with respect to the host and incapable of control by the host immunologist defenses. This process then leads to an increased incidence of malignant diseases in such patients, who do not have overt T cell deficiency. Finally, we suggest that in overt genetic or acquired T cell defioiency, cells responsible for removing mutant cells, which contain antigens not present in host tissue, are quantitatively or qualitatively deficient so that mutant cells persist and multiply [8,9]. Experimental data for these concepts are provided by several lines of evidence from both human subjects and animals: (1) Normal subjects have low concentrations of rheumatoid factor and other “autoantibodies” in their serum [ll]. (2) In neonatally thymectomized mice (strains other than Balb/c and NZB) whose kidneys have been radiated, renal disease develops at six months. By immunofluorescence we have found gamma globulin deposition in their kidneys [12]; the pattern of fluorescence observed is indtistinguishable from that seen in the NZB and other NZ strains in which such lesions develop spontaneously. Treatment with agents which result in interferon production markedly retards the appearance of this disease in
296
NEOPLASIA -
FUDENBERG
these thymectomized and radiated animals [13]. Presumably, the “autoimmune” disease is due to activation of latent viruses in the presence of compromised T cell function.‘: (3) In NZB mice that recover from Coombs’-positive hemolytic anemia the rate of malignancy is high [16]. (4) Antilymphocyte serum apparently acts selectively by suppression of T cells [17]; patients given antilymphocyte serum appear to have a greater incidence of malignant diseases than normal [18]. (5) We have described a subject with normal or high immunoglobulin concentrations, a positive Coombs’ test, hemolytic anemia and anergy as measured by six skin test antigens [19]. A genetically determined defect may not be universal for all antigens; specific unresponsiveness to a single synthetic polypeptide antigen has been demonstrated in terms of humoral antibody by McDevitt and Sela [20], Levine and Benacerraf [21] and others; this defect has been shown to be genetically determined. We have seen one sumbject with specific unresponsiveness to staphylococcal antigens (both humoral [22] and cellular [23]), who had repeated staphylococcal infections; Hobbs has observed a similar patient [24]. It is probable that selective T cell defects for one or another antigen, genetically determined, exist in man and mouse; such selective defects may exist for T cells monitoring one given type of “autoantibody”-producing cells. For accurate assessment one must differentiate between true “autoantibody” and antibody to viral, bacterial or other antigens; it seems not unlikely that systemic lupus erythematosus in man, the disease of NZB mice and other “autoimmune” dliseases are antigen-antibody complex diseases with viral antigens as the antigen. These extrapolations in mice seem justified on the basis of data of Schur and Monroe [25], Steinberg, Baron and Talal [26] and others, since the antibodies to DNA and RNA found in such serum may well be antibodies to an exogenous virus. Aleutian mink disease is probably another example of an immune complex disease due to abnormal response to a viral antigen in a genetically predisposed host. At least in the NZB mouse, T cell functlion seems defective [27]. We have previously postulated that “autoimmune” disease is due to selective immune deficiency permit* Neonatally thymectomized mice also have a high incidence of other “autoimmune” phenomena, including Coombs’-positive hemolytic anemia [14]; similar phenomena are observed in neonatally thymectomized rabbits v51.
The American Journal of Medicine
IMMUNE
DEFICIENCY
AS
CAUSE
proliferation of one or another slow virus [13]. Perhaps germ-free synthetic diets, which would preclude viral contamination of dietary nutrients, might prevent the “autoimmune” phenomena in mice. Several groups have found large numbers of viruses in the tissues of both NZB mice and of patients with systemic lupus erythematosus; viruses have also been found widely distributed in tissues of neonatally thymectomized mice in which “autoimmune” manifestations ultimately develop [28]. In addition to virus-antibody complexes, other situations may produ,ce “autoimmune” disease. We have previously documented that at least some cases of “autoimmune” hemolytic anemia, i.e., hemolyti,c anemia with positive direct Coombs’ bystander” diseases. The test, are “innocent mechanism appears to be that antigens are absorbed to red cells in vivo, and serum antibody to the exogenous antigen reacts in vivo (and in vitro) with the antigen--the killed red cells being “innocent bystanders.” This phenomenon has been proved for Coombs’-positive hemolytic anemias caused by both penicillin [29] and insulin [19]. We have also documented keflin-induced granulocytopenia caused by a similar process: keflin ab. sorbed to granulocytes in vivo, high titers (1:60,000) of anti-keflin antibodies and binding of the patient’s serum to keflin-coated granulocytes [30]. Thus, our definitions of “autoimmune” disease must be redefined and minimal criteria set for call-
ting
OF
AUTOIMMUNITY
AND
LYMPHOID
NEOPI
ASIA
-
FUDENBERG
mg an antibomdy “autoantibody.” We do not know whether T cell function in those suffering “innocent bystander” disease is abnormal; this is now being tested. Further, we believe that T cell, B cell and granulocyte function cannot be as sharply separated as one might infer from the literature. As stated earlier, we have seen one experiment of nature in which a patient had defective cellular and humoral immunity only to staphylococci and who had a defect in neutrophil bactericidal activity specific for staphylococci [22]. We also believe that there is more than one type of T cell, since at least with certain antigens a dissociation exists between skin test and migration inhibition factor on the one hand, and lymphocyte response in vitro on the other, in both animals [31] and children with immune deficiency [32]. Whether one specific subtype of T cell controls proliferation of autoantibodyproducing clones warrants further experimentation; such experiments are now in progress. Obviously, additional test systems for the various kinds of T cells must be established, and their function, B cell function and granulocyte function must be measured in both selective and general immune deficiency before genetically determined defects in T cell function can be proved to be the cause (1) of “autoimmunity” and (2) of the defective immunologic surveillance that results in malignancy.
REFERENCES 1.
2.
3.
4.
5. 6.
7.
8.
Fudenberg H, Solomon A: “Acquired agammaglobulinemia” with auto-immune hemolytic disease: graft-versus-host reaction? VOX Sang 6: 68, 1961. Fudenberg H, German JL III, Kunkel HG: The occurrence of rheumatoid factor and other abnormalities in families of patients with agammaglobulinemia. Arthritis Rheum 5: 565, 1962. Kamin RM, Fudenberg HH, Douglas SD: A genetic agammaglobulinemia. Proc defect in “acquired” Nat Acad Sci USA 60: 881,1968. Douglas SD, Goldberg LS, Fudenberg HH: Clinical, serologic and leukocyte function studies on patients with idiopathic “acquired” agammaglobu;y7;ia and their families. Amer J Med 48: 48, Spitler L, Fudenberg HH: In preparation. Fudenberg HH, Good RA, Hitzig W, Kunkel HG, Roitt IM, Rosen FS, Rowe DS, Seligmann M, Soothill JR: Immune deficiency states: report of a WHO expert committee. Pediatrics (in press). Burnet FM: The Clonal Selection Theory of Acquired Immunity, Nashville, Tenn, Vanderbilt University Press, 1959. Fudenberg HH: Immunologic deficiency, autoimmune disease, and lymphoma: observations, implications, and speculations. Arthritis Rheum 9: 464, 1966.
Volume 51. September
1971
9. 10. 11. 12.
13.
14.
15.
16.
17.
Fudenberg HH: Are autoimmune disease immunologic deficiency states? Hasp Pratt 3: 43, 1968. Waldmann TA, Strober W: Metabolism of immunoglobulins. Progr Allerg 13: 1, 1969. Fudenberg HH: Unpublished observations. Guttman PH, Wuepper KD, Fudenberg HH: On the presence of rG and glC globulins in renal glomeruli of aging and neonatally x-irradiated mice. VOX Sang 12: 329, 1967. Guttman PH, Davis WC, Fudenberg HH, Merigan TC: Effect of interferon on the course of spontaneous and radiation-induced renal lesions in the RF/Un mouse. VOX Sang 17: 279,1969. Miller JFAP, Howard JG: Some similarities between the neonatal thymectomy syndrome and graftversus-host disease. J Reticuloendothel Sot 1: 369, 1964. Sutherland DER, Archer OK, Peterson RDA, Eckert E, Good RA: Development of “autoimmune processes” in rabbits after neonatal removal of central lymphoid tissue. Lancet 1: 130, 1965. Mellors RC: Autoimmune disease in NZB/Bl mice. II. Autoimmunity and malignant lymphoma. Blood 27: 435, 1966. Stewart PB, Bell R: Selective suppression of cell mediated immunity by equine anti-rabbit lymphocyte serum. Nature (London) 227: 279, 1970.
297
IMMUNE
18.
19.
20.
21.
22.
23. 24. 25.
298
DEFICIENCY
AS CAUSE OF AUTOIMMUNITY
AND LYMPHOID
Starzl TE, Porter KA, Andres G, Halgrimson CG, Hurwitz R, Giles G, Terasaki PI, Penn I, Schroter GT, Lilly J, Starkie SJ, Putnam CW: Long-term survival after renal transplantation in humans (with special reference to histocompatibility matching, thymectomy, homograft glomerulonephritis, heterologous ALG, and recipient malignancy). Ann Surg 172: 437,197O. Faulk WP, Tomsovic EJ, Fudenberg HH: Insulin resistance in juvenile diabetes mellitus: immunologic studies. Amer J Med 49: 133, 1970. McDevitt HO, Sela M: Genetic control of the antibody response. I. Demonstration of determinant-specific differences in response to synthetic polypep tide antigens in two strains of inbred mice. J Exp Med 122: 517, 1965. Levine BB, Benacerraf B: Genetic control in guinea pigs of immune response to conjugates of haptens and oolv L-lvsine. Science 147: 517. 1965. Davis WC: Douglas SD, Fudenberg HH: A selective neutrophil dysfunction syndrome: impaired killing of staphylococci. Ann Intern Med 69: 1237, 1968. Spitler L, Fudenberg HH: Unpublished observations. Hobbs J: Personal communication. Schur PH. Monroe M: Antibodies to ribonucleic acid in systemic lupus erythematosus. Proc Nat Acad Sci USA 63: 1108, 1969.
NEOPLASIA -
26.
27.
28.
29.
30.
31.
32.
FUDENBERG
Steinberg AD, Baron S, Talal N: The pathogenesis of autoimmunity in New Zealand mice. I. Induction of antinucleic acid antibodies by polyinosinicpolycytidylic acid. Proc Nat Acad Sci USA 63: 1102, 1969. Leventhal BG, Talal N: Response of NZB and NZB/ NZW spleen cells to mitogenic agents. J lmmun 104: 918,197O. Wilson R, Sjodin K, Bealmear M: The absence of wasting h-r thymectomized germ-free (axenic) mice. Proc Sot EXD Biol Med 117: 237. 1964. Petz LD, Fudenberg HH: Coombs-positive hemolytic anemia caused by penicillin administration. New Eng J Med 274: 171,1966. Levin AS, Weiner RS, Fudenberg HH, Spath P, Petz L: Granulocytopenia caused by anticephalothin antibodies (abstract). Clin Res 19: 424, 1971. Spitler L, Benjamini E, Young JD, Kaplan H, Fudenberg HH: Studies on the immune response to a characterized antigenic determinant of the tobacco mosaic virus protein. J Exp Med 131: 133, 1970. Levin AS, Spitler LE, Stites DP, Fudenberg HH: Wiskott-Aldrich syndrome, a genetically determined cellular immunologic deficiency: clinical and laboratory response to therapy with transfer factor. Proc Nat Acad Sci USA 67: 821, 1970.
The American
Journal of Madiclna