Progress in immunology

MEDICAL PROGRESS

Progress in immunology Syndromes o] diminlsbed resistance to injection

In this review of progress in immunology, an attempt is made to synthesize some of the rapidly accumulating observations in clinical medicine and experimental biology into a workable scheme, which may help pediatricians in their approach to the study and management of patients suspected of abnormalities in their resistance to infection. Like all hypothetical schemes, based on incomplete knowledge and imperfect interpretation, it must be considered tentative and useful mainly in establishing hypotheses to be demolished by future investigation. However, it may clarify the bewildering torrent of case reports, experimental observations and speculations which are pouring out in the current immunological and clinical literature. The roles of the phagocytic system, the thymus, the lymphocytes, and the plasma cells with their secretory products, the immunoglobulins, in defense against infection, as well as the clinical manifestations arising from deficiencies of each of these elements in the immunological system of the body, are discussed.

Charles A. Janeway, M.D. BOSTON, MASS.

CONSIDERING "altered" reto infection, it is necessary to survey what we know about normal mechanisms of resistance. The vast majority of severe infections due to pyogenic bacteria invade the body through the skin or the respiratory BEFORE

sistance

From the Department of Pediatrics, Harvard Medical School, and the Department of Medicine, Children's Hospital Medical Center, Boston, Mass. Supported by grants from the National Institutes of Health, Public Health Service, A1-05877 and FR 00128. This review is based on the T. Duckett ]ones Lecture, delivered Oct. 20, 1967, before the annual meeting of the Council on Rheumatic Fever and Congenital Heart Disease, American Heart Association, at San Francisco. Address, 300 Longwood Ave., Boston, Mass. 02115.

tract. Each of these organ systems is anatomically and physiologically arranged to prevent penetration of the surface by bacteria. These nonspecific defenses, which keep most of us well most of the time, may be breached by chemical or physical injury of various sorts. Recurrent infections of the middle ear, paranasal sinuses, or lungs may occur because of local anatomical anomalies or damage or physiological disturbances such as allergy or cystic fibrosis, which prevent adequate drainage of secretions or removal of pathogenic organisms when they are encountered. Such localized recurrences of infection are very common in pediatric practice but are not the subject of this report. It is the patients with invasive infections due to Vol. 72, No. 6, pp. 885-903

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different organisms, which may recur but do not follow a strictly repetitive pattern, that concern us in this review of diminished host resistance. T h a t there were such individuals could not be fully appreciated until the introduction of antimicrobial chemotherapy made it possible to save these patients from their early infections, thus permitting them to manifest the repeated severe or continuing infections which are so characteristic of individuals with immunological deficiencies. The lymphoreticular system of the body, which is responsible for its immunological functions, is composed of a series of morphological elements which must not only be present in adequate quantities but in proper structural arrangement if they are to function properly in concert. The hallmark of immunological responses is their specificity, the chemical basis for which was clearly established by Landsteiner's classic work upon the nature of antigens and haptens. Behind specificity lies the ability of the immunological system to recognize what is foreign to the organism, the capacity, as Burnet has put it, "to distinguish self from not-self." Biologists, armed with the sophisticated tools of modern research, are bearing down hard upon the chemical basis of this recognition process but, to my knowledge, have not yet penetrated the curtain of ignorance which surrounds this fundamental phenomenon. The objective of this review is to paint a broad picture, relating the general characteristics of syndromes, which clinicians have come to recognize, to morphological, biochemical, and functional deficits in the immunological system which have been uncovered by laboratory investigation. First, let me sketch our present concepts of how the organism responds to bacterial infection, once its outer defenses--the skin, the ciliated epithelium of the upper respiratory tract, or the oropharyngeal mucosa--have been breached, and invasion has begun. The first stage in the specific response to bacterial infection is capture of the invading organism. This stage involves at least three

The Journal o[ Pediatrics June 1968

processes, if it is to be fully effective in resistance: Ingestion (phagocytosis) Intracellular killing Intracellular digestion. These processes are carried out by two groups of cells:

(1) Wandering phagocytes, the polymorphonuclear leukocytes and monocytes, or histiocytes, of the blood and tissue spaces. (2) Fixed phagocytes, the macrophages lining the sinusoids of liver, spleen, and lymph nodes, in other words, the clearing mechanism of the reticuloendothelial system for blood and lymph. Once the phagocytic cells have ingested the invading organisms, antigens derived from their intracellular digestion are passed along to the lymphoid cells, which are responsible for the next two stages, recognition and response. These second and third stages, unlike the first stage of capture, which is usually a nonspecific process, although the phagocytosis of certain organisms may be greatly enhanced by antibody, are specifically directed against the antigens derived from the first stage. That these three sequential stages are linked together into a coordinated response to infection has its morphological expression in the anatomical organization of the lymph nodes and spleen, in which lymphoid follicles are juxtaposed to the macrophage-lined sinusoids, through which lymph or blood is flowing. The second, vitally important but poorly understood, stage is recognition. Recognition implies that, in some way, lymphoid cells can distinguish those chemical configurations of bacterial antigens from those native to the host. They must be able to do this the first time these are encountered in order to initiate a primary immunological response. Having once recognized a particular antigen as foreign, the body possesses an immunological memory, which enables it to mobilize the specific immunological responses of the third stage much more rapidly and to a greater degree upon subsequent encounter. Thus, recognition, and its corollary, immunological

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memory, are fundamental to the specific nature of the immunological response to infection. Immunological memory is clearly associated with the small lymphocyte. Recognition is a function of lymphoid cells, and is dependent upon an important and unique lymphoid organ--the thymus. This impressive structure in the upper mediastinum of infants has long been an organ without any known function until the last few years, when a series of brilliant experimental investigations begun by Miller 1 in England and by Jankovic, Waksman, and Arnason 2 in this country demonstrated that immunological competence, the ability to recognize antigens as foreign and to respond to them, could be markedly impaired in newborn animals by thymectomy and restored by reimplantation of the thymus. How the thymus confers immunological competence is still under investigation, but to be fully immunologically competent, an animal must have a normally developed thymus in utero and possibly for some time after birth. Whether the thymus itself supplies lymphocytes to the rest of the lymphoid system or merely conditions those brought to it from other sites of lymphopoiesis, such as the bone marrow and extramedullary sites, is not yet clear. That it secretes a hormone which plays a role in lymphoid function has been definitely established? Finally, Cooper, Peterson, South, and Good 4 whose extraordinary energy and insight has taken them into every aspect of this field, have demonstrated that in the chicken, while the thymus is essential for the competence of the small lymphocytes which are responsible for immunological memory and recognition, the bursa of Fabricius, a similar organ at the lower end of the gut, controls the competence of larger lymphoid cells, from which antibody-forming cells are derived. Intensive searches have thus far failed to identify the bursa's counterpart in man, though both appendix and tonsils have been suspected, without their role being clearly established. Thus, having associated the first stage of response to infection--capture and processing

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of antigens--with the phagocytes of the body, and the second stage--recognition and immunological

memory--with

lymphocytes,

conditioned in some mysterious way by the thymus, we come to the third stage---the specific immunological responses themselves. By oversimplification we may condense these to 2 main types of response: (1) delayed hypersensitivity, a function of specifically instructed small lymphocytes, and (2) antibody formation, a function of specifically instructed cells of the plasma cell series. The development of delayed hypersensitivity is a fundamental response to all types of infection, but varies markedly in intensity with different microorganisms. There is little doubt that it plays a role in the tissue responses to pyogenic infection and that it is probably induced by antigens derived from the infecting organisms which are chemically different from those giving rise to specific protective antibodies. Except in the case of the mycobacteria, very little work has been done in this field. It is our impression that delayed hypersensitivity is primarily group specific rather than type specific; for example, the first infection with /?-hemolytic streptococci will alter the patient's tissue response to subsequent /?-streptococcal infections, although the humoral antibody formed will only protect against the infecting type. The rejection of homografts, as a result of recognition of the foreign nature of the histocompatibility antigens of the transplanted cells, is a parallel phenomenon, primarily dependent upon small lymphocytes. The relationship of the lymphocyte to delayed hypersensitivity was established by the classic experiments of Lawrence 5' 6 on the passive transfer of tuberculin sensitivity by white cells and later even by disrupted lymphocytes. Antibody formation has been subjected to far greater scrutiny by immunologists, histologists, and chemists than delayed hypersensitivity. From a series of beautiful studies, we know that the morphological hallmarks of antibody formation are hyperplasia of the lymphoid follicles, with enlargement of

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germinal centers and the development of secondary follicles at their periphery, and the appearance of plasma cells in lymph nodes and spleen, as well as in other local sites of infection or tissue damage. The true precursors of plasma cells have not been clearly identified, although they probably arise from a stem cell which may differentiate at an early stage of development into lymphocytic and preplasma cells. When specifically stimulated by an antigen, these preplasma cells undergo mitosis and assume the histological appearance of plasma cells, with the abundant endoplasmic reticulum characteristic of a secretory cell, as shown by electron microscopy, and intense staining with methyl green pyronine, indicating the presence of large amounts of ribonucleic acid as evidence of active protein synthesis. Whether this is the same process as is observed in vitro when peripheral lymphocytes are stimulated by phytohemagglutinin to transformation and mitosis is not proved, but it seems probable. The secretory products of the plasma cells, the g a m m a globulins, are now called immunoglobulins, ever since Gitlin, Hitzig, and Janeway 4 showed that not one but three proteins were lacking in the serum of agammaglobulinemic patients, and Grabar and Williams s demonstrated by immunoelectrophoresis that electrophoretic mobility of the antibody proteins extended far beyond the g a m m a range. Structural analyses have shown that immunoglobulin molecules are composed of four polypeptide chains, a pair of heavy chains, and a pair of light chains held together by disulfide bonds. By their reaction with antibodies to human immunoglobulins prepared in animals, the immunoglobulins can now be divided into five classes (.rM, .rA, "/c. 7D, and 7E)'~); the distinction depends upon the heavy chains, which differ for each class (labeled with the corresponding Greek letter), while the light chains (labeled kappa [K] and lambda IX] are the same in all classes, about two thirds of the molecules containing a pair of K chains and one third, a pair of ,k chains under normal circumstances. The molecular for-

The Journal o[ Pediatrics June 1968

Table I. H u m a n immunoglobulin classes Average $r co~2cen-

Molecular Molecular globulin [ormulas weight 7-~ (#_~:).~or (#.x._.)~ 900,000 7-~ ~K~or a.,X., 160,000 (32o,ooo) /~; 7~K~or 7~X... 170,000 7t) 8~K:or 82X,., -"/s E=.~or E.,X: --

]rlltl~uno-

tration (adult) 70 150 1,200 3

5

mulas for the human immunoglobulins may be written as shown in Table I. The functional importance of these different classes of immunoglobulins is beginning to be understood, yD and "rE are present in minute amounts (5 mg. per cent or so) in human plasma; atopic reagins now appear to be .rE globulins. TM Neither .rM nor .rA cross the placenta from mother to fetus, while .r(b owing to specific properties of the .r chain, is transferred rapidly from maternal to fetal circulation n and thus, an infant, at the time of his birth, possesses all his mother's 7, antibodies but almost no .r.~t or .rA globulins, unless he has been infected during gestation, when .rM globulins and yA produced by his own plasma cells may be present at birth. 1~ The detection of "r~Tglobulins in cord blood has been suggested as a screening test for congenital prenatal infections? ~ Although "/A globulins are found in the blood, they represent the class of antibodies found predominantly in secretions, and seem to play an important role in local immunity? 4 The first type of antibody to appear in response to immunization or infection is the 19S macroglobulin or YM globulin. After continued immunization or reimmunization with most antigens, this .r~ antibody is replaced by yG globulin in much larger amounts? ~ Thus, the primary response is characterized by a relatively low titer of yM antibody, which can be identified by its loss of activity after treatment of the serum with a sulfhydryl reagent, such as mercaptoethanol. The secondary response is characterized by a much higher titer of 7- anti-

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Table II.

Stage Primary response 1. Capture (a) Phagocytosis (b) Killing (c) Digestion

I

Cell

I

Organ

Wandering phagocytes Fixed macrophages

Tissues Lymph nodes Liver Spleen

2. Recognition

Lymphocytes

Lymph nodes Spleen

3. Specific responses (a) Development of delayed hypersensitivity

Lymphocytes

Lymph nodes Spleen Lymph nodes Spleen

(b) Synthesis of antibody, primarily yM globulin

Secondary response 1. Capture Enhanced by antibody

Plasmacytoid cell

Wandering phagocytes Fixed macrophages

Tissues Liver Spleen Lymph nodes

2. Recognition Immunological memory

Lymphocytes

Tissues Lymph nodes Spleen

3. Specific responses (a) Delayed hypersensitivity reaction (b) Synthesis of antibody, primarily ya globulin

Lymphocytes Plasma ceils

Tissues Tissues Lymph nodes Spleen

body, resistant to mercaptoethanol, which either shuts off the synthesis of ~,~ antibody or renders it undetectable. 16 This difference in the class of immunoglobulin formed in the initial response to a specific infection from that formed in a subsequent exposure has been used to distinguish an initial attack of typhus fever from Brill's disease, which is a recurrence occurring m a n y years later. 17 Thus, we can summarize our present concept of the responses to bacterial infection as shown in Table II. Not only does the scheme presented provide a framework to which the syndromes of altered resistance encountered in patients may be related, but much of the scheme itself has been derived from studies of immunologically deficient patients. Let us examine some of the syndromes which have been uncovered in the past 15 years, while

stressing the fact that our knowledge is not complete, and new information is constantly being published in this rapidly moving field, so that any classification is tentative. DISTURBANCES

OF T H E

C A P T U R E SYSTEM A. Wandering cells. The polymorphonuclear leukocytes, as the first line of defense against pyogenic bacteria, m a y be deficient either in quantity or in quality. Quantitative deficiency, as in severe neutropenia from any cause, usually results in undue susceptibility to staphylococcal infection, as well as to pseudomonas infection, particularly in patients treated intensively with antimicrobial chemotherapy. Recent work has demonstrated that qualitative deficiencies in phagocytic cells, particularly the polymorphonuclear leukocytes,

8 9 0 Janeway

give rise to a syndrome, described under various names in the literature over the past 13 years but now generally called chronic granulomatous disease of children, as In this disease, chronic infection of the skin, subcutaneous tissues, or lungs, principally with staphylococci, gives rise to lymphadenopathy, hepatosplenomegaly, hypergammaglobulinemia, and fever. Microscopically, the involved organs show microabscesses and granulomata with many plasma cells and pigmented histiocytes. Holmes, Quie, Windhorst, and Good 19 first demonstrated in 1966 that leukocytes from these patients were normally active as phagocytes, but that they were unable to kill the ingested organisms. Subsequently, Baehner and Nathan 2~ were able to show that there is a metabolic defect in the cells, which results in failure of the normal sequence of events which follows the ingestion of bacteria. In normal polymorphonuclear Ieukocytes, the ingestion of bacteria or other particles results in the formation of vacuoles around the particles, into which the enzymes and bactericidal substances contained in the granules are liberated, with resultant degranulation of the cells and killing and digestion of the bacteria. This process is accompanied by an increase in oxygen consumption and stimulation of the hexose-monophosphate shunt? 1 In chronic granulomatous disease, the cells fail to show degranulation or increased shunt activity after the ingestion of particles, apparently due to lack of an oxidase for reduced nicotinamide adenine dinucleotide. This defect can be demonstrated by a simple test in which nitroblue tetrazolium is added to a suspension of burly coat. If the granules are separated from these defective cells, they are found to contain a normal complement of enzymes and normally active bactericidal substances, indicating that the functional deficiency is due to failure of the degranulation process rather than to an abnormality in the composition of the granules. This inborn error of metabolism is inherited as a sex-linked recessive character, occurring only in boys, while the range of

The Journal o/ Pediatrics June 1968

activity of the leukocytes from carrier females is approximately half that of normals. Occasional carriers may have some difficulty with infection. Recently Baehner 22 has identified a 17-year-old girl, with the complete metabolic defect, and a long history of chronic and recurrent infection, who is the product of a consanguineous marriage, but with no demonstrable defect in the leukocytes of either parent, thus strongly suggesting an autosomal recessive inheritance in her case. In view of the complex nature of the metabolic events and the enzymes involved in the processes of phagocytosis, killing, and digestion, it would not be surprising if other specific defects affecting leukocyte function would be brought to light. Treatment of deficiencies, both qualitative and quantitative, of the polymorphonuclear leukocytes is still quite unsatisfactory. Intensive surgical and chemotherapeutic treatment of infections and strict isolation of hospitalized patients in order to protect them from cross infection are the main therapeutic approaches. The technical difficulties of separating white blood cells for transfusion, their short life-span after infusion, and problems of compatibility make repeated white blood cell infusions impractical at present. B. Splenic insufficiency. A completely different clinical syndrome occurs in certain children with splenic insufficiency. This was first recognized by Shumacher, "3 who observed severe meningococcemia in 8 children, from whom he had removed the spleen for hematological disease. Overwhelming, rapidly fatal bacteremia, principally with pyogenic organisms, such as H. influenzae and pneumococci, often with meningitis, characterizes splenic insufficiency. Great controversy has raged over this matter, with some reports indicating that there was no danger of overwhelming bacteremia following splenectomy and others suggesting that there was. A careful analysis by Eraklis, Kevy, Diamond, and Gross 2~ of the subsequent course of 467 children subjected to splenectomy, as well as their more recent ex-

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perience, suggests that at least two factors are involved in the increased susceptibility to bacteremia in the absence of normal splenic function: (1) the age at which splenectomy is performed (2) the disease for which splenectomy is performed. The age factor is of great importance. During the first few years of life, pyogenic infections represent the individual's first encounter with a particular organism, and thus primary immunological responses occur. It is well known that during this time bacteremia and its sequel, meningitis, occur far more frequently than at any other time of life. The clearing of microorganisms from the blood is carried out predominantly by the Kuppfer cells of the liver, particularly in an immune animal, but the spleen has been shown to be especially effective in clearing pneumococci from the blood of nonimmune rabbits. 25 The liver lacks the combination of macrophages and immunologically active tissue present in the lymphoid follicles of the spleen, and it has been shown experimentally that antibody formation to intravenously injected antigens, such as heterologous red cells, which do not readily escape from the circulation, is markedly depressed by splenectomy. 26 Thus, in an age group particularly susceptible to bacterial invasion, absence of the spleen might well be critical, as it seems to be. Evidence for the importance of age is shown by the frequency of overwhelming infection in infants with congenital absence of the spleen, and in sex-linked congenital hypoplasia of the spleen, recently described by Kevy and associates 27 as well as in infants with severe idiopathic hypoglycemia, from whom the spleen had been removed, in the course of partial pancreatectomy to combat the hypoglycemia.2s All of these instances occurred in otherwise apparently immunologically normal individuals. The disease for which splenectomy is required may affect the results in two ways: first, by affecting the age at which splenectomy is performed and second, by affecting

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the state of the rest of the clearing (reticuloendothelial) system. Thus, infection has seldom been a problem in children in whom the indication for splenectomy was traumatic rupture, congenital spherocytosis or idiopathic thrombocytopenia. On the other hand, overwhelming infection has occurred in children splenectomized for the treatment of severe thalassemia or one of the lipid storage diseases. In both of these situations all the macrophages are affected: in one case by hemosiderosis from multiple transfusions; in the other by the accumulating lipids and probably by a state of partial reticuloendothelial blockade. The practical considerations in relation to splenectomy would therefore seem to be the following: (1) defer splenectomy as long as possible in young children; (2) alert the parents of the splenectomized child to take all febrile episodes seriously, to call the physician immediately, and to initiate therapy with full doses of penicillin as soon as fever appears. Any consideration of deficiencies in the specific immunological responses of the second and third stages is handicapped by incomplete knowledge and by the fact that the components of the immunological system may perhaps, like the phagocytic system, either be quantitatively reduced or qualitatively deficient. Furthermore, the lymphoid tissues are peculiarly labile, with marked changes taking place as the result of prolonged infection, stress, or the administration of large doses of corticosteroids. Thus, interpretation of the postmortem appearance of the immunological system in children dying after severe or prolonged infections is difficult. Finally, the thymus, upon the proper functioning of which immunological competence appears to depend, has only become the object of intensive scrutiny by pathologists in recent years, after a long period of neglect since the early days of histopathology. With these reservations in mind, let us consider deficiencies involving the specific second and third stages of the response to infection.

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D I S T U R B A N C E S OF R E C O G N I T I O N AND IMMUNOLOGIC MEMORY

The thymus, as has been indicated by experimental studies, seems to play an essential role in the establishment of immunological competence in early life. This is particularly so for the lymphocyte, which is considered to be a thymus dependent cell, 29 and which appears to be essential to the recognition process and, once it has been instructed, to be the carrier of immunological memory. This latter function well may be related to the fact that the survival of small lymphocytes in man may be at least as long as 10 years, and that lymphocytes contain a "transfer factor" which permits them to instruct other lymphocytes and even to initiate a secondary response in nonimmune animals? ~ Consequendy, the pathology of the thymus has been looked at with great care in immunological disorders in recent years. Congenital disorders of the thymus appear to have devastating clinical effects, but can only be suspected indirectly during life, since methods for direct measurement of thymic function are lacking; even anatomic recognition may be difficult roentgenographically because of the marked involution which takes place during any acute or chronic disease as well as that which occurs normally as the infant progresses into childhood. The most striking form of immunological deficiency is the Swiss or alymphocytic type of congenital agammaglobulinemia, originally described under the term, lymphocytophthisis or alymphocytosis, al This represents total immunological incompetence, with inability to develop delayed hypersensitivity, to reject homografts, or to synthesize immunoglobulins. Clinically, these infants develop a syndrome in the first few months of life characterized by lymphocytopenia, failure to thrive, chronic recurrent pulmonary infections, oral and cutaneous moniliasis and chronic diarrhea, and they all succumb, despite heroic efforts at therapy, by 2 years of age. Vaccination leads to progressive vaccinia in these infants, bacillus Calmette-Guerin vaccine may produce disseminated tuberculosis, and pneurnocystis carini infection may

The Journal ot Pediatrics June 1968

occur. In this country, family history suggests a sex-linked recessive inheritance; in Europe, infants of both sexes have been observed. Pathologically, the lymph nodes are very small, with almost complete absence of all normal elements except for a stroma of reticulum cells, macrophages and sinusoids; lymphoid cells are absent from the lamina propria of the intestinal mucosa; and the thymus is very small and rudimentary, lacking differentiation into cortex and medulla, lymphocytes, or Hassall's corpuscles. This has led to the use of the term, thymic alymphoplasia, to describe this disorder? 2 We prefer to use the term, hereditary thymic aplasia. In most such cases there is hypoplasia of the epithelial thymus, but a few cases of thymic agenesis with hypoparathyroidism have also been described? 3 Attempts to rectify the immunological deficiency by the transplantation of thymus tissue, fetal hematopoietic cells, or bone marrow cells, have failed? 4 As so often happens, once the classic picture of a syndrome has been recognized, variants begin to be discovered. Nezelof and associates 85 were the first to show that in such patients immunoglobulin synthesis and plasma ceils might be found. By now a number of other cases have been observed in which the basic deficiency of thymic function and its dependent lymphocytes exists, as shown either by low levels of circulating lymphocytes, or failure to develop delayed hypersensitivity or to reject homografts, even though synthesis of one or more of the immunoglobulins and antibody formation may occur. 36 These cases are taken as evidence that the development of plasma cells and their secretory products, the immunoglobulins, are not under thymic control. The finding of a rudimentary tonsil in one case suggested that it might be the "gut-associated" mammalian equivalent of the bursa of FabHcius. ~z Two diseases of a hereditary nature in which there is a "blunting" or diminution of the thymus-dependent delayed hypersensitivity reactions are the Wiskott-Aldrich syndrome 3s and ataxia telangiectasia. 4~

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The Wiskott-Aldrich syndrome is transmitted by sex-linked recessive inheritance and characterized clinically by eczema, thrombocytopenia, and recurrent infections of the skin and respiratory tract, frequently with suppurative lymphadenopathy. Death occurs in infancy or childhood. Pathologically, there may be hypoplasia of the thymus, and immunologically a depression of delayed hypersensitivity reactions often with decreased numbers of peripheral lymphocytes. Isohemagglutinins and yM globulins are markedly reduced, while 7a globulins may be increased. 39 In ataxia telangiectasia, a hereditary disease with progressive cerebellar ataxia, telangiectasia, and frequent bronchosinusitis, there is also evidence of thymic dysfunction, with lymphopenia and failure of delayed hypersensitivity.4~ Although serum yA globulin is markedly diminished or absent in about 80 per cent of the cases, it may either be present or be replaced by yG globulin antibody in nasal secretions, so that this deficiency does not seem to be responsible for the frequent respiratory infections?1 The thymic disorders which have been discussed above are congenital and hereditary in most instances and indicate that, when the thymus is not developed or is missing during fetal and early extrauterine life, lymphocyte function is inadequate. In addition, the various experimental attempts in animals to suppress lymphocyte function so as to permit the establishment of a state of tolerance for homografts,* indicate that the normal recognition process can be upset by various measures taken in early life. Other procedures will ablate lymphocytic function and thus create a state of tolerance after the neonatal period which will permit homografts to survive. Three principal methods have been used in laboratory experiments or in clinical investigation to evaluate lymphocytic functions: (1) the removal of lymphocytes by diversion of thoracic duct lymph~~ (9) the administration of cytotoxic drugs ("immuno~Thls occurs following neonatal thymectomy or the injection during fetal life of splenic cells of the strain from which the graft is to be derived.

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suppressive" therapy); (3) the administration of antilyrnphocyte serum? 2' 43 The last is the most interesting because it not only has been shown to be effective in the suppression of both recognition and immunological memory, but it may do so without diminishing the numbers of circulating lymphocytes. This suggests that it may coat the surfaces of the circulating lymphocytes and thus cover the recognition sites upon which recognition and immunological memory presumably depend. This reasoning is supported by clinical observations from two different centers. Kretschmer, Janeway, and Rosen 44 in Boston have observed a patient with severe recurrent infections associated with hypergammaglobulinemia and dysgammaglobulinemia, but with recurrent lymphopenia which appears to be due to the development of lymphocytotoxic antibody, with consequent loss of immunological memory. The patient is capable of exhibiting a primary response, but incapable of delayed hypersensitivity reactions or the rapid, marked rise in antibody titer characteristic of a secondary response; likewise, there was no accelerated second-set rejection of a skin homograft. Thus immunological memory was erased, presumably by the lymphocytotoxic antibody in a fashion analogous to that seen in animals treated with antilymphocytic serum; we have therefore termed this condition "immunological amnesia." Rossi and his associates45 have observed an identical case in Bern, Switzerland. To summarize, deficient thymic function in early, and particularly in fetal, life results in the loss or depression of those functions carried out by the thymus-dependent lymphocyte. These functions are: (1) recognition, which results in the development of delayed hypersensitivity in response to infection, in the initiation of the rejection of homografts, and presumably in the "commitment" or "instruction" of a certain number of lymphocytes to respond to the antigenic configuration which stimulated the response; (9) immunological memory, due to the presence and persistence for years of these "committed" or "instructed" lymphocytes, so that upon subsequent contact with the same

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antigenic configuration, the delayed hypersensitivity response occurs within 48 hours, homograft rejection is greatly accelerated (second-set rejection) and cells of the plasma cell series are stimulated to multiply and secrete large amounts of specific immunoglobulin antibody within a short time. Measures which reduce the numbers of, or block the recognition sites on, the lymphocytes, as the effector cells, will diminish or obliterate these functions. Many diseases of the lymphoid tissues, such as disseminated Hodgkin's disease, sarcoidosis, and the lymphomas, may alter the numbers or functional capacity of the lymphocytes. Obviously, much remains to be learned about how delayed hypersensitivity reactions are blunted by these processes or by measles, since other components are involved in these reactions besides the lymphocytes.

The lournal of Pediatrics June 1968

Table III. Antibody deficiency syndromes Transient states in infancy 1. Deficiency of y~, globulins in the neonatal period 2. Delayed maturation of immunological responses (a) Transient hypogammaglobulinemia or dysgammaglobulinemia 5. Inadequate immunological responsiveness (?) Congenital antibody deficiency syndromes 1. Hereditary thymie aplasia with agammaglobulinemia or dysgammaglobulinemia (a) Sex-linked recessive (b) Autosomal recessive 2. Hereditary sex-linked agammaglobulinemia or dysgammaglobulinemia 3. Sporadic congenital agammaglobulinemia or dysgammaglobulinemia Acquired antibody deficiency syndromes 1. Primary acquired agammaglobulinemia or dysgammaglobulinemia

2. Secondary hypogammaglobulinemia (a) "Hypereatabollc" hypogammaglobulinemia

ANTIBODY D E F I C I E N C Y SYNDROMES The term antibody deficiency syndrome, first coined by Swiss investigators, seems like the best one to describe in functional terms the group of disorders, which are dependent upon inadequacies of plasma cell function, and which have usually been referred to as agammaglobulinemia, hypogammaglobulinemia, or dysgammaglobulinemia in the American literature. Originally recognized in 1953 in its most striking, clear-cut form (congenital sex-linked recessive agammaglobulinemia), an increasing number of clinical entities and pathophysiological disturbances have subsequently been described. These syndromes have as their common feature a deftciency in the synthesis of one or more immunoglobulins in response to infection or immunization, which usually is reflected in some morphological change in the lymphoid tissues and in an inadequate number of plasma cells. Any classification of these disorders is still tentative, but Table III gives one based on the type of developmental and functional thinking which is now prevalent. A. Transient states in infancy. The normal fetus does not appear to develop immunologically competent cells until the

(b) Diseases of lymphoreticular system 1. Neoplasms of lymphoid tissues 2. M component diseases

twelfth week or so of fetal development. It is interesting that it is about from that time that most of the normal plasma protein components can be detected in fetal serum by immunoelectrophoresis, although not in the same amounts as in the adult? ~ In addition, there is another protein present which is peculiar to the fetusW The question arises as to whether the proteins of fetal serum are produced by the fetus, produced in the mother and transferred across the placenta, or are the result of both of these processes. Gitlin, working with Kumate and others in Mexico, has been deeply engaged in the study of the transfer of labeled proteins from the maternal to the fetal circulation, but most of these studies must necessarily be performed near term, and very little information is available in the earlier stages of pregnancy? 1 There are several lines of evidence which suggest that immunoglobulins are not synthesized by the fetus under normal circumstances, and that only 7o globulins are transferred across the placenta, starting at about the third month so that,

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by term, maternal 7G antibodies are present in the fetal circulation at approximately the same concentration as in the mother. These may be summarized as follows: (1) The injection of labeled methionine into fetal guinea pigs by Dancis and Shafran 48 resulted in rapid labeling of all the major plasma proteins in the fetal circulation except the gamma globulins. 4s (2) Kumate and Gitlin and associates n showed that labeled gamma globulin was transferred from the maternal to the fetal circulation much more rapidly than any other plasma protein. (3) Good's group showed that, whereas infants born with congenital sex-linked agammaglobulinemia have levels of gamma globulin and antibodies at birth comparable to those in their phenotypically normal mothers, an infant born to a mother with acquired agammaglobulinemia had no gamma globulin in his serum at birth, although later he synthesized gamma globulin and antibodies in a normal fashion. 49 (4) The lymphoid tissues of the normal fetus and normal newborn infant seem hypoplastic, resembling those of animals raised in a germ-free environment. As the infant develops and is subjected to colonization by saprophytic bacteria, to infection, and to immunization, the lymphoid tissues develop their normal architecture, plasma cells are formed, and gamma globulin antibodies synthesized by them appear in the circulation after antigenic stimulation. 49' 50 The infant infected in utero will exhibit plasma cells and greater signs of lymphoid activity, and his serum wiI1 contain antibodies at birth, but these are usually principally of the yM, and to some extent yA, class. Thus, it has been suggested that a test for more than traces of TM globulin in cord blood at birth would make an excellent screening test for congenital infections such as rubella or toxoplasmosis? 3

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Deficiency of maternal y~ in the neonatal period. As has been implied above, the normal newborn infant, who has not been infected in utero is born with what appears to be a normal level of circulating gamma globulins. However, analysis for the different immunoglobulins indicates that this is practically all yo globulin derived from the maternal circulation, while the amounts of 7~, "/A and probably ~,D and ~'E globulins are virtually undetectable. This passively transferred maternal 7G antibody is important in two ways: first, it protects the infant against the vast majority of viral and bacterial infections against which the mother has adequate levels of effective ~,G antibodies (measles, infectious hepatitis, poliomyelitis, diphtheria, tetanus, gram-positive bacterial infections, for example, but not varicella and variola or pertussis, where serum antibodies are low or relatively ineffective in protection); second, it may prevent an adequate primary response to immunization with toxoids or subclinical infection with living attenuated virus vaccines (measles, poliomyelitis, but seldom vaccinia) .~1 Multiple antigenic stimuli, as the result of clinical infections, the far more frequent subclinical infections and asymptomatic carrier states, or repeated vaccination, give rise to y~ type antibody at first, which is soon replaced by ye antibody. 5~ However, repeated contacts with the gram-negative bacilli of the intestinal tract, both pathogenic and ordinarily saprophytic organisms, usually only results in the formation of bactericidal antibodies against their somatic O antigens, which are yM globulins. 53 In a few individuals there is some ya antibody as well but usually in low titer. As ~/~i globulins, these bactericidal antibodies are not transferred to the fetus~4; normally, within the first month or two of life, y~ and yA globulins begin to appear in the infant's circulation, 55 presumably as a result of the many antigenic stimuli which he receives from his environment, including the gram-negative flora of the intestinal tract. Adaptation from a sterile gut to one teeming with bacteria normally takes place without difficulty, unless patho-

8 9 6 ]aneway

genic Escherichia coli, Salmonella, or Shigella are acquired from the nursery environment. However, if the mother herself is suffering from gram-negative infection (e.g., of the urinary tract or as a result of premature rupture of the membranes or prolonged labor) the infant may acquire a large dose of pathogenic gram-negative bacilli by aspiration or invasion of the cord, and gram-negative pneumonia, sepsis, or meningitis may develop. This is the commonest form of serious infection in the first two weeks of life. Whether or not adequate levels of y.~ globulin from pooled adult blood would prove protective to these high-risk babies can only be determined by a carefully controlled clinical trial once an adequate preparation of ~/.~ antibodies is available. There is no satisfactory concentrate of these antibodies at present; only minimal amounts are present in standard gamma globulin preparations. "~

Delayed maturation of immunological responses. We have given the name, Transient Agammaglobulinemia (Hypogammaglobulinemia, or Dysgammaglobulinemia) of Infancy, to those infants in whom there is a prolongation of the drop in the level of circulating gamma globulins, which normally occurs during the first 4 to 8 weeks of life, as growth expands the size of the infant and normal catabolism of the maternally derived y(. globulin reduces the total amount in the body by approximately 50 per cent each month. If the infant fails to commence the synthesis of his own immunoglobulins, which normally occurs during the first two or three months and results in a gradually accelerating rise in the total circulating gamma globulins, catabolism of the maternal gamma globulin results in a continuing decline in passively acquired antibodies below those levels which are normally protective (l to 2 months against pyogenic bacteria, 6 to 8 months for measles, polio, and certain other virus diseases), and severe infections begin to occur?; This form of antibody deficiency syndrome is frequently associated with episodes of bronchitis and wheezing and possibly accounts for the tendency of some allergists to feel that gamma globulin injections are helpful in

The Journal o[ Pediatrics June 1968

the control of infectious asthma, a conclusion not substantiated by controlled studies. Treatment of this transient hypogammaglobulinemia requires vigorous antimicrobial therapy of acute bacterial infections and gamma globulin injections in full doses (p. 31) to prevent serious infection until such time as an appreciable rise in the level of gamma globulins, a rise in serum antibodies after immunization, or definite growth of tonsils and lymph nodes indicates that the development of normal lymphoid function has begun. In addition to these cases of transient deficiency of all three immunoglobulins (dysgammaglobulinemia), selective deficiency of one or more of the immunoglobulins, may occur in transient form. Commonest is a deficiency of yG and often yA, with increased amounts of y~ globulin. Absence of "/A globulin may occur throughout most of life in perfectly normal individuals, may be seen in the first few years of life, or may indicate the individual who will later develop ataxia telangiectasia. 55 In addition, a group in Switzerland have associated absence of )'A globulin in infancy with undue susceptibility to recurrent otitis media and claim benefit from this transient disturbance by the injection of large doses of gamma globulin, which contains very little yA globulin, but might be generally protective against invasive infection by pyogenic bacteria. 5s A number of reports continue to appear suggesting that gamma globulin is protective against recurrent respiratory infections, sometimes in ridiculously small doses. The natural tendency for the health of children to improve with time, the extreme difficulty of getting a critical, controlled evaluation of such a procedure rather than just clinical impressions and mother's reports, not to mention the potential hazards of isosensitization by the repeated administration of large doses of pooled isologous gamma globulin to immunologically normal children makes us skeptical of the results claimed and against such use of a very valuable therapeutic agent.

Inadequate immunological responsiveness.

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This has been postulated by a group of Dutch workers as a transient partial immunological deficiency on the basis of failure of yA and ~'o globulins to increase following an episode of infection in certain children, otherwise normal, who seem to be unduly susceptible to recurrent severe respiratory tract infections. 59 Their improvement when a normal rise in ~'A or ~,G globulin is observed following a severe infection is further adduced as evidence that, although the levels of immunoglobulins may be normal in many of these children, maturation of their responsiveness to infection has been delayed. This interesting hypothesis deserves critical study to see if it can be confirmed, and to determine where in the chain of events leading to an immunological response the defect lies. Congenital antibody deficiency syndromes. Hereditary thymic aplasia. This condition, which may occur with or without marked lymphocytopenia and with agammagtobulinemia or dysgammaglobulinemia, has already been described under Disturbances of

Recognition and Immunological Memory. Hereditary sex-linked agammaglobulinemia. This disease, occurring only in boys and transmitted by carrier female subjects whose immunoglobulins are normal, is the commonest form of the antibody deficiency syndrome in childhood. Since the thymus and circulating lymphocytes are normal, delayed hypersensitivity and the ability to reject homografts are preserved, but antibody formation is markedly depressed. This is due to a lack of the normal follicular architecture of spleen and lymph nodes, with a marked paucity or absence of plasma cells even in nodes draining areas of infection or immunization sites. In the majority of cases, total gamma globulins are markedly reduced ( < 100 rag. per cent), while ~/M, ~'A and ~'G are usually undetectable or greatly diminished upon immunoelectrophoretic examination of serum. These patients tend to handle viral infections better than bacterial infections, and their story is one of repeated episodes of fever, pneumonia, otitis media, sinusitis, pyoderma, sepsis, and meningitis, usually beginning late in the first year or during the sec-

Progress in immunology 8 9 7

ond year of life. The only helpful physical sign is a marked paucity of tonsillar and adenoid tissue despite recurrent respiratory infections. Their infections respond welt to antimicrobial therapy, and regular injections of gamma globulin in adequate dosage (p. 31) will prevent the episodes of invasive infection, but not low-grade local infections which may require antimicrobial chemotherapy. 6~ Of great interest is the frequency of a somewhat indolent arthritis (about 30 per cent), which usually clears when gamma globulin prophylaxis is begun and the late appearance in some cases of a dermatomyositis-like syndrome, which has a grave prognosis. Typical allergic reactions may occur in these patients. First recognized as a disease entity in 1953, the oldest living patients with congenital sex-linked agammaglobulinemia have now reached their twenties and are living relatively normal lives, except for their continuing requirement for gamma globulin therapy and such residua as middle ear deafness or bronchiectasis from their previous infections. In certain cases of this syndrome, a higher level of gamma globulins is found (200 to 400 mg. per cent), which usually indicates dysgammaglobulinemia. 6z The commonest form (so-called Type I) is associated with a marked deficiency of "/A and yG globulins, but a considerable increase in YM globulins together with plasmacytoid cells which are positive to periodic acid-Schiff stain and positive to immunofluorescent staining with antibody to yM globulin. In some of these children cyclic neutropenia or thrombocytopenia may create additional problems. Autoimmune phenomena, lymphadenopathy, and splenomegaly have been observed in a few instances, and marked tonsillar hypertrophy due to hyperplasia of the plasmacytoid cells has necessitated tonsillectomy on occasion. Finally, there is a tendency to invasion and widespread proliferation by the plasma-cytoid cells, suggestive of lymphoma or leukemia. Most of the possible combinations of the three immunoglobulins have been observed by now, and there is at least one sporadic or

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transient case in which the antibody deficiency syndrome occurred in a child with normal 7~ globulins but absence of 7~ and 7x globulins, plasma cells in his tissues, but no ability to form specific antibodies, a state from which he later recovered. 62

Sporadic congenital agammaglobulinemia. Occasional cases of a syndrome corresponding clinically and pathologically to what has been described in the preceding paragraphs occur sporadically in young girls as well as boys without a family history of the disease. Acquired agammaglobulinemia.

Primary acquired agammaglobulinemia. This condition, which may develop at any age and in patients of either sex, bears many resemblances to the hereditary sex-linked form of agammaglobulinemia, and is characterized by deficiency of the immunoglobulins in the serum and by a paucity of plasma cells in the tissues21, 6~ Dysgammaglobulinemia may also occur. Pyogenic infection of the respiratory tract, with recurrent sinusitis, pneumonia, and often bronchiectasis, is the rule. The major differences from the congenital form are later onset, a low frequency of arthritis and the occurrence of a spruelike syndrome, with diarrhea, malabsorption, and protein-losing enteropathy, in about half the cases. The immunoglobulin deficiency is usually somewhat less marked than in the congenital variety, with higher serum immunoglobulin values. Lymph nodes and spleen show abiotropy of the lymphoid follicles, and noncaseating granulomas have been found in skin, lungs, liver, and spleen. Lymphadenopathy and hepatosplenomegaly may be manifest. These patients often develop lymphoreticular neoplasia, and thymomas have been found in several cases. 64 Although primary acquired agammaglobulinemia does not appear to be hereditary, a few instances have been observed with two cases in a single kindred; in contrast, Cruchaud and associates6~ have reported a case in only one of a pair of identical twins. An unusually high incidence of other immunological disorders in relatives of these patients has been reported. 66

The Journal o[ Pediatrics June 1968

Secondary acquired agammaglobulinemia. HYPERCATABOLIC

HYPOOAM MAGLOBULINE-

M~. In all the conditions, previously described, the antibody deficiency syndrome is caused by inadequate synthesis of immunoglobulins. Thus, in agammaglobulinemia the half-life of injected yc globulin has been shown, if anything, to be longer than usual2 T Processes which lead to rapid loss or catabolism of gamma globulins, with or without an increased rate of synthesis, can result in a lowering of their serum concentrations. In such conditions, the serum albumin level is usually even more affected. Chronic severe oozing of plasma from the skin, as in pemphigus or severe eczema, or heavy proteinuria, as in the nephrotic syndrome, can lead to marked hypoproteinemia. Most instances of so-called idiopathic hypoproteinemia are due to occult loss of plasma proteins into the gastrointestinal tract-protein-losing enteropathy. Such "hypercatabolic" hypogammaglobulinemia seldom results in undue susceptibility to infection because immunoglobulin synthesis and antibody formation are normal, although the serum levels are low. However, in the nephrotic syndrome, protein losses and increased catabolism are so great and the serum levels so markedly reduced that recurrent episodes of bacteremia do occur, ss We believe this to be due to a combination of very low immunoglobulin levels in the interstitial fluids as a result of further dilution by the edema fluid, lymph stasis, and the ready growth of certain microorganisms in the edematous tissue spaces. DISEASES OF T H E

LYMPHORETICULAR SYS-

Inadequate synthesis of immunoglobulins occurs frequently with neoplasms of the lymphoreticular system, such as Hodgkin's disease, chronic lymphocytic leukemia, or lymphosarcoma. Here the tendency to recurrent infection has complex causes related to the disease and its treatment. Patients with WaldenstrSm's macroglobulinemia or multiple myeloma, who are usually adults, may synthesize very large amounts of M components which may be confused with normal y globulins on simple electrophoresis. They TEM.

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often exhibit a severe antibody deficiency syndrome, with recurrent infections, due to an inability to synthesize normal immunoglobulins. D I A G N O S I S AND M A N A G E M E N T Diagnosis. The proper evaluation of any patient with a suspected disorder of resistance begins with a careful history. The physician must distinguish between an overanxious mother with a child, who, because of frequent exposure to infections brought home by preschool and school age siblings, has his "immunological education" compressed into a shorter period than usual and the child whose infections, though not too unusual in frequency, are exceptionally severe and may be repetitive, and therefore make one suspicious of an antibody deficiency syndrome. A carefully taken family history is very important in suspected cases of diminished resistance, both because many of these disorders have a genetic basis, and because family patterns of susceptibility to frequent bouts of tonsillitis, bronchitis, or otitis media in early childhood seem to repeat themselves from one generation to another. Upon physical examination the size and character of the tonsils are helpful in estimating the state of the lymphoid tissues; the tonsils tend to be small and without normal follicular structure in the agammaglobulinemias. The size of lymph nodes, spleen, and liver also should be noted. Certain simple tests can be used for rapid screening of suspected cases: (1) white blood and differential counts to rule out neutropenia; (2) determination of blood group and isohemagglutinin titer for the presence of yM antibodies; (3) Schick test for diphtheria immunity in an immunized child; (4) total serum protein and electrophoresis for the level of gamma globulins. The last may be deceptive, since paper strip electrophoresis is very inaccurate at low concentrations of gamma globulins, and the level changes markedly during the first year of life. Immunoelectrophoresis is far more valuable, but the interpretation of divergences from the

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normal pattern during the first year of life requires experience. Any child suspected of an immunological deficiency disorder deserves study in a center where there are people with experience and knowledge, since early recognition and proper therapy of the treatable forms of the antibody deficiency syndrome can prevent invalidism and death, and in the hereditary forms the commitment to treatment is for life and thus is not to be undertaken lightly, without accurate diagnosis and evaluation. The tests which may be undertaken in properly staffed and equipped centers are the following: 1. Phagocytic [unction. *(a) Blood counts, bone marrow smears for polymorphonuclears and their precursors. (b) Scanning of liver and spleen with radioactive colloid. (c) Nitroblue tetrazolium test of leukocytes. 2. Lymphocyte function. *(a) Absolute lymph counts of blood. *(b) Response of lymphocytes to phytohemagglutinin. (In thymic aplasia, transformation and mitosis usually does not occur and karyotyping is impossible.) (c) Delayed hypersensitivity. *(1) Response to monilia antigen or to purified protein derivative in bacillus-Calmette Guerin-inoculated infant. (2) Induction of delayed hypersensitivity by Dinitrofluorobenzene. ~(d) Morphology of lymphoid tissues. (1) Biopsy of regional lymph node 4 days after booster injection of DPT in immunized child or 10 days after primary injection. (e) Immunological memory. (1) Evidence of delayed hypersensitivity to previously encountered antigen (see Delayed hypersensitivity (c), No. I). (2) Rapid, marked antibody rise after booster injection of diphtheria-polio-tetanus vaccine. (f) Rejection of homogra/ts. (These tests would only be done under very special circumstances.) (1) First-set rejection of skin graft. (2) Immunological memory may be tested by regrafting from same donor, *These tests should be done in all suspected cases of antibodydeficiencysyndrome.

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3. Plasma cell/unction. *(a) Identification of immunoglobulins by immunoelectrophoresis, with quantitation of each and of total gamma globulin value where possible. (b) Isohemagglutinin titer. *(c) Antibody response to antigenic stimulation. (1) Primary: H and O agglutinins following single dose of typhoid vaccine. (2) Secondary: Diphtheria and tetanus antitoxin levels following booster injection. ~(d) Search for plasma cells in a biopsied lymph node taken after proper interval following injection of antigen (preferably secondary response). Management. Once the diagnosis of a disorder of the immunological system has been made in one member of the family, it is essential to study the patient's siblings and all future siblings at the most appropriate age for the condition, since, in those disorders which are hereditary, the goal is to make the diagnosis and institute treatment in the presymptomatic phase. This may prevent a great deal of illness and resultant impairment of auditory, pulmonary, and/or neurological function. The management of the affected individuals will depend on the nature of the disorder. In disorders of the "capture system," caused by leukocyte abnormalities, only intensive treatment of the infections which develop can be offered at present. In deficiencies of splenic function, immunization against pneumococci would be desirable, but the most practical measure would seem to be to educate the child's parents to initiate antimicrobial therapy with penicillin (and ampicillin to combat Haemophilus influenzae in the first few years of life) at home themselves at the onset of fever or malaise. Treatment of the disorders of the thymus at present is purely experimental. Until we find a way to replace thymic function, no progress can be made. In the case of the antibody deficiency syndromes with an intact thymus, in which plasma cell function is deficient, the objective of treatment is to pre~These tests should be done in all suspected cases of antibody deficiency syndrome.

The ]ournal o/ Pediatrics 1une 1968

vent infection. This may be done with antimicrobial chemotherapy, particularly in older individuals, or by periodic injections of gamma globulin, reserving antimicrobials for the treatment of infections when they develop. Provided the individual does not have residual damage from preceding infections, such as bronchiectasis or sclerosis of the mastoid, which render him susceptible to local recurrences of infection, we have found gamma globulin to be very effective when given in adequate doses (a loading dose of 0.2 to 0.3 Gm. per kilogram of body weight and a dose of approximately 0.1 Gm. per kilogram per month for maintenance). One tenth of a gram is about 0.6 ml., which means a dose of 0.3 ml. per pound per month, and 2 to 3 times this amount as a loading dose. 6~ Adequate doses of gamma globulin will prevent invasive infections over a period of many years, but will not control all local infections, which may require appropriate chemotherapy from time to time. The principal drawback of gamma globulin, which may be obtained for properly diagnosed cases from regional blood centers of the American National Red Cross, is the discomfort of repeated large intramuscular injections. Preparations of gamma globulin, which are safe for intravenous use, even in agammaglobulinemic patients who are abnormally susceptible to reactions from the intravenous injection of standard gamma globulin preparations, 60 are under development, and will, we hope, be available in the future to overcome this drawback. SUMMARY This review has attempted to clarify the various syndromes of diminished resistance to infection on the basis of functional disturbances and morphological changes in the immunological system. The syndromes fall into several different categories, and may be congenital, hereditary or acquired. The major syndromes described are: 1. Increased susceptibility to staphylococcal and other bacterial infections due to neutropenia. 2. Chronic granulomatous disease of child-

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3. 4.

5.

6.

7.

8.

hood due to a defect in intracellular killing by phagocytes. O v e r w h e l m i n g b a c t e r e m i a due to splenic insufficiency. Increased susceptibility to a wide variety of viral, bacterial a n d fungal infections due to failure of recognition in thymic disorders affecting lymphocyte function. R e c u r r e n t infections with lack of immunological memory, due to antilymphocytic antibody. Increased susceptibility to g r a m - n e g a tive sepsis in the early neonatal period due to transient 7M globulin deficiency. Increased susceptibility to recurrent pyogenic infections in disorders of p l a s m a cells with consequent i m m u n o g l o b u l i n deficiencies. R e c u r r e n t pyogenic infections resulting from massive u r i n a r y loss a n d catabolism of immunoglobulins in the nep h r o t i c syndrome.

The author is indebted to his colleagues, Fred S. Rosen, M.D., and Ezio Merler, Ph.D., of the Immunology Division, for their added information and stimulating ideas. REFERENCES

i. Miller, J. F. A. P.: The thymus in relation to the development of immunological capacity, in Wolstenholme, G. E. W., and Porter, R., editors: The thymus: Experimental and clinical studies, Ciba Foundation Symposium, Boston, 1966, Little, Brown and Company, p. 153. 2. Jankovlc, B. D., Waksman, B. H., and Arnason, B. G.: Role of the thymus in immune reactions in rats. I. The immunologic response to bovine serum albumin (antibody formation, Arthus reactivity, and delayed hypersensitivity) in rats thymectomized or splenectomized at various times after birth, J. Exper. Med. 116: 159, 1962. Arnason, B. S., Jankovic, B. D., and Waksman, B. H.: Role of the thymus in immune reactions in rats. II. Suppressive effect of thymectomy at birth on reactions of delayed (cellular) hypersensitivity and the circulating small lymphocyte, J. Exper. Med. 116: 177, 1962. 3. Klein, J. J., Goldstein, A. L., and White, A.: Enhancement of in vivo incorporation of labeled precursors into DNA and total protein of mouse lymph nodes after administration of thymic extracts, Biochem. 53: 812, 1965.

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4. Cooper, M. D., Peterson, R. D. A., South, M. A., and Good, R. A.: The functions of the thymus system and bursa system in the chicken, J. Exper. Med. 123: 75, 1966. 5. Lawrence, H. S.: The transfer of hypersensitivity of the delayed type in man, in Lawrence, H. S., editor: Cellular and humoral aspects of hypersensitivity states, New York, 1959, Hoeber Medical Division, Harper and Row, Publishers, Inc., chap. 7, p. 279. 6. Lawrence, H. S.: The transfer in humans of sensitivity to streptococcal M-substance and to tuberculin with disrupted leukocytes, J. Clin. Invest. 34: 219, 1955. 7. Gitlin, D., Hitzig, W. H., and Janeway, C. A.: Multiple serum protein deficiencies in congenital and acquired agammaglobulinemia, J. Clin. Invest. 35:1199, 1956. 8. Grabar, P., and Williams, C. A.: M~thode permettant l'6tude conjug6es des propri6t6s 61ectrophor~tiques et immunochimiques d'un m~lange des prot~ines. Application au serum sanguin, Biochim. & biophys, acta 10: 193, 1953. 9. Merler, E., and Rosen, F. S.: The gamma globulins. I. Structure and synthesis of the immunoglobulins, New England J. Med. 275: 480, 1966. I0. Ishizaka, K., and Ishizaka, T.: Physicochemical properties of reaginic antibody. I. Association of reaginic activity with immunoglobulin other than yA or 70 globulin, J. Allergy 37: 169, 1966. 11. Gitlin, D., Kumate, J., Urrusti, J., and Morales, C.: Selectivity of human placenta in transfer of plasma proteins from mother to fetus, J. Clin. Invest. 43: 1938, 1964. 12. Alford, C. A.: Studies on antibody in congenital rubella infections. I. Physicochemical and immunologic investigations of rubella neutralizing antibody, Am. J. Dis. Child. 110: 455, 1965. 13. Sever, J. L., and Berendes, H.: Cord blood gamma.~ as a screening test for congenital viral infections, Pediat. Res. 1: 217, 1967 (abst.). 14. Tomasi, T. B., Tau, E. M., Solomon, A., and Prendergast, R. A.: Characteristics of immune system common to certain external secretions, J. Exper. Med. 121: 101, 1965. 15. Smith, R. T., and Eitzman, D. V.: Development of immune response: Characterization of response of human infant and adult to immunization with Salmonella vaccine, Pediatrics 33: 163, 1964. 16. Robbins, J. B., Kenny, K., and Suter, E.: Isolation and biological activities of rabbit yM and 7o anti-Salmonella typhimurium antibodies, J. Exper. Med. 122: 385, 1965. 17. Murray, E. S., O'Connor, J. H., and Gaon, J. A.: Differentiation of 19S and 7S complementfixing antibodies in primary vs. recrudescent typhus by either ethane thiol or heat, Proc. Soe. Exper. Biol. & Med. 119: 291, 1965. 18. Carson, M. J., Chadwick, D. L., Brubaker, C. A., Cleland, R. S., and Landing, B. H.: Thir-

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24.

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27. 28. 29.

30. 31. 32.

33.

34.

35.

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teen boys with progressive septic granulomatosis, Pediatrics 35: 405, 1965. Holmes, B., Quie, P. G., Windhorst, D. B., and Good, R. A.: Granulomatous disease of childhood, Lancet 1: 1225, 1966. Quie, P. G., White, J. G., Holmes, B., and Good, R. A.: Decreased bactericidal activity of polymorphonuclear leukocytes in children with chronic granulomatous disease, J. Clin. Invest. 45: 1058, 1966 (abst.). Baehner, R. L., and Nathan, D. G.: Leukocyte oxidase: Defective activity in chronic granulomatous disease, Science 155: 835, 1967. Karnovsky, M. L.: Metabolic basis of phagocytic activity, Physiol. Rev. 42: 143, 1962. Cagen, R. H., and Karnovsky, M. L.: Enzymatic basis of the respiratory stimulation during phagocytosis, Nature 204: 255, 1964. King, H., and Shumaeher, H. B., Jr.: Splenic studies. I. Susceptibility to infection after splenectomy performed in infancy, Ann. Surg. 136" 239, 1952. Eraklis, A. J., Kevy, S. V., Diamond, L. K., and Gross, R. E.: Hazard of overwhelming infection after splenectomy in childhood, New England J. Med. 276: 1225, t967. Schulkind, M. L., EIIis, E. F., and Smith, R. T.: Effect of antibody upon clearance of I leslabeled pneumococci by the spleen and liver, Pediat. Res. 1: 178, 1967. Rowley, D. A.: Formation of circulating antibody in splenectomized human beings following intravenous injection of heterologous erythrocytes, J. Immunol. 65: 575, 1950. Kevy, S., Tefft, M., Vawter, G., and Rosen, F. S.: Hereditary splenic hypoplasia, Pediat. Res. 1: 216, 1967. Crigler, J. F., Jr.: Personal communication. Good, R. A., Gabrielson, A. E., Cooper, M. D., and Peterson, R. D. A.: The role of the thymus and bursa of Fabricius in the development of effector mechanisms, Ann. New York Acad. Sc. 129: 130, 1966. Gowans, J. L., and MacGregor, D. D.: The immunological activities of lymphocytes, Prog. Allergy 9: 1, 1965. Rosen, F. S., and Janeway, C. A.: The gamma globulins. III. Antibody deficiency syndromes, New England J. Med. 275: 769, 1966. Gitlin, D., and Craig, J. M.: The thymus and other lymphoid tissues in congenital agammaglobulinemia. I. Thymic alymphoplasia and lymphocytic hypoplasia and their relation to infection, Pediatrics 32: 517, 1963. DiGeorge, A. M.: Discussion, J. PEDIAT. 67: 907, 1965. Lisehner, H. W., Dacon, C., and DiGeorge, A. M.: Normal lymphocyte transfer (NLT) test: Negative response in a patient with congenital absence of the thymus, Transplantation 5: 555, 1967. Hitzig, W. H., Kay, H. E. M., and Cottier, H.: Familial lymphopenia with agammaglobulinemia: Attempt of treatment by implantation of fetal thymus, Lancet 2: 151, 1965. Nezelof, C., Jammet, M. I., Lortholary, P.,

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44. 45. 46.

47.

48. 49.

50. 51.

Labrune, B., and Lamy, M.: L'hypoplasie herSditaire du thymus: Sa place et sa responsabilit~ dans une observation d'aplasie lymphocytaire, normoplasmocytaire et normoglobulin~nique du nourrison, Arch. fran~, p$diat. 21: 897, 1964. Fireman, P., Johnson, H. A., and Gitlin, D.: Presence of plasma cells and 71M globulin synthesis in patient with thymic alymphoplasia, Pediat. 37: 485, 1966. Rothberg, R. M., and ten Bensel, R. W.: Thymic alymphoplasia with immunoglobulin synthesis, Am. J. Dis. Child. 113: 639, 1967. Wolff, J. A.: Wiskott-Aldrich syndrome: Clinical, immunological, and pathologic observations, J. PEDIAT.70: 221, 1967. Good, R. A., Cooper, M. D., Peterson, R. D. A., Kellum, M. J., Sutherland, D. E. R., and Gabrielsen, A. E.: The role of the thymus in immune process, Ann. New York Acad. Sc. 135: 451, 1966. Peterson, R. D. A., Kelly, W. D., and Good, R. A.: Ataxia telangiectasia, its association with defective thymus, immunological deficiency disease, and malignancy, Lancet 1: 1189, 1964. Bellanti, J. A., Artenstein, M. S., and Buescher, E. L.: Ataxia telangiectasia: Immunological and virological studies of respiratory secretions, Pediatrics 37: 924, 1966. Levey, R. H., and Medawar, P. B.: Some experiments on the action of antilymphoid sera, Ann. New York Acad. Sc. 129: 164, 1966. Monaco, A. P., Wood, M. L., and Russell, P. S.: Studies on heterologous anti-lymphocyte serum in mice. III. Immunological tolerance and chimerism produced across the H-2 locus with adult thymectomy and anti-lymphocyte serum, Ann. New York Acad. Sc. 129: 190, 1966. Kretschmer, R., Janeway, C. A., and Rosen, F. S.: Immunological amnesia. To be published. Rossi, E., et al.: To be published. Von Muralt, G.: In Hitzig, W. H., editor: Die Plasmaproteine in der klinische medizin, Berlin-Gottingen-Heidelberg, 1963, Springer-Vetlag, chap. 3, p. 98. II. Pr~inatale Periode und Placentarschranke. Bergstrand, C. G., and Czar, B.: Paper electrophoretic study of human fetal serum proteins with demonstration of a new protein fraction, Scandinav. J. Clin. & Lab. Invest. 9: 277, 1957. Dancis, J., and Shafran, M.: The origin of plasma proteins in the guinea pig fetus, J. Clin. Invest. 37: 1093, 1958. Bridges, R. A., Condie, R. M., Zak, S. J., and Good, R. A.: Morphological basis of antibody formation. Development during the neonatal period, J. Lab. & Clin. Med. 53: 331, 1959. Stiehm, E. R., and Fudenberg, H.: Serum levels of immune globulins in health and disease: Survey, Pediatrics 37: 715, 1966. Janeway, C. A.: The immunological system of

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