J. clin. Path., 28, Suppl. (Ass. Clin. Path.), 6, 83-91

Immune deficiency diseasesW. H. HITZIG

From the Department ofPediatrics, University ofZurich, Switzerland

Paediatricians have long been deeply concerned withproblems of infection. The sharp decrease in child-hood mortality in recent decades in highly developedcountries is mainly due to progress in preventing andtreating infection: for example, in Switzerland in1973 there were about 88 000 births and only 16deaths due to infection in children aged between 2and 4 years in contrast to 76 killed by accidents. Inunderdeveloped countries more than 50% of thechildren die during childhood, infection being apredominant cause.

Individual differences in the ability to cope withpathogens have been assumed for a long time, butwere not studied scientifically until the introductionof antibiotics had resulted in control of the majorinfections. At this time paediatricians began to paymore attention to constitutional and inheriteddiseases, and made observations on congenitaldeficiencies of selective defence mechanisms whichhave contributed to a better understanding of thenormal immunological functions.The basis of the currently used classification of

primary immune deficiency diseases is the 'two-component concept' (Cooper, Paterson, and Good,1965; Good and Fisher, 1971). Its main postulate,the distinction between T and B lymphocytes, iswellknown, and provides a useful workinghypothesisclinically.

Methods of Study

Many methods for measuring immune reactionshave been devised in the last two decades. Theydistinguish between cell-mediated and antibody-mediated immune reactions, which correspondalmost completely with T- and B-cell-mediatedreactions respectively.

Simple in-vivo procedures have been used for manyyears. Thus, circulating antibodies are detected byan immediate skin reaction after intracutaneousadministration of the corresponding antigen. Incontrast the cell-mediated reaction needs time todevelop; it is therefore a reaction of delayed hyper-sensitivity. For both tests the patient must be exposedto the antigen, which is not only painful but involves

also the danger of hyperergic reactions. Therefore,in-vitro tests are preferable.

CELL-MEDIATED RESPONSESThe simple count of circulating lymphocytes givesone important figure. The size of some lymphoidorgans can roughly be estimated by palpation. Thethymus can be visualized radiologically, and itshistology can be studied if a biopsy is available. Mostimportant, however, are functional methods formeasuring the reaction of the lymphocyte to anexogenous antigenic stimulus. The lymphocytes areactivated to undergo mitosis, which can be assessedby various methods, most accurately by the measure-ment of incorporation of precursor substances suchas 3H-thymidine into DNA. The stimulus may behomologous cells, specific antigens, or non-specificplant mitogens like phytohaemagglutinin (WHOreport, 1970).

ANTIBODY-MEDIATED RESPONSESHumoral immune mechanisms can be evaluated bythe overall determination of circulating immuno-globulins but more accurately by titration of specificantibodies. When a functional method is used todetermine the response to antigenic stimulation, thechange in serum antibody titres can be measuredas well as the anatomical changes in the lymphoidorgans.

In addition to these classical methods, a newprinciple was introduced two years ago: by chance,a previously well known enzyme, adenosine deamin-ase (ADA), was shown to be important for immunereactions by observations on patients who had bothcongenital absence of the enzyme and immunedeficiency. It turned out that ADA might be a keyenzyme for the synthesis of DNA. This is of interest,because only the homozygous individual shows animmune deficiency, the heterozygous parents beingphenotypically normal.

Classification

PRIMARY IMMUNE DEFICIENCY SYNDROMESA number of clinical immune deficiency syndromes

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Immunodeficiency Syndrome Suggested Cellular Defect Inheritance

B Cells T Cells X-linked Autosomal OtherRecessive

Absent Present Absent

X-linked agammaglobulinaemia x (x) xThymic hypoplasia x xSevere combined IDS x x x x x x

With dysostosis x ? x xWith ADA deficiency x x xWith generalized haemopoietic hypoplasia x x x

Selective Ig deficiencyIgA ? x (x) xOthers ? xX-linked IDS with increased IgM x x

IDS with ataxia teleangiectatica x x xIDS with thrombocytopenia and eczema (Wiskott-Aldrich

syndrome) x xIDS with thymoma x x xIDS with normo- or hypergammaglobulinaemia x x (x) xTransient hypogammaglobulinaemia of infancy xVariable immune deficiencies (largely unclassified and very

frequent) x or x (x) (x) x

Table I Classification ofprimary immune deficiency syndromes (WHO Committee, February 1973)

can be convincingly classified on the basis of the Tand B cell defects (Cooper et al, 1974) as shown intable I. There is also reason to hope that the conceptwill accommodate any new and more refinedclinical findings in the future. However, some welldelineated diseases, especially ataxia telangiectaticaand thrombocytopenia with eczema, are notadequately explained on this basis (for detailedreferences see Stiehm and Fulginiti, 1973; Hitzig,1974).The following syndromes are of importance for

clinical chemists.

Sex-linked agammaglobulinaemiaIn 1952 Bruton described a patient with severe wide-spread infections due to pyogenic organisms, inclu-ding cutaneous infections with abscess formation,respiratory infections including otitis, sinusitis andsevere bronchopneumonia, gastrointestinal infec-tions, and finally blood stream invasion resulting inpurulent meningitis and septicaemia. The detectionof a complete lack of immunoglobulins gave thename to the disease, and stimulated investigationsof the role of immunoglobulins as specific antibodies.The normal antibody response to stimulation byspecific antigens is completely absent, and this is inkeeping with the morphology of the lymphoidsystem which shows severe atrophy and absence ofgerminal centres and plasma cells. In a number offamilies the heredity of the disease could be demon-strated; the phenotypically healthy mothers transmitthe disease only to their sons. This proves that theanomalous gene is located on the X chromosome.The importance of antibody deficiency in thissyndrome is shown by the therapeutic success of the

injection of human gamma globulin preparations.In these patients B lymphocytes are usually absent.

In the normal human fetus B cells appear around theeleventh gestational week, ie, long before the actualsecretion of specific antibodies. Animal experimen-tation has clearly demonstrated that the synthesisof the three main immunoglobulin classes is acquiredin a rigidly fixed sequence, starting with IgM,proceeding to IgG, and finally followed by IgA(Lawton, Self, Royal, and Cooper, 1972). Thissequence recapitulates the phylogenetic developmentof antibodies as demonstrated in a large number ofdifferent animal species (Good, Finstad, Gewurz,Cooper, and Pallora, 1967). It must therefore beconcluded that in congenital sex-linked agamma-globulinaemia this development is lacking, andseveral authors claim that the absence of membraneimmunoglobulins as markers ofB lymphocytes is themost sensitive test for the early diagnosis of thisdisease.A few cases, however, were not consistent with

this concept, since they had normal membraneimmunoglobulin but virtually no circulating immu-noglobulins or specific antibodies. It was thereforeconcluded that in this disease the normal differen-tiation into functional B cells is blocked, and that thesite of the block can vary; in the first instance thereis a failure of transition of the primitive stem cellinto the B cell, whereas in the second instance theB cells produce immunoglobulins but do not releasethem.A recent study of an unusual patient seems to

throw some light on the mechanism of this tran-sition (Hitzig and Kenny, 1975). The parents werefirst cousins and had already lost two boys from

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pancytopenia, which was diagnosed as Kostmann'ssyndrome (infantile genetic agranulocytosis). Thismale infant was born by Caesarean section understerile conditions and immediately transferred intoa sterile laminar airflow cabinet, where he wasnursed for 78 days without any bacterial contamina-tion. During this time extensive investigationsexcluded Kostmann's syndrome, but agamma-globulinaemia with inability to synthesize specificantibodies developed. During this time, however,B lymphocytes in normal number were detected byimmunofluorescence, thus proving that the patientbelonged to the rare category of agammaglobulin-aemia with B lymphocytes. About two months afterexposure to bacterial contamination, respiratory andintestinal infections appeared which did not respondto appropriate intramuscular gamma globulintherapy; the boy slowly developed pancytopeniaexactly like his two siblings and rapidly deterio-rated. Haematological investigations revealed themorphological changes of pernicious anaemia in thepresence of normal serum vitamin B12 levels, and,almost at the last minute, made us suspect thesyndrome of transcobalamin II deficiency describedby Hakami, Neimann, Canellos, and Lazerson(1971). Transcobalamin II is a beta globulin (table IL)

TCI TCII TCIII

Electrophoresis alpha 1 beta alpha 2Molecular weight 120 000 35 000 120 000B12 clearance 10 days 10 min ?Free B,,-binding capacity Low High ?Biological function Storage Transport Fetal binderHeLa cell uptake No Yes No

Table II Transport proteins for vitamin B12

which is normally present in concentrations of about25 ,ug/l plasma. It is necessary for the transport ofvitamin B12 from the gut wall to the cells, andprobably also for its penetration into the cells. Afterthe administration of large doses (1000 microgramstwice weekly) of vitamin B12 the boy made aspectacular recovery, the blood picture returned tonormal, and the gastrointestinal and respiratoryinfections disappeared (Dohmann, Gimpert, Vischer,Pluss, and Hitzig, 1974). Gamma globulin injectionswere continued, but in the course of the next twomonths it was suspected that he had started tosynthesize his own immunoglobulins, since heexhibited very high IgM levels which could not beaccounted for by the injected material which con-sisted almost entirely of IgG. The gamma globulininjections were stopped, and the rise of immuno-globulins continued. In addition, specific antibodiesto diphtheria and tetanus appeared, much to oursurprise, as although diphtheria and tetanus toxoids

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had been given with KLH' three times during thefirst three months of life, no antibodies had appearedpreviously. Now, six months after the last antigeninjection, significant titres appeared, and after asingle booster injection these titres rose to very highvalues within 10 days. To characterize the nature ofthis antibody response further, the serum samplestaken three and 10 days after the booster injectionwere fractionated in the ultracentrifuge and provedto contain IgG antibodies exclusively (Hitzig andKenny, 1975).

In this case there is evidence that the lymphoidcells showed normal differentiation initially, sinceshortly after birth B lymphocytes with all threeclasses of membrane Igs were present in approxi-mately normal numbers (Cooper, Lawton, andKincade, 1972). For these cells to proceed to anti-body secretion, however, two conditions arenecessary, namely, antigenic stimulation and normalmetabolism. In the sterile surroundings in which theboy was nursed during the first months of life,bacterial antigens were excluded, but specific andlong-lasting stimulation was provided by steriletoxoids. From other patients reared under sterileconditions we know that antibody formation isperfectly possible, and the failure to produce anti-bodies in this patient is therefore attributed to aninsufficiency of vitamin B12. When B12 was admini-stered, antibody secretion occurred. A boosterinjection elicited an anamnestic response, thusproving that the first three antigen injections hadleft an impression on the immunological system withformation ofmemory cells. We conclude, therefore,that differentiation of these cells had proceededbefore birth in the usual way but that clonal expan-sion and the synthesis and secretion of antibody wasdependent on adequate concentrations of vitaminB12. The lymphoid system thus appears to havebehaved like the haematopoietic system and theintestinal mucosal epithelium, both of which haverapid cell replication dependent on B12.

Thymic hypoplasia (third and fourth branchial pouchsyndrome)In 1968 DiGeorge and Lischner described severalchildren with congenital absence of the thymus andthe parathyroids. This defect, which is often com-bined with other malformations such as hypo-plasia of the mandible or aortic arch, is easilyexplained embryologically as an inhibition of thedifferentiation of the organs derived from the thirdand fourth branchial pouch.The sequence of clinical signs is very important.

Within the first days of life severe tetany due to'KLH = keyhole limpet haemocyanin, a strong stimulant of T cells-ED.

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hypoparathyroidism becomes manifest. Only afterappropriate treatment of this life-threatening mani-festation do the patients survive and, at a later date,produce the signs of immune deficiency, ie, infectionsmainly localized in the respiratory system, and theadditional signs of a severe cellular immune defici-ency, associated with a normal lymphocyte count.Total immunoglobulin levels are normal, butspecific antibody formation may be deficient.

Significantly a transplant of fetal thymus almostcompletely reverses the signs of immune deficiency.

Severe combined immune deficiencyThe most severe and probably also the most commonhereditary immune deficiency syndrome involvesboth the antibody- and cell-mediated immunemechanisms (Swiss type, thymic alymphoplasia).Accordingly the clinical symptoms and signs arevery severe (Hitzig, Barandun, and Cottier, 1968).Infections start in early infancy, and all contactsurfaces of the body are involved, namely, the gastro-intestinal tract (leading to severe malnutrition), therespiratory tract (with lung damage and an earlysevere pertussoid cough), and the skin which showsmorbilliform rashes; blood stream invasions arefrequent. All kinds of microorganisms are respon-sible for these infections, pyogenic and saprophyticbacteria, viruses, protozoa and fungi, especiallyCandida albicans. These infections almost invariablylead to death within the first weeks or months oflife, malnutrition playing an important additionalrole.

Relatively simple laboratory data are sufficient toconfirm the diagnosis as soon as the clinical suspicionis aroused. The patients are usually lymphopenicand the lymphocytic functions are invariably de-ficient. The thymus shadow on an antero-posteriorradiograph is absent and at necropsy the pathologistfinds either no thymus at all or a very hypoplasticone high up in the neck. The severe depression ofimmunoglobulin synthesis becomes manifest onlyafter the age of 3 or more months, ie, when thematernal supply of IgG has been used up. The moretedious and time-consuming test of antibodyformation is always negative. Postmortem findingsare very characteristic with a marked diminution inthe amount of lymphatic tissue. Even more strikingare the histological findings: the lymph nodes arefew and very small and exhibit a severely disturbedarchitecture-no lymphocytes, no germinal centresand no plasma cells. The intestinal mucosa showssevere atrophy of the lymphoid tissue which is veryobvious in the appendix; this finding might explainthe gastrointestinal infections. Subsequent atrophyof the intestinal villi leads to malabsorption. Thechanges in the thymus, if the thymus can be found

at all, are pathognomonic: the architecture canbarely be recognized, there arevery few lymphocytes,the predominant cells are large, clear reticulum cells,and there are no Hassal's bodies at all.

Before the two-component theory it was suspectedthat a failure in the development of the thymus wasthe sole causative factor. When it became knownthat the antibody-mediated functions were alsoseverely impaired, a separate analogous defect inthe development of this system (or in modernterminology, lack of T and B lymphocytes) waspostulated. This, however, seems improbable, and adefect of the stem cell from which both chains oflymphocyte develop is a much more logical explana-tion, and this is accepted by most investigatorstoday. Different genetic forms have been distin-guished on purely clinical grounds, namely, auto-somal-recessive X-linked and sporadic forms, butthe hereditary basis is not clear.Almost two years ago a new finding threw some

light on at least one group of these patients (Giblett,Anderson, Cohen, Pollara, and Meuwissen, 1972).During the search for genetic markers theabsence of adenosine deaminase (ADA) was foundin two such patients. The parents of these childrenshowed significantly reduced enzyme activity, andit was considered that they were heterozygous,whereas the children were homozygous for thedeficiency. Very little was known about the frequencyof this special subgroup of severe combined immunedeficiency, and we decided therefore to investigateagain all the families of our previously deceasedpatients. Eight families were available for study, andin three pairs of parents the enzyme deficiency waspresent. One was a family described previously asan apparently incomplete manifestation of thissyndrome (Hitzig, Landolt, Muller, and Bodmer,1971). We reviewed, therefore, the data from all ourpatients and compared them with the findings inthe literature. We now suspect that the 'normo-gammaglobulinaemic antibody deficiency syndromewith severe lymphopenia' might be the clinicalcounterpart of ADA deficiency. It seemed possiblethat the Nezelof syndrome, which usually is regardedas a special entity, is also an example of this newlydefined deficiency disease. Preliminary estimatesindicate a frequency of one quarter to one half ofall cases of severe combined immune deficiency.The following hypothesis has been presented to

explain the pathogenesis of the severe combinedimmune deficiency syndrome: ADA catalyses thecritical metabolic step leading from adenosine toinosine. In its absence adenosine monophosphateaccumulates and this product has been shown to betoxic to lymphocytes. On the other hand, theconsequential fall of inosine concentration might be

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a limiting factor in cell metabolism. PresumablyT cells are more sensitive than B cells.Such a hypothesis suggests new therapeutic

approaches, eg, attempts to remove toxic substancesor to avoid their accumulation, or to increase theconcentration of the metabolites beyond the block,in this case presumably inosine.

Selective IgA deficiencyThe complete absence of IgA from the blood isapparently the most frequent hereditary immuno-globulin deficiency. It was found in one per 700apparently normal blood donors (Bachmann,1965).According to phylo- and ontogenetic studies, theformation of the IgA system seems to be the latestdevelopmental step. Apparently it is often missed.Each patient studied up to now has possessed anormal or high percentage of IgA-bearing B cells inthe peripheral blood. The most likely explanationof the pathogenesis of this disorder is therefore afaulty mechanism for secreting IgA into the serum,and indeed Cooper and Lawton (1972) have beenable to induce this release of IgA by treatinglymphocytes from such patients in vitro with poke-weed mitogen. An alternative possibility is theexistence of a serum inhibitor of IgA release;antibodies against IgA and other autoantibodies arecommonly found in selective IgA deficiency andconceivably might inhibit IgA secretion in vivo.Finally, animal experiments suggest that a defectof B and T cell cooperation or even a primarydefect of T cell function might be the basic failure;IgA levels are very low in nude mice, an inbredstrain with congenital aplasia of the thymus, and inrabbits thymectomized soon after birth. This is inaccordance with recent studies in patients withselective IgA deficiency, who showed decreasednumbers of E-rosette-forming lymphocytes in theirperipheral blood.The phylogenetically 'young' IgA system is highly

developed on mucosal surfaces, and seems to protectthem against invasion by microorganisms. It hastherefore been called the secretory immunoglobulinsystem and compared with a mucosal 'antisepticpaint' (Heremans, Crabbe, and Masson, 1966;Tomasi and Bienenstock, 1968). IgA antibodies haveno bacteriostatic or bacteriolytic properties butapparently just coat the surface of bacteria andchange their properties in such a way that theadhesion to and subsequent invasion of epithelialcells is greatly inhibited. This provides a very effec-tive protection against bacterial invasion (Williamsand Gibbons, 1972).

Surprisingly the clinical expression of IgAdeficiency is extremely variable, showing a widespectrum ranging from apparent clinical health to

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severe liability to infections. The factors involvedare not yet fully understood. However, a good dealis known about the mechanism of IgA secretion.The newly formed IgA molecule released from thesubmucosal plasma cell is transported to themucosal surface with the aid of a well characterizedmolecule, the secretory piece; usually two moleculesof IgA are linked together by one secretory piece.In addition, this complex is surrounded by onemolecule of J chain. Secretion in the absence ofsecretory piece seems to be impossible. Thisapparently occurs if large areas of mucosal surfaceare destroyed, for instance, during necrotizingenteritis or in coeliac disease. In such cases high IgAlevels are usually found in serum: apparently theIgA is synthesized at an increased rate but cannotbe secreted onto the mucosal surface; it is thereforedeviated 'backwards' into the bloodstream. Theapparent paradox that congenital absence of IgAsecretion occasionally leads to a similar state ofmaldigestion and malabsorption is well explained ongrounds of the pathogenesis, since these patientsare not protected against invasion by microorganismsfrom the gut lumen.Some of the gastrointestinal changes seen in

alpha-chain disease, which are discussed elsewherein this symposium by Professor Seligmann, mighthave the same explanation since the secretedimmunoglobulin is incomplete and functionallyinefficient.

Individuals with IgA deficiency and no tendencyto infection have been shown to secrete largeamounts of IgM on to their mucosal surfaces. Insome, but not all, of these the same secretory pieceis operative. It seems therefore that the phylo-genetically oldest immunoglobulin can effectivelytake over the missing function of the youngest.IgA deficiency has been discussed extensively

because it is the most important example of deficiencyof a single immunoglobulin. Severe diminution andincrease of all the other immunoglobulin classeshave been described, but the associated clinicalfeatures are variable and inconstant.

Transient hypogammaglobulinaemia of infancyAlmost 100 years ago clinical observation led tothe conclusion that the newborn infant is protectedagainst infections by substances transferred fromthe mother. The basis of this 'loan immunity'(Leihimmunitdt) was explained when it was shownthat IgG is able to cross the placenta and that inthe full-term infant the plasma concentration is ashigh as or even higher than that of the mother. Thistransplacental transport is highly selective andprobably involves partial degradation and sub-sequent rearrangement of the complicated IgG

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molecule. Many studies have shown that thismaternal IgG is gradually used up during the firstthree to six months of life and is slowly replaced bythe infant's own immunoglobulins. It has long beenknown that resistance against infection reaches itslowest point around the third month of life, andthis corresponds with the lowest point of a trough inplasma IgG concentration. Exact knowledge of thenormal values and their variation is essential forthe detection of these infants who need, and willbenefit greatly from, gamma globulin injection duringthis critical phase.There is a great variation in the plasma IgG values

in infants. In premature babies who are born witha considerably smaller supply of maternal IgG themean value decreases to very low levels. If thestandard deviation is calculated in the usual manner,extremely low and physiologically unlikely 'normal'values will be obtained. We have studied thedistribution pattern and have found it greatlyskewed towards the higher values (fig 1) in both

Fig 1 Distribution pattern of IgG concentrations in

premature infants of 30-33 weeks gestational age, andof 4-8 weeks chronological age. Percentiles andarithmetic values.

'normal' premature and full-term infants (Pilgrimet al, 1975). It therefore seems much more logicalto plot the deviation in the form of percentilecurves instead of standard deviations (fig 2).Since the gestational age which determines theamount of transferred maternal gamma globulin isof crucial importance, we have divided infants intothree groups according to gestational age (30-33weeks, 34-37 weeks and 38 weeks or more) andhave studied their postnatal development. The IgGlevels are different up to a postnatal age of about14 weeks by which time the premature infant hasmade up for its immunological handicap at birth(fig 3).

I. Cord < 1 1-3 4-8 9-13blood Postnatal age, weeks

Fig 2 Development of IgG concentrations in prematureinfants of 30-33 weeks gestational age. Percentiles andarithmetic mean with standard deviation.

Cord <1 1-3 4-8 9-13blood Postnatal age, weeks

Gestationol oge groups. a=30-33 wks.; b - 34-37wks.; c >38 wks.

Fig 3 Development ofIgG concentrations in prematureinfants of different gestational age. Gestational agegroups: a = 30-33 weeks; b = 34-37 weeks;c = > 38 weeks.

Primary immune deficiency syndrome with ataxiatelangiectaticaIn this very peculiar progressive neurologicaldisease with autosomal recessive inheritance, thereare striking telangiectases of the conjunctivae, othermucosae and skin, together with a liability torecurrent respiratory infections; IgA levels arereduced. At necropsy the thymus shows abnor-malities similar to those described in patients withsevere combined immune deficiency. The usuallyaccepted assumption of a T lymphocyte abnormality,however, fails to give a fully satisfactory explanationfor all the clinical observations. The disease becomesmanifest at school age and gets progressively worse.There is an associated high incidence of malignanttumours.

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Immune deficiency syndrome with thrombocytopeniaand eczema (Wiskott-Aldrich syndrome)This clinically well delineated syndrome with sex-linked inheritance is associated with very severeinfections which usually kill the patient within thefirst years of life. However, no consistent or reallysevere defects of the functions of B and T cells havebeen found, despite extensive studies. At present anabnormality of the macrophages is suspected(Cooper, Chase, Lowman, Krivit, and Good, 1968)but this question is still wide open.

ACQUIRED AND TRANSIENT IMMUNEDEFICIENCY DISORDERSAcquired deficiencies of both the B and T cellsystems are much more frequent than the congenitalforms. Table III exemplifies some typical situations,but is far from being comprehensive. The laboratoryprocedures used for the evaluation of the immuno-logical potential of such patients are the same asthose outlined earlier. One example is the transientdepression of cell-mediated immune functions occur-ring during some virus infections; even in VonPirquet's time it was known that the cutaneoustuberculin reaction is abolished for several weeksafter an attack of measles, during which time theremay be a very rapid exudative spread of a tuber-culous infection. It seems likely that the virus altersthe membrane surface of lymphocytes in such a waythat the normal triggering by specific antigens is notpossible.

Condition Deficient System

B T Granulocytes Macrophages

Newborn infant +Virus infection +Neutropenia +Splenectomy +Malignant lymphomasChronic lymphaticleukaemia +Hodgkin's disease +

Mucocutaneous candidiasis +Endocrine disorders + + +Uraemia + (+)Diseases with protein loss +Diseases with lymph loss +

Table III Acquired and transient immune deficiencies

Therapeutic Approaches (Hitzig, 1971)

CONVENTIONAL TREATMENTPatients with constitutional immune deficienciessuffer from recurrent infections or are chronicallyill. In some of them symptomatic treatment is

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effective: congenital sex-linked agammaglobulin-aemia can usually be kept under control by regularinjections of human gamma globulin (0-3 ml/kg eachweek or 1.0 ml/kg every three weeks). This replace-ment treatment has been reviewed extensively.Table IV shows the preparations available and tableV the indications for treatment and dose schedules.However, such treatment does not solve all problems.Disadvantages are that the usual intramuscularinjections are painful for the patient and that intra-venous injections may lead to very severe reactions.At all stages of acute or chronic infection the usualantimicrobial treatment is given but this will not bediscussed here.

Preparation Immunoglo- Route of Approximatebulin Admini- PhysiologicalContained stration Half-life

Plasma (blood) IgG, IgA, iv 1 to 3 weeksIgM

Standard y globulin IgG im 3 weeksSpecial v-globulin IgG iv i to 2 weeks

preparations for ivadministration

Special multiclass y IgG, IgA, im ? to ?globulin preparations IgM 3 weeks

Table IV Therapy with immunoglobulins

The real problems arise with cellular immuno-deficiencies which are invariably fatal if untreated.To help these patients, exceptional and even heroictherapeutic approaches are necessary.

BONE MARROW TRANSPLANTATIONOn the assumption of a stem cell deficiency a con-siderable number of patients with severe combinedimmune deficiency have received bone marrowtransplants. Last year 25 patients were known to havehad replacements and this number has steadilyincreased since. The greatest danger is graft-versus-host reaction which is still difficult to treat. Theprinciples of the procedure are well outlined in aprotocol set up by the Society for ExperimentalHaematology. In the majority of cases, however,no compatible donor is available. It is now evidentthat in such cases no attempt should be made totransplant incompatible bone marrow. The above-mentioned protocol in these cases recommends theuse of fetal tissues.

IMPLANTATION OF FETAL TISSUESIn late embryonic and early fetal life the haemo-poietic stem cells differentiate and proliferate in theliver. Before the 18th gestational week these stemcells have no immunological competence. Firstattempts at implantation of fetal liver resulted in aconsiderable increase in the number of lymphoid

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Prophylaxis and Therapy Protective Value Time of Application Dose (ml/kg)

Immunoglobulin, normal human (16 %, im)Measles

Full protection X + First 4 days after exposure 0.2Mitigation + First 4 days after exposure 0-02-0 04Mitigation + + to (+) From 5th day after exposure to appearance 0.02-0.2

of Koplik spotsRubella

Mitigation ? First 8 days after exposure 0.2In pregnancy ? First 8 days after exposure 1 0-2.0

Varicella + -? - As early as possible 04-1.0Viral hepatitis + First 2 weeks after exposure 001-0 1Poliomyelitis + Before or early after exposure (in unvaccinated

persons) 0-3-0.5Antibody deficiency syndrome + Every 3-4 weeks 1 0-2.0Infants with severe infections + First day, if necessary, same dose on 3rd day 1.0Sepsis, resistance to antibiotics, severe burns + First day, if necessary, same dose on 3rd day 1.0

Immunoglobulin, human antitetanusProphylaxis -+- + Early; at same time active immunization 250-500 IU imTherapy + Immediately 500-5000 Iu

Intnunoglobulin, human antivacciniaLate primary vaccination + Simultaneously with active vaccination 001-0.05 ml/kgRelative contraindication for revaccination - ? Simultaneously with active vaccination 0.2 ml/kgMitigation of variola + + to- Early after exposure 0-2-0.6 ml/kgComplications of vaccinationGeneralized vaccinia + or- J0225 mI/kg

Inmnmunoglobulin, human antipertussisComplications in infants (up to 2 years) + ? Early 0.2-0.5 mt/kg

lInmunoglobulin, human antiparotitisProphylaxis of orchitis + ? Early 0 05-0.1 mI/kg

Imtimunoglobulin, human anti-DProphylaxis of Rh-sensitization + + After birth, if 0.1 ml fetal Hb-containing

erythrocytes is present in the maternalcirculation 0 1-0 5 ml/kg

Table V Therapy with immunoglobulins

cells, but not in functional reconstitution of thepatient. The excellent results of bone marrow trans-plants discouraged further work in this direction forseveral years. However, recent experience in patientsfor whom no matched bone marrow donor wasavailable seems to be more encouraging. We knowof three successful transplants. One of them is ourpatient with ADA deficiency who received 108 livercells from a fetus aged 14 gestational weeks. Shesubsequently showed a dramatic clinical improve-ment, and also the ADA activity increased to lownormal values. After a transient drop, the level ofenzyme activity is now in the subnormal range foundin the heterozygous but immunologically healthyparents of our patient.

TRANSFER FACTORThere is still great controversy over the value ofLawrence's dialysable transfer factor, presumably aproduct of sensitized lymphocytes. It has the uniqueadvantage of not being antigenic and not producinggraft-versus-host reactions. We recently reviewedwork on transfer factor (Hitzig and Grob, 1974),and, owing to the lack of standardization both ofthe preparation and of the clinical application, wefound it very difficult to make a final judgment. Itseems that in the Wiskott-Aldrich syndrome it is

helpful in about half the patients treated. The mostdramatic success has been obtained in patients withchronic mucocutaneous candidiasis, especially thegranulomatous form, but even in this condition somefailures have been recorded.

Therapeutic trials on patients with congenitalimmune deficiency have contributed to the basicunderstanding of physiological immune mechanismsand to the treatment of acquired diseases as well.In particular the knowledge gained from bonemarrow transplantation in severe combined immunedeficiency has opened the way to similar treatmentof patients with leukaemia and aplastic anaemia andmay become quite important in the future.

References

Bachman, R. (1965). Studies on the serum y A-globulin level. III.The frequency of a yA-globulinemia. Scand. J. clin. Lab.Invest., 17, 316.

Cooper, M. D., Peterson, R. D. A., and Good, R. A. (1965). A newconcept of the cellular basis of immunity. J. Pediat., 67, 907.

Cooper, M. D., Faulk, W. P., Fudenberg, H. H., Good, R. A.,Hitzig, W., Kunkel, H. G., Roitt, I. M., Rosen, F. S., SeligmannM., Soothill, J. F., and Wedgwood, R. J. (1974). PrimaryImmunodeficiency Diseases in Man. Clin. Immunol. & Immuno-pathol., 2, 416.

Cooper, M. D., and Lawton, A. R. (1972). Circulating B cells inpatients with immunodeficiency. Amer. J. Path., 69, 513.

Cooper, M. D., Lawton, A. R., and Kincade, P. W. (1972). A two-stage model for development of antibody-producing cells.Clin. exp. Immunol., 11, 143.

copyright. on 15 S

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j.com/

J Clin P

athol: first published as 10.1136/jcp.s1-6.1.83 on 1 January 1975. Dow

nloaded from

Immune deficency diseases 91

Cooper, M. D., Chase, H. P., Lowman, J. T., Krivit, W., and Good,R. A. (1968). Wiskott-Aldrich syndrome: an immunologicdeficiency disease involving the afferent limb of immunity.Amer. J. Med., 44, 499.

Dohmann, U., Gimpert, E., Vischer, D., Pluss, H. J., and Hitzig,W. H. (1974). Untersuchungen uber Vitamin B-,, Transportim Blut: Anomalie des Transcobalamins II. Schweiz. med.Wschr., 104, 1392.

Fudenberg, H., Good, R. A., Goodman, H. C., Hitzig, W., Kunkel,H. G., Roitt, I. M., Rosen, F. S., Rowe, D. S., Seligmann,M., and Soothill, J. R. (1971). Primary immunodeficiencies:report of a World Health Organization committee. Pediatrics,47, 927.

Giblett, E. R., Anderson, J. E., Cohen, F., Pollara, B., and Meuwissen,H. J. (1972). Adenosine-deaminase deficiency in two patientswith severely impaired cellular immunity. Lancet, 2, 1067.

Good, R. A., Finstad, J., Gewurz, H., Cooper, M. D., and Pollara,B. (1967). The development of immunological capacity inphylogenetic perspective. Amer. J. Dis. Child., 114, 477.

Good, R. A., and Fisher, C. B. (1971). Immunobiology. Hosp. Pract.(Minneapolis).

Hakami, N., Neimann, P. E., Canellos, G. P., and Lazerson, J. (1971).Neonatal megaloblastic anemia due to inherited transco-balamin II deficiency in two sibling. New Engl. J. Med., 285,1163.

Heremans, J. F., Crabbe, P. A., and Masson, P. L. (1966). Biologicalsignificance of exocrine. A-immunoglobulin. Acta med. scand.,Suppl. 445, 179, 84.

Hitzig, W. H. (1971). Therapy of immunological deficiency diseases.In Immunologic Incompetence, edited by B. M. Kagan andE. R. Stiehm, p. 203. Year Book Medical Publishers, Chicago.

Hitzig, W. H. (1974). Immunmangel-Krankheiten. Pathophysiologieund Klinik. In Handbuch der inneren Medizin, edited by

H. Schwiegk. Springer, Berlin.Hitzig, W. H., Barandun, S., and Cottier, H. (1968). Die Schweize-

rische Form der Agammaglobulinamie. Ergebn. inn. Med.Kinderheilk., 27, 79.

Hitzig, W. H., and Grob, P. J. (1974). Therapeutic uses of transferfactor. Prog. clin. Immun., 2, 69.

Hitzig, W. H., and Kenny, A. B. (1974). The r6le of vitamin B12and its transport globulins in the production of antibodies.Clin. exp. Immunol., in press.

Hitzig, W. H., and Kenny, A. B. (1975). The role of vitamin B12and its transport globulins in the production of antibodies.Clin. exp. Immunol., 20, 105.

Hitzig, W. H., Landolt, R., Muller, G., and Bodmer, P. (1971).Heterogeneity of phenotypic expression in a family withSwiss-type agammaglobulinemia: observations on the acquisi-tion of agammaglobulinemia. J. Pediat., 78, 968.

Lawton, A. R., Self, K. S., Royal, S. A., and Cooper, M. D. (1972).Ontogeny of B-Iymphocytes in the human fetus. Clin. Immunol.,1, 84.

Pilgrim, U. P., Fontanellaz, H. P., Evers, G., Hitzig, W. H. (1975).Normal values of immunoglobulins in premature and full-terminfants, calculated as percentiles. Helv. Paed. Acta, in press.

Stiehm, E. R., and Fulginiti, V. A. (1973). Immunologic Disorders inInfants and Children. Saunders, Philadelphia.

Tomasi, T. B., Jr., and Bienenstock, J. (1968). Secretory immuno-globulins. Advanc Immunol., 9, 1.

Williams, R. C., and Gibbons, R. J. (1972). Inhibition of bacterialadherence by secretory immunoglobulin A: a mechanism ofantigen disposal. Science, 177, 697.

World Health Organization (1970). Immunological problems in leprosyresearch. 5. Protocol for the investigation of depression ofimmunological function in leprosy. Bull. Wld Hlth Org., 43,884.

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