Humoral immunodeficiency

CL~N~CALIMMUNOLOGY

AN,,hE,K,NOPATHOLOGY

Humoral

ital

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globulins.

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than Disorders

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rangement abnormality at a specific stage of B-cell maturation. B-cell deficiency and institution of adequate immunoglobulin prevent extensive damage to the lungs and other life-threatening and

allow

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childhood

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adult

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deficiency

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considerable the primary

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high-grade

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cellular immunodeficiency. affecting B-cell function

of B-cell

are seen in a majority of these function in large pedigrees of

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with

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or as autosomal traits. at a functional and cellular

B-cell malfunction morphology and

agammaglobulinemia

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is more prevalent the latter defects.

recessive defects

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syndromes may occur as apparent congenin all or in only some classes of immuno-

pathogens.

hypogammaglobulinemia population statistics

humoral immunodeficiency due to early death from

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immunodeficiency with deficiencies

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INTRODUCTION

Humoral (or antibody) deficiency disorders may occur in children or adults as apparent congenital or acquired abnormalities, with deficiencies in all or in only some classes of immunoglobulins (I -3). The latest revision of the World Health Organization’s (WHO) “Classification of Primary lmmunodeficiency Diseases” lists 13 defects characterized predominantly by antibody deficiency (Table 1). Most patients have recurrent infections with high-grade encapsulated bacterial pathogens; however, some with selective IgA deficiency or infants with transient hypogammaglobulinemia may have few or no infections. Although the true incidences of these diseases are unknown, they are generally considered to be rare. Selective IgA deficiency is the most common, with reported incidences ranging from I in 3000 to 1 in 328 in “healthy” blood donors (4, 5). In contrast, the frequency of agammaglobulinemia has been estimated at I :50,000. Antibody deficiency syndromes are more prevalent in children than in adults and, during childhood. are approximately five times more common among males than females. t Presented Prevention, ton. D.C. z To whom Center,

as part and

Durham.

of a symposium

requests

for

entitled February

Management.” reprints

N. C. 37710.

should

“Childhood 25-26. 1985.

lmmunodeficiency National Academy

be addressed:

P.0.

Box

2898.

Duke

Disorders: of Sciences.

Diagnosis. Washing-

University

Medical

I-l

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B cells T-cell dkorder

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autoantibodies

to B or T cells

Despite enormous progress in characterizing these various defects phenotypitally and functionally at both clinical and cellular levels, the primary biologic errors remain unknown for all of them. Disorders of B-cell function may be inherited as X-linked recessive or as autosomal traits. Apparent abnormalities of B-cell maturation and/or intrinsic B-cell malfunction are seen in a majority of these defects. The genetic errors in some must, by definition, be located on the X chromosome. Since trace amounts of immunoglobulins of all five isotypes can usually be found by radioimmunoassay in the serum of even the most severely agammaglobulinemic patient, it is unlikely that immunoglobuiin deficiency states are due to deletions of genes encoding for immunoglobulin heavy chains on chromosome 14. This does not, however, exclude the possibility of regulatory gene defects. Not one of these defects has been found to have associated deficiencies of particular HLA antigens; thus, they are unlikely to represent defects involving HLA-linked immune response genes on chromosome 6. X-LINKED

(BRUTON’S)

AGAMMAGLOBULINEMIA

This was the first described of all human immunodeficiencies. A majority of boys afflicted with it remain well during the first 6 to 9 months of life, presumably by virtue of maternally transmitted IgG antibodies. Thereafter. they repeatedly acquire infections with high-grade extracellular pyogenic organisms such as pneumococci, streptococci, and hemophilus unless given prophylactic antibiotics or gamma globulin therapy. Infections with other organisms such as meningococci, staphylococci. and pseudomonas occur less frequently. The most common types of infections include sinusitis. pneumonia. otitis. furunculosis, meningitis.

HUMORAL

IMMUNODEFICIENCY

15

and septicemia. Despite these chronic or recurrent infections, patients with this disorder usually grow normally unless they develop bronchiectasis or persistent enterovirus infections. Chronic fungal infections are not usually present and Pneumocystis carinii pneumonia rarely occurs unless there is an associated neutropenia. Viral infections and live virus vaccines are also usually handled normally, with the notable exceptions of hepatitis and enterovirus infections. Several examples of paralysis after polio vaccine administration have occurred, presumably due to mutation of the vaccine virus to a more neurotropic form. In addition, chronic progressive, eventually fatal CNS infections with various Echoviruses have occurred in over 20 such patients (6). Several have presented with a dermatomyositis-like picture before neurological abnormalities were apparent, raising the possibility of a viral etiology for other collagen-like diseases seen in themsuch as rheumatoid arthritis, which occurs in approximately 20% of such patients. The diagnosis of X-linked agammaglobulinemia should be suspected in boys with onset of recurrent bacterial infections in infancy or early childhood if (a) serum concentrations of IgG. IgA, and IgM are far below the 95% confidence limits for appropriate age and race-matched controls (i.e.. usually ~100 mgldl total immunoglobulin), and (b) if there is a family history of early death from infection in lateral maternal male relatives. The demonstration of antibody deficiency in serum and in external secretions is of great importance in distinguishing this disorder from transient hypogammaglobulinemia of infancy. Tests for natural antibodies to blood group substances, for antibodies to antigens given during standard courses of immunization, e.g., diphtheria, tetanus, or pneumococcal, and for antibodies to and ability to clear bacteriophage 4 X 174 are useful in this regard. Polymorphonuclear leukocyte functions are usually normal if heat-stable opsonins (e.g., IgG antibodies) are provided, but some patients with this condition have had transient, persistent, or cyclic neutropenia. Because of remarkable homogeneity in the clinical and immunologic findings in patients with this defect, it has generally been considered to “breed true.” There have been no reports of other phenotypes of immunodeficiency (such as IgA de& ciency or severe combined immunodeficiency) in pedigrees of such patients. Blood lymphocytes bearing surface immunoglobulin, “la-like” antigens, the Epstein-Barr virus (EBV) receptor or reacting with specific anti-B-cell monoclonal antibodies are absent or present in very low number (Table 2). Hypoplasia of adenoids, tonsils, and peripheral lymph nodes is the rule: germinal centers are not found and plasma cells are rare. However, we and Levitt rt al. (7) have succeeded in establishing EBV-induced IgM-secreting plasmacytoid-lymphoblastoid cell lines from the peripheral blood of such patients, suggesting that B-cell precursors are present in the blood. In addition, normal numbers of pre-B cells are found in the bone marrow. Defective heavy chain variable and constant region gene rearrangement at the pre-B cell stage has been postulated by some workers to be the basic defect (3). However, the author and others (8) have observed significant variability in B lymphocyte phenotypes. serum immunoglobulin concentrations, and antibody responses among affected males within large pedigrees. This, together with the fact that IgM-secreting cell lines can be established from

X-linked agammaglobulinemia (20) Common variable immunodeficiency (30) Hyper-IgM

0.5 t 0.3 0.Y I?- I.1 0.x .- 0.3 (1.4 + 0.3

14)

Normal (31)

controls

IO.2 7 7.0 IX.7 1l.h

f -

I I .o 5.2

the blood of such patients (7). makes it highly unlikely that this defect is due to a distinct gene rearrangement abnormality at a specific stage of B-cell maturation. Studies by Schuurman et al. (9) suggested that the gene responsible for this defect is on the short arm of the X-chromosome. However, studies by others place it on the long arm near the centromere. The number of total T cells is usually increased and the percentages of T cell subsets have been found to be normal in most of these patients (10). Ceil-mediated immune responses can be detected in vitro and itz V~VO,and the capacity to reject allografts is intact. The thymus has appeared morphologically normal in all autopsied cases, Hassall’s corpuscles are present, and lymphoid cells are abundant in thymus-dependent areas of peripheral lymphoid tissues. Except in those unfortunate patients who develop polio, persistent enterovirus infection, or lymphoreticular malignancy (an incidence as high as 6% has been reported), the overall prognosis is reasonably good if adequate antibody replacement therapy is instituted early (I 1). However, many patients go on to develop crippling sinopulmonary disease despite this. since presently no effective means exists for replacing secretory IgA at the mucosal surface. X-LINKED

HYPOGAMMAGLOBULINEMIA HORMONE DEFICIENCY

WITH GROWTH

This abnormality has thus far been seen only in a single pedigree in which four male members were affected with hypogammaglobulinemia and isolated growth hormone deficiency (12). The immunodeficiency resembled most closely classic X-linked agammaglobulinemia in that there was a similar inheritance pattern, there were diminished to absent circulating B lymphocytes in the affected members, one of them has recently acquired a persistent enterovirus meningoencephalitis, and T-cell function has been normal in all four. However, the fact that one of the four had normal serum IgA and IgM concentrations and did have some detectable circulating B cells has led some to feel that this is a distinct immuno-

HUMORAL

17

IMMUNODEFICIENCY

deficiency syndrome. Considering that similar variability has now been seen in pedigrees of classic X-linked agammaglobulinemia, however, this argument seems no longer tenable. The concurrence of isolated growth hormone deficiency would also favor a distinct entity, but, until other such pedigrees or unrelated patients with similar features are described, one must consider that this may have been a chance association of the two disorders in this unique pedigree. AUTOSOMAL

RECESSIVE

AGAMMAGLOBULINEMIA

Barely, female infants and children have been described who are similar to patients with X-linked agammaglobulinemia clinically and in that they lack circulating surface-immunoglobulin-positive B lymphocytes: they have similar marked immunoglobulin and antibody deficiency and normal T cell numbers and function. The author has evaluated and followed two such young girls, both of whom had enterovirus meningoencephalitis, similar to that seen in boys with the Xlinked defect. However, the condition has been documented in the literature only rarely (13) and, until there are further reports of patients with similarly affected male and female relatives, it will be difficult to know whether a separate form of agammaglobulinemia with an autosomal recessive mode of inheritance truly exists. It is always possible that such females could be homozygotic for the Xlinked abnormality. IMMUNOGLOBULIN

DEFICIENCY

WITH INCREASED

IgM (AND IgD)

This disorder is characterized by very low serum concentrations of IgG and IgA but either a normal or, more frequently, a markedly elevated concentration of polyclonal IgM and sometimes IgD. Some of these patients have low-molecular weight IgM molecules that given falsely high IgM values on radial diffusion. High titers of IgM antibodies to blood group substances and to salmonella 0 antigen have been found in some patients, but very low titers or no IgM antibody have been noted in most. Similar to patients with X-linked agammaglobulinemia. patients with this defect may become symptomatic during the first or second year of life with recurrent pyogenic infections, including otitis media, sinusitis, pneumonia, and tonsillitis. In contrast to patients with X-linked agammaglobulinemia, however, the frequent presence of lymphoid hyperplasia in this condition often leads the physician away from a diagnosis of immunodeficiency. Even more than with some of the other antibody-deficiency syndromes, there is an increased frequency of autoimmune disorders. Hemolytic anemia and thrombocytopenia have been seen in several patients. and transient, persistent, or cyclic neutropenia is a common feature. The neutropenia is considered a possible explanation for the unusually high frequencies of Pneumoc-ystis cnrinii pneumonia and extensive verruca vulgaris lesions seen. Thymic-dependent lymphoid tissues and T-cell functions are usually normal, but several have had partial T-cell deficiencies. An X-linked mode of inheritance has been proposed, but several examples in females now make this less certain and at times this has been reported as an acquired disorder. The precise defect in this syndrome has yet to be elucidated. Normal or only slightly reduced numbers of IgM and/or IgD B lymphocytes have been found in

IX

REBECCA

H. BUCKLEY

the blood of these patients (Table 2). However, cultured B cell lines from 5uch patients have shown the capacity to synthesize only IgM. suggesting an intrinsic B-cell defect that involves isotype switching. Histologic studies of peripheral lymphoid tissues have revealed the presence of primary follicles in some but not all of these patients. When plasma cells have been present in the perifolliculal areas or in the medullary cords of lymph nodes, they have usually contained only 1gM. Because these patients have an inability to make IgG antibodies, the treatment for this condition is the same as for agammaglobulinemia ( I I ). IgA DEFICIENCY An isolated absence or near absence (i.e.. < 10 mgidl) of serum and secretory IgA is thought to be the most common well-defined immunodeficiency disorder (4). In a recent study of 6240 healthy blood donors in Tennessee. a frequency of I:328 was reported (2). While this disorder has been observed in apparently healthy individuals, it is also commonly associated with ill health (4). In some sick patient populations the incidence of this defect approaches 15%.The kinds of health problems experienced by such patients often reflect the type of clinic from which they are drawn. Among a group of 75 such patients derived from an allergy-immunology clinic. there were high frequencies of chronic or recurrent respiratory tract infections and atopic diseases (4). In contrast. among 30 IgA-deficient patients drawn primarily from a rheumatology clinic. there was a high f’requency of autoimmune and/or collagen-vascular disease. The disorder has been found predominantly among Caucasians and occurs almost twice as often in males as in females (4). As would be expected when there is a deficiency of the major immunoglobulin of external secretions, infections occur predominantly in the respiratory, gastrointestinal, and urogenital tracts. Bacterial agents responsible are essentially the same as in other types of antibody deficiency syndromes. There is no clear evidence that patients with this disorder have an undue susceptibility to viral agents. Children with IgA deficiency vaccinated with killed polio virus intranasally produced local IgM and IgG antibodies. Recent studies suggest that the compensating IgM is locally synthesized and capable of combining with secretory piece for local secretion similar to IgA. Serum concentrations of other immunoglobulins are usually normal in patients with selective IgA deficiency, although an lgG2 subclass deficiency has been reported in some and IgM (usually elevated) may be of the low-molecular-weight variety. In addition to limiting the attachment of infectious agents lo mucosal surfaces, secretory IgA antibodies probably act to prevent absorption of other foreign antigens. such as those in the diet. Patients with IgA deficiency have a high incidence of IgG antibodies against cow’s milk and ruminant serum proteins. The anti-ruminant antibodies often present technical problems in radial diffusion measurement of IgA. since most antibody-agar plates are made with goat antisera. A very high incidence of autoantibodies was noted in one group of IgA-deficient subjects; this may have bearing on the frequent association of IgA deficiency with collagen-vascular and autoimmune diseases. Nodular lymphoid hyperplasia of

HUMORAL

IMMUNODEFICIENCY

19

the intestine has been seen in a few such patients, and there is a high incidence of a sprue-like syndrome in adults with selective IgA deficiency; the latter may or may not respond to a gluten-free diet. The basic defect leading to selective IgA deficiency is unknown. In 10 of 11 IgA-deficient individuals studied, more than 80% of the IgA-bearing B cells also coexpressed surface IgM and IgD (similar to cord blood B cells), as compared with less than 10% triple isotype-bearing IgA B cells in controls (14). Other studies demonstrated that blood lymphocytes from most such patients synthesized cytoplasmic but not secreted IgA when stimulated by pokeweed mitogen in r,itro; increased IgA isotype-specific suppressor T cells were found in some. Studies of T-cell function have been normal in most patients with selective IgA deficiency. Reports that certain drugs, notably diphenylhydantoin, sulfasalazine and D-penicillamine, can induce selective IgA deficiency in patients with idiopathic epilepsy, rheumatoid arthritis, and Wilson’s disease are intriguing, since this abnormality often reverses when the drug is discontinued. These observations, plus the association of this defect with congenital rubella, chromosomal defects, and the other aforementioned immunodeficiency diseases, suggest that IgA deficiency may result from multiple causes. This defect may not always be permanent, as the author has observed spontaneous development of normal serum IgA concentrations in more than a dozen children from a group of over 150 patients documented for several years to have absent or extremely low IgA. Conversely, she has also occasionally observed patients with this defect to go on to become profoundly antibody deficient and to resemble those with common variable immunodeficiency. This may be related to the fact that this defect may occur in the same sibship or pedigree as common variable agammaglobulinemia (Fig. 1). The occurrence of IgA deficiency in both males and females and in families suggests autosomal inheritance. In some families this appears to be a recessive trait. and in others it appears to be dominant with variable expressivity (Fig. 2). Of possible etiologic and great clinical significance is the presence of antibodies to IgA in the sera of approximately one-third of patients with serum IgA concentrations below 5 mgidl. At least eight IgA-deficient patients have been reported as having severe or fatal anaphylactic reactions after intravenous administration of blood products, and anti-Igh antibodies appeared to be clearly incriminated in

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FIG. I. Pedigree in which two haploidentical siblings have two different immune defects-absent IgA and common variable hypogammaglobulinemia (IgG 93, IgA 0, IgM 5). A normal sibling (fourth from the left) is HLA identical to the boy with absent IgA. (Reproduced by permission of the publisher from Ref. (19b.j

REBECCA

H.

BUC‘KLE\r

Uoie remole

3.7 3.7 v23,12

FIG.

2. Pedigree

of patient

with

of the

publisher

from

selective

Ref.

Normal IqA Markedly

W33,Y

absence

have selective absence of serum IgA. All three patient’s mother. however. who is H1.A identical permission

‘Deceased

of IgA.

affected to the

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four of these. Recently. the author and her associates have demonstrated IgE anti-IgA antibodies in two patients with anaphylactic reactions caused by blood products containing IgA. For this reason. only multiply 15 x ) washed normal erythrocytes or blood products from other IgA-absent individuals should be administered to these patients. and all presently commercially available im or iv gamma globulin preparations (which contain >700 g/ml IgA) are contraindicated in therapy (I I). Currently there is no treatment for IgA deficiency beyond the vigorous treatment of specific infections with appropriate antimicrobial agents (Ill. Even if serum IgA could be replaced (in the face of anti-IgA antibodies) it would not be transported into the external secretions. since the latter is an active process involving only locally and endogenously produced IgA. In addition to IgA deficiency occurring for the reasons just discussed, 1gA can also be deficient in external secretions due to a deficiency in the production of secretory component. A patient with chronic intestinal candidiasis and diarrhea was found to lack IgA in his external secretions. despite having a normal concentrations of serum IgA. This was ultimately traced to a lack of secretory piece. which prevented the normal secretion of locally produced IgA onto his mucous membrane surfaces. SELECTIVE

DEFICIENCY

OF OTHER

IMMUNOGLOBULIN

ISOTYPES

There are very few well-documented cases of selective deficiency of other isotypes. Septicemia due to meningococci and other gram-negative organisms. pneumococcal meningitis, tuberculosis. recurrent staphylococcal pyoderma, periobital cellulitis. bronchiectasis, recurrent otitis, and other respiratory infections have been reported in selective IgM deficiency. In \$w production of IgM antibodies is markedly impaired in the latter defect. However. in tdro studies of B-lymphocyte function in two IgM-deficient patients revealed normal production of immunoglobulins of all isotypes when cocultured with normal T cells. This was not due to excessive autologous suppressor T-cell activity but apparently to a

HUMORAL

31

IMMUNODEFICIENCY

lack of adequate T-helper-cell function, The selective absence of IgM is difficult to explain from the standpoint of molecular biology, since IgM synthesis precedes that of IgG and IgA. Recently there has been considerable interest in the selective deficiency of one or more IgG subclasses. As noted above, IgG2 deficiency has been seen most commonly in patients with selective IgA deficiency but also in patients with ataxia telangiectasia. How prevalent or clinically significant IgG subclass deficiency is has been difficult to establish because of technical problems with the production of truly subclass-specific diagnostic reagents. Patients found to have such deficiencies should be first studied to determine their antibody-forming capacities to a range of protein and polysaccharide antigens before beginning gamma globulin therapy. The latter could suppress the patient’s existing intrinsic antibody-synthesizing capacities, since there are no preparations of individual specific IgG subclasses available for therapy. There is at present no specific treatment for these disorders; early diagnosis of IgM deficiency and vigorous treatment with antibiotics is recommended to avoid fatal septicemia. KAPPA-CHAIN

DEFICIENCY

Possibly related to disorders of specific antibody production in patients with normal or near-normal immunoglobulins (see below) are deficiencies of IgG subclasses, as discussed above, or, much more rarely, of kappa-chain synthesis. The latter has been reported both as disturbances in the normal kappa:lambda-chain ratio of 2: I or as an apparent absence of kappa chains in one patient with cystic fibrosis ( 15). ANTIBODY

DEFICIENCY WITH NORMAL GAMMA OR HYPERGAMMAGLOBULINEMIA

GLOBULIN

LEVELS

Only scattered reports have appeared in the literature describing patients with apparently normal T-cell function and normal or near-normal immunoglobulin concentrations but with deficient antibody responses (16). These patients resemble those with the Wiskott-Aldrich syndrome in the latter respect. In 12 such patients studied by the author, blood group antibody titers were absent in all but 2, diphtheria titers were low in all, and tetanus titers were low in 10. Geometric mean antibody titers to 13 pneumococcal serotypes were significantly lower than those of 27 normal controls before and after immunization with tridecavalent pneumococcal polysaccharide vaccine. All patients cleared bacteriophage 4 X 174 normally, but all primary immune responses were far below the normal range. Secondary responses to d, X 174 were also below the normal range in all but two but, in both cases, most of the secondary response was IgM rather than IgG. Longitudinal studies of the author’s patients have demonstrated that several have gone on to become immunoglobulin deficient with time, suggesting that this entity may be an earlier stage of common variable immunodeficiency. Since these patients do not have the ability to produce antibodies normally, they are candidates for immune serum globulin replacement therapy ( I I ).

17 --

KEBECCA

IMMUNODEFICIENCY

H.

BUCKLE1

WITH THYMOMA

This disorder has been reported primarily in older adults. It i\ often accompanied by an aregenerative anemia and other abnormalities of hematopoiesis a\; \ve\I as autoimmune diseases. Although it is presumed to be an acquired defect. those affected having striking deficiencies of both me-B and B cells. suggesting that lymphoid stem cells are affected as well. Excessive T-suppressor-ceil activity has been found in a majority of such patients, but it is not known whether this plays a primary or secondary role in the hypogammaglobulinemia. Removal of the thy moma often results in improvement in all parameters. TRANSIENT

HYPOGAMMAGLOBULINEMIA

OF INFANCY

This condition has been described as a prolongation and accentuation of the “physiologic” decline in serum immunoglobulin concentrations normally seen during the first 3 to 7 months of life. Until recently there had been scant documentation of this disorder. Eleven patients with this defect were evaluated with various tests of immunologic functions in the author’s laboratory over a I?-year period (17). Two groups were identified: six who were found by screening relatives of patients with other types of immunodeficiency and five whose sera wet-c sent because the patients were having frequent or unusual infections. Those in the first group had no significant health problems during early infancy or childhood. In the second, recurrent infection was a problem during early infancy but not in later years. All 11 patients could synthesize antibodies to human type A and B erythrocytes and to diphtheria and tetanus toxoids, usually by 6 to I I months of age, and well before immunoglobulin concentrations became normal. Lymphocyte studies in t~itro showed no abnormalities in the percentages of cells in the different subpopulations or in their responses to the mitogens. The finding of only I I cases of transient hypogammaglobulinemia of infancy among over 10,000 patients whose sera were sent for immunoglobulin studies over a I?-year period suggests that this is not a common entity. contrary to earlier opinions. Long-term follow-up of those patients revealed that the immunoglobulin concentrations did not all normalize by 2-3 years of age. as implied in earlier textbook descriptions. Indeed, some of those patients had persistently low immunoglobulin concentrations, particularly of IgA; however, normal antibody-forming capacities were maintained. Gamma globulin replacement therapy is not indicated in this condition ( I I ). In addition to the known risk of inducing anti-allotype antibodies, passively administered IgG antibodies could suppress endogenous antibody formation in the same manner that RhoGAM suppresses anti-D antibodies in Rh-negative mothers delivering Rh-positive infants. COMMON

VARIABLE

IMMUNODEFICIENCY

This syndrome, also known as idiopathic late-onset immunoglobulin deficiency, may appear similar clinically in many respects to X-linked agammaglobulinemia. While these defects have often been considered to be acquired, there are

HUMORAL

IMMUNODEFICIENCY

23

few documentations of true “acquisitions” of immunoglobulin deficiency. Moreover, the high incidences of abnormal immunoglobulin concentrations, autoantibodies and autoimmune disease, and malignancy in families of such patients suggest a hereditary influence. The principal differences between this disorder and X-linked agammaglobulinemia are the generally later age of onset, the somewhat less severe infections and an almost equal sex distribution. In contrast to patients with the X-linked form, patients with common variable agammaglobulinemia may have normal-sized or enlarged tonsils and lymph nodes. Splenomegaly is relatively common in this disorder. The serum immunoglobulin and antibody deficiency may be just as profound as in the X-linked disorder, and the kinds of infections experienced and bacterial etiologic agents involved are generally the same for the two defects. Thus far, only a few cases of fatal Echovirus meningoencephalitis have occurred in patients with common variable agammaglobulinemia. This condition has been variably associated with a sprue-like syndrome, with or without nodular follicular lymphoid hyperplasia of the intestine: thymoma; alopecia areata; hemolytic anemia, gastric atrophy, achlorhydria, and pernicious anemia. Frequent complications include giardiasis (seen more often here than in X-linked agammaglobulinemia), bronchiectasis, gastric carcinoma, lymphoretitular malignancy, and cholelithiasis. Lymphoid interstitial pneumonia, pseudolymphoma, amyloidosis, and noncaseating granulomata of the lungs, spleen, skin. and liver have also been seen. The latest WHO classification lists three different forms of common variable immunodeficiency, based on three general postulated types of cellular abnormalities (Table 1). In the author’s experience, an overwhelming majority of such patients have intrinsic B-cell defects. Table 2 demonstrates that mean numbers of circulating B cells are similar to those of normal controls. However, as the WHO classification implies, there is considerable heterogeneity in the number of such B ceils among patients with common variable immunodeticiency. Despite normal numbers of circulating immunoglobulin-bearing B lymphocytes and the presence of lymphoid cortical follicles, however, the lymphocytes do not differentiate in \>i~o into immunoglobulin-producing plasma cells nor in ~ituo even in the presence of the polyclonal B-cell activator, pokeweed mitogen. Thus, the defect appears in most patients to be due to abnormal terminal differentiation of the B cell line. Because this disorder occurs in first-degree relatives of patients with selective 1gA deficiency and some patients with hyper-IgM have later become panhypogammaglobulinemic (or vice versa), it is possible that these diseases all belong to the same spectrum of B-cell abnormality. The inconstancy of excessive suppressor-T-cell activity and the quantitatively poor plasma cell differentiation even in the presence of optimal numbers of T helper cells suggest that excessive Tsuppressor-cell activity is probably not basic to the disorder in most patients. As noted at the beginning, the primary biologic error is unknown for all of these disorders. The treatment of patients with common variable hypogammaglobulinemia is essentially the same as for the X-linked disorder (18).

23

REBECCA

H.

BUCKL,E\r

REFERENCES I.

Buckley. pp. 1X55-

2.

Buckley.

R. H..

3. Rosen. 4. Buckley. Gad.

Textbook Philadelphia.

./. .-l/lqv.

(‘/;,I.

N.

W. Paul.

Ed\.).

pp.

J. A.. Callicoat. C. M., Buckley. lY77.

Levitt.

8. Wedgwood. Hitzig. Press.

D.,

Och\.

H..

of Medicine” IYX?.

/~UUJUUO/.

F. S.. Coopel-. M. I).. and R. H.. I// “Immunodeficienc!,

5. Clark. 6. Wilferl. 14x. 7.

R. H.. 1~ “Cecil 1861. Saunders.

and

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Wedgwood.

Ochs.

Eda.). INSERM Amsterdam/New

H.

72, 627.

I

H. Smlrh.

R. J.. J. Clitr. No.

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l~~rtrrr~ol.

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17 t,l

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pp.

6Y-7%.

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