New and Old Immunodeficiencies
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003 I -3998/93/3301-OOS2$03.00/0 PEDIATRIC RESEARCH Vol. 33 (Suppl), No. 1, 1993 Copyright O 1992 International Pediatric Research Foundation, Inc. Printed in U.S. A. New and Old Immunodeficiencies E. RICHARD STIEHM UCLA Department of Pediatrics, UCLA School of Medicine, Los Angeles, California 90024 ABSTRACT. Yesterday's immunodeficiencies emphasized YESTERDAY the clinical and familial associations of the syndromes and date from the 1920s (ataxia-telangiectasia, chronic muco- Phenotypic syndromes were the first immunodeficiency syn- cutaneous candidiasis), the 1930s (Wiskott-Aldrich syn- dromes described (Table I), usually without noting the patients' drome), skipping the 1940s, but blossoming in the 15-y increased susceptibility to infection. These date from the 1920s period from 1950 to 1965. In this period, primary immu- when Syllaba and Henner (2) in Paris described ataxia-telangi- nodeficiencies affecting all the major limbs of the immune ectasia and Thorpe and Handley (3) in Philadelphia described system were first described (1950: severe combined im- mucocutaneous candidiasis. Ataxia-telangiectasia was rediscov- munodeficiency; 1952: X-linked agammaglobulinemia; ered in 1941 by Madame Louis-Bar (4) in Paris and again in 1957: chronic granulomatous disease; 1965: C2 deficiency). 1957 by Boder and Sedgwick (5) in Los Angeles. Today's immunodeficiencies, as detailed in Stiehm's Im- In the 1930s, Wiskott (6) in Munich, Germany, identified munologic Disorders in Infants and Children (Edition 1, what is now known as the Wiskott-Aldrich syndrome; this was 1973; Edition 2, 1980; and Edition 3, 1989) emphasize the independently rediscovered in 1954 when Aldrich et al. (7), in immunologic and genetic aspects of immunodeficiency. Rochester, Minnesota, wrote an article on the subject in English. These increased from 43 syndromes in the 1973 edition Glanzmann and Riniker's 1950 paper from Bern, Switzerland, (34 primary, nine secondary) to 94 syndromes in the 1989 described a fatal case of severe combined immunodeficiency, edition (66 primary, 28 secondary). This means that about noting the lymphopenia that accompanied the disorder (8). The two primary and one secondary immunodeficiencies have 1953 paper of Keidan et al. (9) from Liverpool, UK, described been uncovered annually. Tomorrow's immunodeficiencies, fatal progressive vaccinia in a child with lymphopenia and agam- to be covered in Edition 4, will include new clinical and maglobulinemia. The syndrome was further elucidated when immunologic observations and molecular and biochemical siblings of the patient reported in the original paper were again studies that characterize some unique immunodeficiencies. described from Bern in 1958, providing the eponym "Swiss-type These include the following six groups of defects: 1) neu- agammaglobulinemia" (10, 11). Agammaglobulinemia in a 39- tropenic syndromes with hypogammaglobulinemia, includ- y-old woman (common variable immunodeficiency) was first ing the WHIM syndrome; 2) phenotypic genetic syn- described by Sanford et al. (12) in 1954. dromes with immunodeficiency including Bloom's syn- A disorder of the phagocytic system was first identified in 1957 drome and Schimke's immuno-osseous dysplasia; 3) by the Minneapolis group, who described chronic granulomatous natural killer cell defects associated with a) other primary disease under the pessimistic name "fatal granulomatous disease immunodeficiencies, b) other nonimmunologic illness, and of childhood" (13). To complete the discovery of the main types c) primary natural killer defects; 4) T-cell membrane de- of immunodeficiency, hereditary C2 deficiency with infection fects; 5) IL defects; and 6) miscellaneous phagocytic ill- was first described in 1965 by Klemperer et al. (14). References nesses including periodontitis and the asplenia syndrome. from Ross and Densen's marvelous review (15) of the comple- (Pediatr Res 33 (Suppl): S2-S8, 1993) ment deficiency syndromes provide the information necessary to construct a unique schema, the complement deficiency dis- Abbreviations covery pathway (Fig. I), starting in 1965 with C2 deficiency (14) and appropriately terminating with C9 deficiency (16) in 1983. NK, natural killer This brief historical review ends with DiGeorge's description TCR, T-cell receptor of thymic hypoplasia in 1965 (17), the same year in which this author finished a fellowship and sought gainful employment, thus ending yesterday and starting today. The conventional wisdom concerning the birth of immuno- deficiency is that this blessed event occurred in 1952 with Bru- TODAY ton's description of congenital agammaglobulinemia (1). In one Today's immunodeficiencies are defined, for this overview, as respect this is true, in another, not so. Agammaglobulinemia those covered in my text, Immunologic Diseases in Infants and clearly was the first immunodeficiency described that necessi- Children, published in 1973, 1980, 1989, and hopefully 1994 tated an immunologic test (in this Case Tiselius' serum electr0- (18-21). The overall incidence of primary immunodeficiency phoresis) to identify the disease and devise a treatment (gamma probably has not changed in this two-decade period, remaining globulin injections). However, several phenotypic syndromes, at about 1 per 10 000 live births (excluding IgA deficiency). now known to have major immunologic defects, were described However, a larger number of primary immunodeficiencies are many years before Bruton's report (2- 17). recognized and more patients are surviving so that the total In this article, I review some historical Papers on primary number of cases is increasing slowly. As the diverse cells and immunodeficiency (yesterday), discuss some trends in Present molecules of the immune system are identified and their inter- day immunology (today), and project some dkorders of immu- actions explored, more and more distinct disorders have been nity that will be forthcoming in the next several years (tomorrow). defined. Correspondence: E. Richard Stiehm, M.D., UCLA Department of Pediatrics, The secondary immunodeficiencies, those illnesses resulting UCLA School of Medicine, Los Angeles, CA 90024. from some nonimmuno~ogicprimary illness, have, by contrast, S2 NEW AND OLD IMhAUNODEFICIENCIES s3 Table 1. Dates of discovery of some primary decades are identified in Table 3. These include multiple new immunodeficiencies 11 926-1 96.5) illnesses. new diagnostic techni~ues,and new and improved Disorder Year treatments, the latter including enz)me (polyethylene glycol- adenosine deaminase) therapy,-. cytokine~ therapy, i.v. immune Ataxia-telangiectasia (2, 4, 5) 1926 (1941, 1957)* globulin, haploidentical bone marrow transplants, and gene ther- Chronic mucocutaneous candidiasis (3) 1929 apy. New and better use of antibiotics and antiviral drugs have Wiskott-Aldrich syndrome (6,7) 1937 (1955) also contributed to the better outlook for immunodeficient pa- Severe combined immunodeficiency (8-10) 1950 (1953, 1958) tients. X-linked agammaglobulinemia (1) 1952 Almost as interesting as the new advances were the blind Common variable immunodeficiency ( 12) 1954 alleys. As noted in Table 4, these include diagnoses that are in Chronic granulomatous disease (1 3) 1957 question (C5 dysfunction) or belong to a better-defined syndrome C2 deficiency (14, 15) 1965 (1966, 1972) (the patient with actin dysfunction had leukocyte adhesion defi- DiGeorge syndrome ( 17) 1965 ciency) or have never been confirmed. Certain treatments have * Indicates publication dates of other early, seminal papers. been shown to be ineffective (transfer factor) or replaced by better therapies (fetal liver transplantation). Some of these may be resurrected with further refinements (thymic hormone ther- 92 (Pneumonia, Otitis) '65 t apy) or under limited circumstances (IgA-deficient plasma for (Pneumonia. Otitis, severe IgA sensitivity in a patient who needs immune globulin Klinefelter's) '7l t treatment). Clr (Pneumonia, C3 (Meningitis, Meningitis, Systemic Pneumonia, Vasculitis) '72 Lupus Erythematasus) '72 I TOMORROW Lc~N~F~(Meningitis, Nephritis) '73 + I have identified six new groups of immunodeficiencies (Table C6 (Gonorrhea) '75 5) that are as yet unreported in my textbook, but that will be t t t Cls (Pneumonia, C5 (Meningitis, 1 Factor P discussed in the next edition. Some of these disorders are new; Systemic Lupus Systemic Lupus C8 (Gonorrhea) '76 (Pneumonia, Erythematosus) '76 Erythematasus) '76 <) '76 others have been around for some time, but their description has \ not been recognized as part of the main stream of immunologic C4 (Bacterem~a,\./ Systemic C7 (Pyelonephr~tts)78 Lupus Erythematasus) '78 information. AIDS is another of tomorrow's immunodeficien- I I cies, just as it is today's immunodeficiency. The number of LC$-(Dermatitis, Meningitis) '79 t C9 (Meningitis) '83 Table 3. Advances in immunodeficiencv 1973-1989 Fig. 1. Complement-infection discovery pathway (Data derivation: New illnesses Medicine 63:243, 1984). AIDS Leukocyte adhesion deficiency Table 2. Number of immunodeficiency syndromes described in Bare lymphocyte syndrome editions I and III of Immunologic Disorders in Infants and IgG subclass deficiencies Children Complement deficiencies Edition I Edition I11 Adenosine deaminase deficiency 1973 (18) 1989 (20) Hypogammaglobulinemia with growth hormone deficiency Polysaccharide unresponsiveness Secondary immunodeficiencies Cocarboxylase deficiency with candidiasis Primary immunodeficiencies Specific granule deficiency Antibody deficiencies New diagnostic