Arch. Dis. Childh., 1966, 41, 366.

The Immunological System of the Child*Part II: Immunological Deficiency States

CHARLES A. JANEWAYFrom the Children's Hospital Medical Center, and the Department of Pediatrics, Harvard Medical School,

Boston, Mass., U.S.A.

In the first lecture, the development of the organs, integrity from a congenital defect such as epidermo-cells, and proteins responsible for the immune lysis bullosa, or to an acquired disease like eczemaresponse was discussed. Resistance to invasive or exfoliative dermatitis. In the eye, lack of tears orinfection depends upon non-specific factors as well loss of the corneal reflux can lead to corneal ulcera-as upon specific immune responses to the infecting tion and infection. Achlorhydria may diminish theorganism. Poor resistance may be the result of resistance of the gastro-intestinal tract to entericdeficiencies in either non-specific or specific infection. In the respiratory tract, failure of themechanisms, but the main concern of this lecture cough reflex, due to anaesthesia or to coma, and losswill be with deficiencies of specific immunological of ciliary action, such as occurs in certain viralmechanisms, which have only been recognized as infections, thermal and chemical injuries, ordisease entities during the past 12 years. However, bronchiectasis, may pave the way for invasion of thein order to put these new disease entities in perspec- lung. Obstruction of the air passages with viscidtive, we must first examine the various ways in which secretions, as in cystic fibrosis, recurrent asthma, orthe body's defences against bacterial infection may bronchitis, or local obstruction by a foreign body,be impaired. frequently leads to pneumonia. Finally, the oedemaFrom the clinical point of view, the physician produced by the viruses of influenza or the common

seeing a child with the complaint of recurrent cold, by the allergic response, or in the nephroticinfections should first get a clear picture of whether syndrome, alters the respiratory tract so thatthese have been repetitive infections of the same pyogenic bacteria, when present, multiply rapidlyanatomical area or a whole variety of severe infections and produce invasive infection.with different anatomical sites. The former typeof history strongly suggests a local cause, the Failure of the clearing mechanism. This islatter a deficiency in the over-all capacity of the another important predisposing cause to infection.individual to resist infection. But, first of all, the Deficiency in production of the principal wanderingphysician must evaluate the mother's anxiety in phagocytic cell-the polymorphonuclear leucocyteorder to determine whether, as so often happens in -usually is followed by infection, very frequentlypaediatrics, her expectations of good health for her due to staphylococci. This occurs very early in achild leave no place for the hundred or so infections, rare condition incompatible with life-congenitalmost of them mild and involving the respiratory - aleukia (de Vaal and Seynhaeve, 1959; Gitlin,tract, which usually develop in the first decade of Vawter, and Craig, 1964)-but is a constant threatlife and constitute the major manifestations of in patients with neutropenia, which may be congeni-immunological maturation of the child. tal, cyclic, or acquired as a result of bone-marrow

failure in leukaemia, reticulo-endotheliosis (Letterer-Impairment of Non-specific Defences Siwe's disease), aplastic anaemia from radiation or

Against Bacterial Infection chemical injury. Failure of the fixed tissueFailure of surface protection. This is a phagocytes of the reticulo-endothelial system may

frequent predisposing cause to local infection by result in severe overwhelming septic infections.bacteria. In the case of the skin this may be due to Although there has been great dispute abouttrauma from burns or penetrating wounds, to loss of whether there is such an entity as a post-splenectomy

syndrome (King and Shumacker, 1952; Gofstein and* The Sir Leonard Parson Lectures, delivered at the University of Gellis, 1956; Horan and Colebatch, 1962), there is

Birmingham on March 22-23, 1965. no question but that following splenectomy,366

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The Immunological System of the Childespecially in infancy or early childhood, the child,who also has a serious underlying disease of theblood-forming organs for which the splenectomywas done, is unusually vulnerable to overwhelmingbacteraemia, and perhaps to viraemia as well.

Failure of the inflammatory reaction. Thismay play an important part in allowing infection tospread unchecked. This is seen when there isimpairment of the blood supply to a part, or whenunder the influence of anaesthetics, narcotics, or

coma the local reflexes involved in vascular responsesare deficient. Finally, the anti-inflammatory andantipyretic effect of the corticosteroids, when givenin massive doses, can produce the strange paradox ofa septic patient feeling and looking comparativelywell while his bacteraemia proceeds unchecked.

Deficiencies of the Immunological SystemDeficiencies in the normal immunological respon-

ses of the host lead to frequent recurrent severe

bacterial infections. Understanding of this field isdeveloping rapidly, as clinical observations andfundamental immunological investigation keepadding to our knowledge. But before presentingwhat has been learned since a-y-globulinaemia was

first reported by Bruton (1952), a miscellaneousgroup of diseases, characterized by unusual suscepti-bility to infection, for which no adequate explanationhas yet been found, must be mentioned for the sakeof completeness and to show that there is still muchto be learned.

Diseases ofUncertain Pathogenesis Associatedwith Unusual Susceptibility to InfectionThe Wiskott-Aldrich syndrome. This is a

familial disease, characterized by recurrent otitismedia, thrombocytopenic purpura, and eczema, inwhich recurrent superficial infections and bleedingusually lead to death in early childhood (Aldrich,Steinberg, and Campbell, 1954; Wiskott, 1937;Krivit and Good, 1959). Laboratory studies havenot revealed any single consistent immunologicalabnormality, though a raised level of yA-immuno-globulin and a decreased or absent titre of iso-haemagglutinins are found in many, but not in allcases.

Ataxia telangiectasia. This is a hereditarydisease in which multiple telangiectases are associa-ted with progressive ataxia developing in childhoodor in early adult life (Young, Austen, and Moser,1964; Peterson, Kelly, and Good, 1964; Fireman,Boesman, and Gitlin, 1964). In many patients,recurrent infections, particularly pneumonia, be-come a problem and may lead to death. In

approximately 70% of the patients who have beenstudied, there is an absence of yA-immunoglobulins,a phenomenon that has been observed in somehealthy children without any evidence of increasedsusceptibility to infection. There does appear to bea defect in the ability to develop delayed hyper-sensitivity in some ataxia telangiectasia patients,despite a normal number of circulating lymphocytes.There is a poorly defined syndrome of serious

granulomatous disease occurring rarely in children,which sometimes is familial. It is characterized byrecurrent or persistent superficial infection often dueto staphylococci and frequently exhibiting relativeneutropenia and an increase in monocytes, lympha-denopathy, hepatosplenomegaly, and hyper-y-globulinaemia (Carson, Chadwick, Brubaker, Clel-and, and Landing, 1965). This has been describedunder different names by different workers. A fewcases have been seen in nearly every paediatricclinic. Whether they represent a heterogeneousgroup of cases with different aetiologies or a fewdistinct clinical entities remains to be discovered.*

Metabolism of the ImmunoglobulinsSince hypo-y-globulinaemia is the characteristic

laboratory finding in most instances of the antibodydeficiency syndrome, a brief discussion of themetabolism of the immunoglobulins is necessary inorder to clarify the mechanisms that may beresponsible for this finding. The work of Gitlinhas given us the clearest understanding of thenormal and pathological metabolism of individualplasma proteins and particularly of the y-globulins.The blood level of any plasma protein is usually areflection of the size of the body pool of that protein.The size of the body pool in turn depends upon therelation between the rate at which that protein isbeing synthesized and the rate at which it is beingremoved from the body pool by loss from the bodyor by katabolic breakdown. Thus hypo-y-globu-linaemia might result from a decrease in the rate ofsynthesis, from an increase in the rate of loss ofkatabolism, from both, or from a greatly increasedrate of loss and katabolism, even with some increasein the rate of synthesis. Ordinarily approximatelyhalf of the body pool of y-globulin is present in thecirculating plasma and the remainder in the extra-vascular portion of the extracellular fluids, but inconcentrations varying considerably in differentareas, with the greatest concentration in thoracicduct lymph. Synthesis of y-globulin occurs where-

* P. G. Quie, J. G. White, B. Holmes, and R. A. Good (AnnualMeeting of American Society for Clinical Investigation, Abstract tobe published in J. clin. Invest. (1966), have demonstrated aninability of the polymorphonuclear leucocytes to kill engulfed bacteriain three cases of this syndrome.

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Charles A. JanewayGAMMA GLOBULIN METABOLISM-70kg.MAN

VIA LYMPHATICS

CELLSSYNTHESIS2-5g./day

tl5g./day

VIA CAPILLARIESPLASMA3500 ml.

900mg./ ml.

= 31 5g. CELLS

KATABOLISMINTERSTITIAL 2-5g./day

FLUID12500 ml.

300mg./ lOOmI.

=37*5g.g.IS±15g./day

BODY POOL - 70g.-1 per kg.HALF LIFE-20days

FIG. 1.-Diagrammatic scheme of y metabolism in a normal adult of 70 kg. (Advances in Pediatrics, Vol. IX, edited byS. Z. Levine. Copyright ©) 1957, Year Book Medical Publishers, Inc. Used by permission of Year Book Medical

Publishers )

ever there are plasma and plasmacytoid cells.Under normal conditions y-globulin is probablylost into the gastro-intestinal tract and urine inrelatively minute amounts, and most of the dis-appearance of y-globulin is accounted for bykatabolism, though where this occurs is unknown.In the steady state, approximately half the circulat-ing y-globulin leaves the blood stream daily,presumably through the walls of the peripheralcapillaries, while the same amount returns to theblood stream by way of the lymphatics (Gitlin andJaneway, 1960) (Fig. 1).

Hypo-y-globulinaemia in the antibody deficiencysyndrome is usually an isolated deficiency of y-

globulins and is due to a failure of synthesis, as

shown by a normal or prolonged half-life of injectedtracer doses of labelled y-globulins, by the failure toform antibodies in response to antigenic stimulation,and by the absence of plasma cells in the lymphoidtissues (Gitlin, Janeway, Apt, and Craig, 1959).Hypo-y-globulinaemia due to increased loss andkatabolism occurs in exudative skin lesions, exuda-tive gastro-intestinal lesions ('exudative entero-pathy'), and in the nephrotic syndrome, and isassociated with deficiencies of other lower molecularweight plasma proteins as well (Gitlin, Janeway, andFarr, 1956). Only in the nephrotic syndrome,where the hypo-y-globulinaemia is very severe andthe concentration of y-globulin extremely low in theextracellular oedema fluid, does this latter type ofhypo-y-globulinaemia predispose to recurrent in-vasive infections.

Antibody Deficiency SyndromeThe antibody deficiency syndrome (Barandun,

Cottier, Hassig, and Riva, 1959), the name given bythe Swiss workers, which is a better term than hypo-y-globulinaemia or a-y-globulinaemia, because it

stresses the fundamental defect in all the patients,exists in a number of different forms as shown inTable I. No classification is entirely satisfactory,but this outline will provide a sequence for presenta-tion.

Thymic alymphoplasia. This clinical entity,undoubtedly first described by Glanzmann andRiniker (1950) as lymphocytophthisis, then byDonohue (1953) as alymphocytosis, and finallyrecognized as a distinct variety of a-y-globulinaemiaby Swiss and French workers (Hitzig and Willi,1961; Tobler and Cottier, 1958; Freycon, Jeune,Larbre, and Germain, 1961), seems to be a familialdisease and the most serious form of immunologicaldeficiency. It is characterized by the early onset ofintractable infection, failure to thrive, and deathfrom infection before the age of 2. Its diagnosticfeature is a striking paucity of lymphocytes both inthe blood and tissues (Table II).Although the families reported by Freycon and by

Hitzig and Willi include children of both sexes, in allofthe families we have observed the affected childrenhave been boys, suggesting a sex-linked inheritance,

TABLE IAntibody Deficiency Syndromes

A. Thymic alymphoplasiaB. Congenital a-y-globulinaemiaC. Acquired a-y-globulinaemia

1. Primary (idiopathic)2. Secondary to

(a) radiation injury(b) chemical suppression(c) replacement of lymphoid tissue (lymphomas)

D. Dys-y-globulinaemia1. Transient

(a) neonatal dys-y-globulinaemia(b) transient hypo-y-globulinaemia of infancy(c) transient dys-y-globulinaemia

2. Congenital dys-y-globulinaemia3. Acquired dys-y-globulinaemia

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The Immunological System of the Childso possibly more than one mechanism of inheritancemay give rise to this syndrome (Rosen, Gotoff,Craig, Ritchie, and Janeway, 1966).The characteristic clinical manifestations are

depressingly uniform-onset of cough with pulmon-ary infiltration, thrush, and failure to thrive, withpoor appetite, poor growth, abdominal distension,and loose stools at a few months of age. Thesesymptoms persist and progress, despite temporaryremissions of the more acute pulmonary or monilialinfections with appropriate chemotherapy, andalmost invariably during the second year if notbefore, the miserably scrawny child succumbs.Injections of y-globulin exert little if any protectiveeffect.The pathological picture is striking. The thymus

is often difficult to find and consists of a smallepithelial structure, without Hassal's corpuscles or

any sign of the thymocytes which make up such alarge portion of the normal infant thymus. Lymphnodes are small and almost unrecognizable, withcomplete absence of follicular architecture, few ifany lymphocytes and no plasma cells (Rosen,Gitlin, and Janeway, 1962). In the bowel thelymphoid follicles and the lymphoid cells, whichnormally crowd the lamina propria, are absent.

Immunologically, these infants are totally incom-petent. They not only have the antibody deficiencysyndrome with a-y-globulinaemia, which becomesapparent with the disappearance after 6 or 7 monthsof the yG-immunoglobulins derived from the mother,but they also lack the capacity to develop delayedhypersensitivity; which probably accounts for thepersistent moniliasis and also for the fact that, as areview of the published reports suggests, the deathsfrom progressive vaccinia, which have been des-cribed in a-y-globulinaemia patients, have occurredprincipally in infants with this disease (Rosen andJaneway, 1964).

Experiments in animals suggest that 'runt disease'bears many resemblances to thymic alymphoplasiain man. It is of interest that runt disease can beprevented with syngenic lymphocytes if they are

given before runting occurs (Yunis, Hilgard,Martinez, and Good, 1965). Efforts to treat thymicalymphoplasia have been directed towards thehomotransplantation of two tissues-thymus andlymphoid cells. These children, lacking the capaci-ty either to develop delayed hypersensitivity or toform antibodies, should be the perfect homograftrecipients and do not exhibit the rejection reaction.The optimal time to help them should be the firstmonth or two of life before runting and infectionsbegin. This means that the disease must berecognized in the sib of an affected child before it

TABLE IISummary of Thymic Alymphoplasia

1. Familial-both sexes2. Onset-early (2-6 months)3. Intractable course:

Pulmonary infection, thrush, diarrhoea, failure to thrive4. Death under 2 years5. Pathology:

Thymus-aplasiaLymph nodes-absent lymphocytes and plasma cellsCirculating lymphocytes < 1,000/c.mm.

6. Immunology:Delayed hypersensitivity 0Homograft rejection 0Antibody formation 0

becomes symptomatic. Nobody has yet succeededin maintaining one of these children for long withtransplanted tissue, but hopeful results have beenachieved by two groups of investigators (Rosen et al.,1966; Rosen et al., 1962; Hitzig, Kay, and Cottier,1965).

Congenital a-y-globulinaemia. Children withthis, the commonest form of the antibody deficiencysyndrome, appear normal for from 9 months to 2 or3 years of age, depending upon the degree to whichthey are exposed to infection in their home andenvironment (Table III). The infections whichthey develop are no different, except for theirseverity, frequency, and tendency to recurrence,from those experienced by normal children, and theyrespond satisfactorily to antimicrobial therapy.Thus it may be some time before the physician'ssuspicions are aroused by the frequency with whichthe infections occur. There are certain signalswhich an alert physician may detect-the small sizeand smooth surface of the tonsils, the absence of anadenoid shadow in a lateral radiograph of thenasopharynx, and the comparatively small size of thecervical lymph nodes in a child with recurrentrespiratory infections. A very high or very lowwhite blood count with an acute infection, recurrenceof infection with the same strain of organism such as

TABLE IIISummary of Congenital A-y-globulinaemia

1. Sex-linked recessive-boys2. Onset-6 months-3 years3. Course:

Recurrent severe bacterial infectionsRespond to antimicrobial therapyProphylactic y-globulin effective

4. Complications:Tissue damage from infection(Bronchiectasis, deafness), arthritis frequent

5. Pathology:Thymus normalLymph nodes-poor follicles, no plasma cellsCirculating lymphocytes normal

6. Immunology:Delayed hypersensitivity + +Homograft rejection +Antibody formation ±

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Charles A. Janeway

VyM yA yGFIG. 2.-Immunoelectrophoretic analysis of normal (lower pattern) and a-y-globulinaemic (upper pattern) serum. Theserum proteins have been separated in a lateral direction by electrophoresis in a gel and then detected by precipitationwith an antiserum against normal human serum which diffuses into the gel from the central trough. The threebands of precipitation due to the immunoglobulins (labelled YM, YA, and YG) in normal serum are absent from the

a-y-globulinaemic Serum.

H. influenzae type B, or the development of hydrar-throsis in a child with a history offrequent infections,are also warnings to look into the situation moreclosely. The vast majority of these children areboys, and the evidence for a sex-linked recessiveform of inheritance is overwhelming from study of alarge number of families. The fact that occasionalgirls develop symptoms of a-y-globulinaemia ininfancy or early childhood suggests that there areother mechanisms of inheritance, or that theantibody deficiency syndrome may be acquired veryearly in life (see below).

Early recognition of the disease is important,because the institution of adequate replacementtherapy with y-globulin before anatomical damagehas been done to the brain, bronchi, middle ear, orjoints by infection usually means that the child canenjoy a relatively normal life. Certain complica-tions do occur, however, which may be serious.The arthritis, which tends to be indolent andrelatively painless with effusion into large joints, andwhich has been observed in about one-third of thepatients, usually disappears with y-globulin therapy.On the other hand, a dermatomyositis-like syndromewith skin rash, brawny oedema, muscular weakness,and contractures has developed in several of ourtreated patients who have ultimately succumbed toit (F. S. Rosen, S. V. Kevy, and C. A. Janeway,unpublished observations). Although these patientscope with viral infections much better than they dowith bacterial infections and can be vaccinated with-out risk, hepatitis has caused death in several

patients, at least one of whom never received anyinjections of y-globulin (Good and Page, 1960).The pathology of congenital a-y-globulinaemia

differs from that of thymic alymphoplasia; thethymus appears relatively normal and lymphocytesare usually present in normal numbers in the blood,as well as in somewhat reduced numbers in thelymph nodes and the lamina propria of the bowel(Gitlin and Craig, 1963). The lymphoid tissues aresomewhat small, and their architecture is distorted,with poor follicular structure. Upon antigenicstimulation there is swelling of the reticulum, givingrise to lymphadenopathy, but no formation ofsecondary follicles or of plasma cells, as is usuallyseen in lymphoid hyperplasia.

Diagnosis of this disease, even in the male sibs ofknown cases, is not possible for 6-9 months, untilthe child's y-globulin level has fallen below 200 mg./100 ml. as a result of katabolism of the maternalglobulins, though it can be strongly suspected if YMor YA globulins are not apparent upon immuno-electrophoresis after 4 months of age. Definitivediagnosis depends upon a consistent family history,the demonstration of a severe deficiency of all threeimmune globulins after 6 months of age (Fig. 2),abnormal architecture, and absence of plasma cellsin a local lymph node after antigenic stimulation andfailure to form detectable serum antibodies inresponse to immunization. Once the diagnosis hasbeen made, these children are committed to y-globulin replacement therapy, presumably for life.The dose required seems to be a loading dose of

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The Immunological System of the Child300 mg./kg., which may be given in divided dosesover a period of a week or so and a maintenance doseof 100 mg./kg. month thereafter, with occasionalchecks to be sure that a blood level of over 200 mg./100 ml. is being maintained (Janeway and Gitlin,1957).From an immunological standpoint, these patients

are capable of developing delayed hypersensitivitybut form antibodies very poorly. They may rejecthomografts but somewhat more slowly than normalsubjects.

Acquired a-y-globulinaemia. The antibodydeficiency syndrome may develop at any time in life.Cases occurring after the first two years fall into twomain groups-those that are primary or idiopathic,and those that are secondary to a variety of processeswhich affect the lymphoid system, such as radiation,immunosuppressive therapy, or lymphomatousdisease. In about one-third of the cases of chroniclymphatic leukaemia significant hypo-y-globulin-aemia with a tendency to recurrent infectionsdevelops, and in many instances of myeloma thereis an antibody deficiency syndrome, despite increasedlevels of myeloma y-globulin (Good, Kelly,Rotstein, and Varco, 1962) (Table IV).

TABLE IVSummary of Idiopathic Acquired A-y-globulinaemia

1. Both sexes-rarely familial2. Onset-any age3. Course:

Recurrent bacterial infectionsRespond to antimicrobial therapyProphylactic y-globulin effective

4. Complications:Bronchiectasis mainlySprue-like syndrome common

5. Pathology:Thymus normalLymph nodes-poor follicles, no plasma cellsCirculating lymphocytes normal

6. Immunology:Delayed hypersensitivity + +Homograft rejection +Antibody formation ±

Idiopathic acquired a-y-globulinaemia. Thismay develop at any age in those of either sex.

Although there is seldom a positive family history,several instances of two cases developing in the samefamily have occurred, thus suggesting that a geneticfactor may sometimes play a role (Wollheim, 1961;Charache, Rosen, Janeway, Craig, and Rosenberg,1965). The clinical manifestations of this diseaseclosely resemble those of congenital a-y-globulin-aemia, but recurrent sinusitis and pneumonia are theprincipal infections, frequently leading to bronchiec-tasis before the disease is recognized. Arthritis isless common in adults than in children, but a sprue-

like malabsorption syndrome occurs much moreoften in older patients.

In general, as in congenital a-y-globulinaemia,there is a deficiency of all three immunoglobulins,though the total y-globulin level is often somewhathigher, and evidence of some antibody formationmay be obtained after antigenic stimulation orinfection (Fudenberg, German, and Kunkel, 1962).Replacement therapy with y-globulin in the samedosage as for congenital a-y-globulinaemia iseffective in preventing most severe infections exceptin those patients with bronchiectasis, who, likeimmunologically normal subjects with this disease,are subject to recurrences of pneumonia.The pathology of idiopathic acquired a-y-

globulinaemia is quite comparable to that ofcongenital a-y-globulinaemia, with a normal thymus,some hypoplasia and disorganization of lymph nodearchitecture, and a paucity of plasma cells. How-ever, in some of these patients, proliferation of thereticulum cells may lead to generalized lymphadeno-pathy, hepatosplenomegaly, and ultimately a pictureresembling lymphoma. Much has been made ofthe association between thymic lesions, particularlythymoma, antibody deficiency syndrome, andmalignancy of the lymphoid system (MacLean, Zak,Varco, and Good, 1956).

The Dys-y-globulinaemiasWe have used the term dys-y-globulinaemia to

describe any condition characterized by abnormalvariations in the relative amounts of the immuno-globulins. Myeloma and macroglobulinaemia,which are primarily seen among adult patients,would certainly fall into this group and are oftenassociated with the antibody deficiency syndrome,but, as a paediatrician without experience with theseclinical entities, I shall omit them from considera-tion here.

Transient dys-y-globulinaemia and hypo-y-globulinaemia in infancy. Neonatal dys-y-globulinaemia. This condition, with an adult levelof y03-globulin, but only trace amounts of y,- andyA-globulins occurs normally in the first few weeksof life and may perhaps predispose to colon bacillussepsis under special circumstances. Hypo-y-glob-ulinaemia is likewise a normal phenomenon from thesecond to sixth month of life, but in a few infantsdelayed maturation of immunological function mayoccur, leading to a persistence and deepening ofhypo-y-globulinaemia for several months longerthan is usual, with increased susceptibility toinfection, requiring the administration of y-globulin.

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Charles A. JanewayThis transient hypo-y-globulinaemia of infancy isfortunately rare.True dys-y-globulinaemia, due to a delay in the

normal sequence of immunological maturation or toan abnormal sequence, may occur as a transientphenomenon for months or several years, and requirea period of y-globulin therapy in order to maintainthe health of the child. Peetoom, Cohen, andSmeenk (1966) in the Netherlands have found agroup of non-allergic children with frequent severerespiratory infections who could be identified byunusually low levels of y,,- or yA-globulins or byfailure of the level of these globulins to rise within afew days after infection (Smeenk, Cohen, andPeetoom, 1966). Infections could be prevented byadministration of y-globulin, and as soon as the levelor the response of the immunoglobulins to infectionbecame normal, recurrent infections ceased, andy-globulin was no longer necessary. Giedion andScheidegger (1957) described a boy in whom,despite a normal level of electrophoretic y-globulin,there were recurrent severe infections, whose bloodcontained normal amounts of YG- but no YM- oryA-globulin. By the age of about 5 his infectionsceased, and the immunoglobulins in his bloodbecame normal. We have studied a boy of 4 whois now completely normal, who was shown byA. Ross and B. Rose in Montreal at 2 years to haveincreased macroglobulins with a severe deficiency of7S y-globulin, whose frequent infections were wellcontrolled by y-globulin injections and tetracyclinedrugs for a two-year period until he became normal(C. A. Janeway and F. S. Rosen, unpublishedobservations).

Congenital dys-y-globulinaemia. The com-monest form of dys-y-globulinaemia which we haveobserved is among children with the antibodydeficiency syndrome which has begun in early life.These children have a typical history of recurrentsevere infections, but on examination of their blood,the level of y-globulin, instead ofbeing below 50mg./100 ml. as in the unusual case of congenital a-y-globulinaemia, is found to be between 200-400 mg./100 ml. Further analysis usually shows that the19S fraction by ultra-centrifugal analysis, corres-ponding to y,-globulin, is increased several times,whereas there is less than 50 mg./100 ml. YG-globulin (Rosen, Kevy, Merler, Janeway, andGitlin, 1961). This condition has persisted inseveral children for all the years they have beenfollowed. In one such child tonsillar hypertrophynecessitated tonsillectomy and the tonsil was filledwith PAS positive plasmacytoid cells containing y,-globulin. It is interesting that the few instances of

cyclic neutropenia we have observed in congenitala-y-globulinaemia and the two instances of floridwarts have been in this dys-y-globulinaemia group(C. A. Janeway and F. S. Rosen, unpublishedobservations).

Acquired dys-y-globulinaemia. Several in-stances of a clinical picture resembling idiopathicacquired a-y-globulinaemia have been observed inadults, where laboratory studies have shown y-globulin levels in the 200-400 mg./100 ml. range,deficiency of yG-globulin, abnormally high concen-trations of yM-globulin, and PAS positive plasma-cytoid cells in their lymphoid tissues (Rosen andBougas, 1963; Hinz and Boyer, 1963).

Finally, one of our patients, followed for a numberof years with typical congenital a-y-globulinaemia,showed a marked increase in y,-globulin followingthe successful chemotherapeutic treatment oftuberculosis. He developed a severe autoimmunedisease affecting liver, kidney, and blood, whichresponded to splenectomy. The spleen containedmany PAS positive plasmacytoid cells, and the levelof y.-globulins declined after its removal. How-ever, several years later there was a recurrence offatigue, fever, jaundice, abdominal pain, and colitisassociated with a rise in yM-globulins, and thefinding of many PAS positive plasmacytoid cells inthe gall-bladder which was removed at an explora-tory operation. He succumbed to this recurrentdisease in a few months for reasons that are far fromclear (C. A. Janeway and F. S. Rosen, unpublishedobservations).My excuse for presenting these last examples in a

rather anecdotal fashion is to indicate that, thoughwe have learned a lot in the past 12 years, there arestill many bewildering clinical phenomena involvingthe immunoglobulins, which we cannot satisfactor-ily explain.

SummaryThe child who is brought to the physician because

of recurrent infection will most frequently have anover-anxious mother or some local factor predispos-ing to infection.

If the infections are severe, repeated, oftenrecurrent but vary in location, some failure of themechanisms of resistance is strongly suggested,either neutropenia, absence of the spleen, or aspecific deficiency of the immunological system.There are a variety of inherited and acquired

conditions where there is a failure of the immuno-logical system, associated with pathological lesionsin the lymphoid tissues and occasionally in thethymus, and with abnormalities of the immuno-

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The Immunological System of the Child 373globulins and sometimes of the peripheral lympho-cytes.There are three well-defined clinical entities with

immunological deficiency:(a) Thymic alymphoplasia is the most severe of the

antibody deficiency syndromes, since it includes aninability to manifest delayed hypersensitivity, and asevere deficiency of lymphocytes with failure toform antibodies.

(b) Congenital a-y-globulinaemia is a sex-linkedrecessive disease, in which the patients can developdelayed hypersensitivity but are severely defective inantibody formation.

(c) Acquired a-y-globulinaemia is either secondaryto various processes which injure or infiltrate thelymphoid tissues or occurs idiopathically at any agein either sex in a form which is clinically andpathologically very similar to congenital a-y-globulinaemia.

In addition there are several poorly understoodconditions such as Wiskott-Aldrich syndrome,ataxia telangiectasia and diffuse granulomata, as wellas a variety of dys-y-globulinaemias, which may betransient, congenital, or acquired.Although replacement therapy with y-globulin is

effective in protecting from infection all patientswith the antibody deficiency syndrome except thosewith thymic alymphoplasia, it is our hope that, asknowledge of the interrelationship of the thymus,the lymphoid follicles throughout the body, and theperipheral lymphocytes increases, we may some daybe able to activate or restore the immunologicalsystem to normal function by other methods.

Much of the work upon which these lectures are basedwas carried out with the support of research grants(A-251, Al-AM, 05877) from the National Institutes ofHealth, U.S. Public Health Service.

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