Primary Deficiencies in Humoral Immunity

Primary Deficiencies in Humoral Immunity

Symposium on The Child with Recurrent Infection Primary Deficiencies in Humoral Immunity Armond S. Goldman, M.D., * and Randall M. Goldblum, M.D. t ...

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Symposium on The Child with Recurrent Infection

Primary Deficiencies in Humoral Immunity Armond S. Goldman, M.D., * and Randall M. Goldblum, M.D. t

In 1952, the first defect in specific adaptive immunity was described in the discovery of a-y-globulinemia. 4 This finding confirmed previous suspicions that antibodies were y-globulins. It was recognized soon thereafter that these y-globulins were a family of proteins with common yet distinctive properties. These proteins were redesignated as immunoglobulins and by 1966 the five major classes of these proteins were described. Much of the information concerning the properties and functions of the immunoglobulins was acquired from study of patients with defects in host resistance. However, our understanding of the defects in these patients has been greatly enhanced by a veritable explosion of basic immunologic information. As a result, we are entering a phase in which the basic mechanisms of the immunologic deficiencies and rational therapy for these conditions may be elucidated. This paper describes the properties and functions of the immunoglobulins, the primary defects in their production, and the current methods of diagnosis and treatment of these disorders.

PROPERTIES OF IMMUNOGLOBULINS Specific adaptive immunity is in large part due to antibodies or immunoglobulins, a family of glycoproteins which are able to combine specifically with foreign antigens. 43•51 There are five major classes of immunoglobulins (Table 1). These proteins are composed of two heavy (H) polypeptide chains and two light (L) polypeptide chains which are connected by disulphide bonds (see Fig. 1 for a structural diagram). L chains are shared by all immunoglobulin classes, whereas H chains are unique

*Professor of Pediatrics, and Chief, Division of Immunology and Allergy, The University of Texas Medical Branch, Galveston, Texas t Assistant Professor of Pediatrics, The University of Texas Medical Branch, Galveston, Texas

Pediatric Clinics of North America-Vol. 24, No.2, May 1977

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Table 1. Major Classes of Immunoglobulins PROPERTIES

IgG

IgA

IgM

IgD

IgE

Molecular weight Heavy chains Adult serum level (mg per dl) Special properties

150,000

160,000 to 350,000

900,000

160,000

190,000

'Y

'"

JL

Il

E

1200

250

125

3

0.03

Surface Ig on B cells, Clfixing

Surface Ig on B cells

Binds to mast cells and basophils

CI fixing, placental transfer

Local protection for mucosal surfaces

for each class. There are two types of L chains, designated by the Greek letters K and A. In anyone antibody molecule, L chains are restricted to one type. H chains are designated by the Greek letter which correspondsto the class of immunoglobulins (Table 1). There are variable (V) and constant (C) regions or domains in H and L chains (Fig. 1). The V regions consist of 100 to 120 amino acid residues at the N terminal portion of the chains which serve as antibody combining sites. The C regions at the carboxyl end of the proteins are responsible for the unique properties of each immunoglobulin class including the antigenic specificity of each class, the binding of these molecules to cell receptors, and their distribution and catabolism. The five classes of immunoglobulins are as follows: 1. IgG, the principal immunoglobulin in adult serum (Table 1), consists of two H chains (y) and two L chains. This protein is evenly distributed in the

vascular and interstitial spaces. The average concentration of IgG in human adult plasma is about 1250 mg per dl and its biologic half-life is approximately 21 days. IgG is the only immunoglobulin which is transported across the placenta from the maternal to the fetal circulation. It is the principal type of antibody which appears in the secondary immune response and is the major type of antibody which persists following repeated immunogenic stimulation. There are four subclasses designated IgG" IgG2 , IgGa , and IgG4 ,4a.52 each of which has somewhat distinctive properties (Table 2).

Figure 1. A simplified presentation of the structure of immunoglobulin molecules. The constant (C) and variable (V) regions of the light (L) and heavy (H) chains are depicted. The polypeptide chains are connected by disulfide bonds (-S-S-). This monometric structure is typical for IgG, serum 19A, and IgD. Secretory IgA molecules are dimers and IgM molecules are pentamers.

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Table 2. Properties of IgG Subclasses PROPERTIES

IgG,

IgG,

IgG.

IgG.

Percentage in plasma Fixation to Clq Monocyte receptor

65-70 +++ +++

20-25 + +

6-7 ++++ ++++

3-4

Antibody Specificity Rh (incomplete) Treponema! Teichoic acid Levan

++++ ++++ ++ 0

0 0 ++++ +++

+++ 0 + 0

o

++

+

o o o

2. IgM, a pentamer of the basic immunoglobulin subunit, has the greatest molecular weight of the immunoglobulins (Table 1). The monomeric subunits are connected by interchain disulphide bonds and by a third polypeptide chain, the joining or J chain.!· IgM is found principally in the blood.· The average concentration of IgM in adult plasma is about 125 mg per dl and its half-life is approximately 4 to 5 days. IgM is one of the principal antibody molecules on the surface of B lymphocytes. IgM antibodies are the first to appear in human development and the first to appear in the primary immune response. 3. IgA occurs in two main forms (Table 1). The first type, monomeric IgA, is found mainly in the vascular and interstitial compartments. Its average concentration in human adult plasma is about 250 mg per dl. The second type, secretory IgA, consists of dimers of IgA molecules which are linked by a J chain!' and covalently bound to a unique polypeptide, the secretory component. 48 Secretory IgA, the predominant immunoglobulin in most external secretions, is produced in response to local antigenic stimuli by lymphoid cells in the respiratory, alimentary, and urogenital tracts. There are two subclasses designated IgA! and IgA2 • 4. IgD, which has a molecular structure siInilar to IgG and serum IgA (Table 1), is present in very small quantities in extracellular fluids. These immunoglobulin molecules are catabolized very rapidly. IgD, like IgM, is found frequently on B lymphocytes, where they may participate in antigen recognition.'7 5. IgE consists of two heavy chains (t:) and two L chains (Table 1). Although the concentration of IgE is the lowest of all immunoglobulins, this class of immunoglobulins is very important because of its role in the pathogenesis . of atopic (allergic) diseases. t: chains have the propensity to bind to surface receptors on basophils and mast cells. When cell bound IgE molecules are bridged by specific antigens, the basophils or mast cells produce or release low molecular mediators which cause immediate allergic reactions. 24

PRODUCTION OF IMMUNOGLOBULINS Antibodies are produced by a specialized group of lymphocytes whose development is thymic-independent. The site of development of these cells in mammals is not completely understood, but because of the decisive role of the bursa of Fabricius in their development in birds and because of the origin of these cells from the bone marrow, antibodyproducing cells are designated as B lymphocytes or B cells. There are sub-populations of B cells which appear in a developmental sequence.

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Circulating B cells, which may be detected by surface membrane IgM and IgD, surface membrane receptors for'Y chains, or receptors for C3 molecules, are progenitors of the plasma cells which synthesize and secrete large numbers of immunoglobulin molecules. 11 B cells with surface immunoglobulins or complement receptors comprise about 20 to 25 per cent of circulating blood lymphocytes. Lymphoid cells which produce and secrete IgM and IgG are found principally in the thymic-independent regions of the lymph nodes and spleen. In contrast, most IgA and IgE producing cells are found in mucosal tissues. The order of appearance of immunoglobulin production in the fetus is IgM ~ Ig~ IgA. 11 Each B cell is restricted to the production of antibodies of a single immunoglobulin class which are specific for one antigenic determinant. The production of antibodies is triggered by antigens in a complex series of events which are not completely understood. The production of antibodies by B cells may be enhanced or suppressed by soluble factors from subpopulations of thymic-dependent lymphocytes (T lymphocytes or T cells).26 In addition, phagocytes aid in the production of antibodies by processing certain antigens. Small amounts of immunoglobulins are produced in fetal life, but the bulk of circulating antibodies in the human fetus are due to the transfer of maternal IgG via the placenta (Fig. 2). At birth the concentration of IgG is slightly higher than the maternal level (Figs. 2 and 3). As the maternal IgG is degraded over the next six to eight months, IgG synthesis by the infant is increasing. The nadir is reached at abou t five to six months, after which IgG levels rise slowly. The serum concentrations of the other immunoglobulins are low at birth. The IgM levels in the plasma increase quickly and approach adult values by age one year (Fig.

PLASMA IgG CONCENTRATION

Figure 2. Temporal relationships between the placental transfer of IgG, the catabolism of maternal IgG, and the synthesis of IgG in the pre- and post-gestational periods.

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B-Lymphocytes

Immunoglobulin Production

IgM IgG IgA

IgM IgG IgA

100

80

~

~

60

"5



40

;fl

20

0

3 Fetal Age

4

..

4

567 8 9 (Months)

Birth

56789

Age (Yeors)

Figure 3. The development of B-Iymphocytes and serum immunoglobulins in the preand post-gestational periods. The serum concentrations of immunoglobulins are agedependent.

3). Serum concentrations of IgA increase slowly and adult levels are not reached for some years (Fig. 3). The concentration of IgA in external secretions is thought to rise much more rapidly.

CONGENITAL AND GENETIC DEFECTS IN B LYMPHOCYTES AND IMMUNOGLOBULINS TRANSIENT HYPO-y-GLOBULINEMIA. In a few otherwise normal infants, there is an unexplained delay in the maturation of immunoglobulin production. 34 •35 The serum levels of immunoglobulins, particularly IgG, do not rise as anticipated after five to six months of life. The number of B lymphocytes with surface immunoglobulins or complement receptors, however, remains normal. Affected infants have a propensity to bacterial respiratory infections, bronchitis, and unexplained fevers. Because of low levels of IgG, treatment with immune serum globulin is indicated. Between 1.5 to 2.5 years of age, immunoglobulin production becomes normal. X-LINKED HYPO-y-GLOBULINEMIA. This genetic disorder is characterized by a deficiency in B lymphocytes which results in a failure to produce immunoglobulins of all classes. 4 ,10,17,34,35 Because of the x-linked transmission, only males are affected. The serum concentration of IgG is usually below 100 mg per dl and IgA, IgM, and IgD are commonly undetectable. IgE, however, is present in many cases. B cells with surface immunoglobulins are reduced in numberj 18,28,40 complement receptor lymphocytes may be normal or decreased. Immunoglobulin-producing cells are virtually absent in the bone marrow, blood, lymph nodes, spleen, and mucosal tissues. Because of the paucity of germinal centers and plasma

1

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cells, lymph nodes, tonsils, and posterior pharyngeal lymphoid tissues are small. In contrast to the B cell deficiency, the thymic-dependent system is normal . . During the first several months of life, affected children are asymptomatic because of the protection afforded by maternal IgG antibodies. After the placentally transferred IgG has been catabolized, these individuals become susceptible to severe, recurrent infections with common pyogenic bacteria. These infections include conjunctivitis, rhinitis, sinusitis, pharyngitis, otitis media, bronchitis, and pneumonia due to Streptococcus pneumoniae, other streptococci, Hemophilus influenzae, Staphylococcus aureus, Pseudomonas aeruginosa and Neisseria meningitidis. Life-threatening sequelae of these infections, such as septicemia, meningitis or bronchiectasis, are common. Intestinal malabsorption due to giardiasis is frequent. Chronic inflammation of the large joints which resembles rheumatoid arthritis occurs in about one-third of the cases. Clinical problems similar to dermatomyositis or scle.roderma may also occur. Although resistance to most viral infections is normal in children with x-linked hypo-y-globulinemia, chronic infections with enteroviruses such as ECHO virus are being recognized in long-term survivors. 34 .53 The diagnosis is made by the demonstration of a panhypo-yglobulinemia, diminished number of B cells, and similarly affected males in the mother's family. There is no current method of detecting the carrier state. It is therefore imperative to screen each male infant of the affected family for this disease. X-LINKED

HYPO-y-GLOBULINEMIA

WITH

NORMAL

OR

INCREASED

IGM. In this disorder, IgG and IgA are deficient, whereas IgM levels are normal to increased.16.34.36 B cells bearing IgM, IgM-synthesizing cells, and IgM-type antibodies can be demonstrated, but this does not hold for IgG or IgA. In some cases, serum concentrations of IgD are increased. Lymphadenopathy and large tonsils and adenoids may occur because of infiltrations with IgM-producing cells. The thymic-dependent system is normal. The immunologic abnormalities suggest an arrest in the development of B cells from IgM~IgG producing cells. Since practically all reported cases are males, it has been postulated that this is an x-linked recessive disorder. The types of infections are very similar to those which occur in x-linked hypo-y-globulinemia, but the incidence of neutropenias, thrombocytopenia, and hemolytic anemias is unusually high and B cell lymphomas characterized by lymphoid cells bearing IgM are frequent. An acquired form of this dys-y-globulinemia may be a consequence of congenital rebella infections,41.42 and this acquired dys-y-globulinemia may be corrected in time. The IgA deficiency persists, however, in some affected infants. TRANS COBALAMIN II DEFICIENCY AND HYPO-y-GLOBULINEMIA. Transcobalamin II deficiency has been found to be associated with a panhypo-y-globulinemia. 14.2o Transcobalamin II is a protein involved in the transport of vitamin B 12 . The disease was inherited as an autosomal recessive trait. Megaloblastic anemia, granulocytopenia, and thrombocytopenia were found. Band T cells were demonstrated by

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their surface markers but antibody production was absent. The hematologic and immunologic abnormalities were corrected by the administration of large quantities of vitamin B 12 . COMMON VARIABLE IMMUNODEFICIENCY. This is the most common type of panhypo-y-globulinemia. 10,34 Both sexes are affected. A genetic basis for this disorder has not been established. In this disease, the degree of immunoglobulin deficiency is less marked than in the x-linked form. The histologic pattern in the peripheral lymphoid tissues varies from disorganized follicular structures to hyperplasia of reticular cells and cortical follicles. The clinical onset is usually delayed until late childhood or adulthood. Sinusitis, pneumonia, bronchiectasis, intestinal giardiasis, and pernicious anemia are common. The incidence of lymphoreticular and epithelial malignancies is increased in these patients. 27 Normal numbers of B cells can be demonstrated in the blood by their characteristic surface markers. 12,28 In these patients, defects in the synthesis or secretion of immunoglobulins by B lymphocytes have been shown in in vitro studies. In those with defective secretion of preformed immunoglobulins, the carbohydrate content of the immunoglobulins is significantly reduced, suggesting that the secretion defect is due to a failure of incorporation of carbohydrate into immunoglobulin molecules. 8 In other cases, there is evidence that the synthesis of immunoglobulins is suppressed by T lymphocytes. 49 THYMOMA AND HYPO-y-GLOBULINEMIA. Hypo-y-globulinemia has been found to be associated with thymomas. 25 The disease usually occurs in adults after 40 years of age. Spindle cell tumors are the most frequent type of thymoma. Besides an increased susceptibility to bacterial respiratory infections, chronic candidal stomatitis, chronic diarrhea, exudative enteropathies, are generative anemia, and eosinophilia commonly occur. SELECTIVE DEFICIENCY OF IGA. Selective IgA deficiency is the most common primary immunodeficiency in humans (0.14 to 0.2 per cent of the population).5,23 Most cases are sporadic but autosomal dominant and recessive inheritance has beeen reported in some cases. Serum IgA levels are usually below 5 to 10 mg per dl. IgA-producing cells are decreased, secretory IgA levels in the external secretions are low to absent, but free secretory component is found. In some cases, IgM levels in external secretions and IgM-producing cells in the external secretory sites are increased. The serum levels of IgG, IgM, and IgD are normal to slightly elevated. Serum IgE concentrations may be normal or decreased. The number of circulating B cells is normal and IgA synthesis can be induced in vitro by pokeweed mitogen stimulation. 28 Although T lymphocyte function is usually reported to be normal in these cases, there is evidence of subtle T cell defects from some investigations. 13 Many IgA-deficient individuals are asymptomatic but others are not. The most frequent clinical problems include chronic or recurrent infections of the upper and lower respiratory tract, allergic rhinitis, intractable asthma, pulmonary hemosiderosis, celiac disease, nodular hyperplasia of the intestinal tract, and autoimmune diseases, particularly systemic lupus erythematosus and rheumatoid arthritis. The res-

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piratory infections are usually suspected to be viral although repeated bacterial infections occur in some patients. The incidence of epithelial malignancies is increased in this disease. Transfusion reactions are common because of the frequent occurrence of antibodies to IgA. Recently, a deficiency of secretory component has been described in a patient with chronic intestinal candidiasis. 46 The serum levels of IgA were normal, but neither IgA nor secretory component could be demonstrated in external secretions. IgA was produced by blood lymphocytes stimulated by pokeweed mitogen, but no IgA synthesis was found in jejunal tissue. The authors proposed that the deficiency of secretory component was the basic defect in the disease. Secretory component deficiency has also been found post mortem in a few infants with sudden infant death syndrome. 3 ' There is no satisfactory treatment for IgA deficiency. Even if IgA transfusions were available and safe, very little of the transfused IgA would enter into the external secretions. IgA deficiency is usually persistent. In some cases, however, IgA synthesis has appeared spontaneously. It should be also noted that selective IgA deficiency may develop following exposure to the anticonvulsant drug, phenytoin. 39 SELECTIVE IGM DEFICIENCY. Selective IgM deficiency may be the second most common primary immunodeficiency (0.1 per cent of hospital admissions).22 The deficiency is probably of genetic origin but the inheritance pattern has not been ascertained. In most affected individuals, the IgM serum levels are below 20 mg per dl. No other immunoglobulin abnormalities are present. About 60 per cent of affected individuals have recurrent infections. Hematogenous ,spread of infections, sudden unexpected septicemia, meningitis, gastrointestinal disorders, atopic diseases, idiopathic splenomegaly, and lymphoreticular malignancies are also common. Replacement therapy is impractical because of the short half-life of IgM. Plasma infusion may be indicated during serious infections in order to temporarily raise the plasma IgM levels. Since the deficiency in IgM is not complete in these cases, isoantibodies to IgM do not form. Therefore there is no predilection for transfusion reactions. IGG SUBCLASS DEFICIENCY. In a few patients it has been found that certain subclasses of IgG may be deficient, whereas others are not. 38,52 These examples include selective deficiency ofIgG" deficiencies in IgG" IgG2, and IgG4 , and deficiencies in IgG" IgG3 , and IgG4 • The total IgG level in these cases is usually normal or slightly decreased. The diagnosis may be suspected by a restricted heterogeneity of the electrophoretic mobility of IgG or by the lack of antibody production against certain antigens. The diagnosis, however, requires the quantitative measurement of IgG subclasses. Such patients should be treated with immune serum globulin which contains all subclasses of IgG. IMMUNOGLOBULIN ABNORMALITIES IN OTHER GENETIC DISORDERS. Ataxia-telangiectasia is an autosomal recessive disorder characterized by degeneration of the central nervous system, oculocutaneous telangiectasia, and progeric changes in the hair and skin. 3 ,:34 In some patients cellular immunity is deficient.' Sinopulmonary infections and

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lymphoreticular malignancies and leukemias 27 are common. About 70 per cent of these patients have IgA deficiency and 80 per cent have IgE deficiency. The serum IgM may be monomeric in this disorder. The production of IgA and IgE is greatly reduced, but the decreased level of IgA is in large part due to hypercatabolism mediated by isoantibodies to IgA.47 WISKOTT-ALDRICH SYNDROME. This is an x-linked recessive disorder characterized by eczema, thrombocytopenia, anergy, and a failure to produce specific antibodies. 2.9 Coombs' positive hemolytic anemia and lymphoreticular malignancies are common in these patients. 27 They display normal number ofT and B cells and normal quantities ofIgG. IgM is usually decreased, and IgA, IgD, and IgE levels are increased. 2.9• 5o These normal to increased levels of immunoglobulins occur despite an increase in the catabolism of these proteins. This is due to a production rate of the immunoglobulins which is up to seven times normal. SEVERE COMBINED IMMUNODEFICIENCY. These are a group of inherited diseases which curtail the development of humoral and cellular immunity.l0 Panhypo-y-globulineInia is the most common manifestation of the defect in humoral immunity,10 but dys-y-globulineInias of various types may also occur. 15

DIAGNOSIS OF DEFICIENCIES IN HUMORAL IMMUNITY Clinical Findings These disorders usually present with recurrent or chronic bacterial infections of the respiratory tract or other organ systems, chronic gastrointestinal problems including giardiasis, allergic reactions, and collagen-like disorders. The most common infections are due to Streptococcus pneumoniae, other streptococci, Hemophilus influenzae, Staphylococcus aureus, and Neisseria meningitidis. Most viral infections appear to be handled normally by these patients. The physical exaInination of the lymphoid system may provide important clues to the diagnosis. The lymph nodes, tonsils, or posterior pharyngeal lymphoid tissues may be small or enlarged. Radiologic studies may aid in the detection of small adenoids such as are found in x-linked hypo-y-globulinemia, small thymus in severe combined immunodeficiency, or an enlarged thymus as is found in hypo-y-globulineInia with thymoma. The lack of bronchial lymphadenopathy on the chest radiogram is also a frequent finding in the hypo-y-globulinemics. Splenomegaly is particularly frequent in the common variable type of immunodeficiency.

Laboratory Diagnosis QUANTITATION OF SERUM IMMUNOGLOBULINS. Quantitative measurement of the major product of B cells is the most valuable test in the diagnosis of these disorders. This is usually performed by radial immunodiffusion using commercial agar plates which are impregnated with antisera to each immunoglobulin class. 29 All classes of immunoglobulins can be measured in this way except IgE, which requires more sensi-

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tive methods such as radioimmunoassays.50 Because of the great variability in normal values between laboratories, it is wise to standardize the radial immunodiffusion test by using international reference sera. Even when the test has been properly standardized, there may be a number of problems in interpretation of the results. (,1) To correctly utilize the results of these quantitations, one must be aware of the agedependency of serum immunoglobulin levels. Immunoglobulin levels in the first few years of life may appear low if they are compared with values in older children and adults. Normal values for each age group may be obtained from the literature 45 or may be developed in laboratories that perform these examinations. (2) In some disorders, such as ataxiatelangiectasia, monomers rather than polymers are the main form of IgM. Because of their smaller size, monomeric IgM diffuses more rapidly through the agar. Consequently, the precipitin ring will be farther from the antigen well and, therefore, a falsely high value for IgM will be found. In order to check for monomers of IgM, some type of molecular sieving procedure is required. (3) In certain patients, particularly individuals with selective IgA deficiency, serum antibodies to bovid proteins may be present. 7 Those antibodies may form immunoprecipitin rings with the proteins in the reagent antisera if the antisera is from a bovid species such as goat. These immune reactions are commonly mistaken for human IgA-anti-IgA complexes. It is therefore indicated to check for IgA by comparative double diffusion or by using antisera from other sources such as the rabbit. Quantitation of the subclasses of IgG may be desirable in selected cases. The performance of these measurements is, however, limited to a few laboratories. The testing will perhaps be more widely used when commercial kits are available. QUANTITATION OF IMMUNOGLOBULINS IN EXTERNAL SECRETIONS. Usually tears, mixed saliva, or parotid secretions are obtained for the quantitation of immunoglobulins in external secretions. The test is of special value in the diagnosis of selective deficiency of IgA since some individuals who lack serum IgA have IgA in external secretions, whereas others with a normal serum IgA lack IgA in the external secretions. There are certain difficulties in interpreting the measurement of IgA in external secretions by radial immunodiffusion because one cannot distinguish the polymeric from the more rapidly diffusing monomeric form of IgA. ANTIBODY PRODUCTION IN VIVO. Diminished antibody production following infection or immunization is one of the most consistent findings in primary defects of B lymphocytes. In certain cases of immunodeficiency, such as the Wiskott-Aldrich syndrome, the quantitative levels of immunoglobulins may be normal or increased but specific antibodies are not produced. The following procedures may be useful in assessing specific antibody formation. Isohemagglutinins which are usually of the IgM class can be measured. Antibodies to streptolysin-O and other streptococcal antigens are found in the serum of most individuals after infancy. It is particularly valuable to test for these antibodies after a known streptococcal infection. The determination of serum antibody

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titers in response to killing immunizing agents, such as tetanus, typhoid, and diphtheria antigens, may be more valuable since the temporal relationship between the exposure to the immunogens and the rise in antibody titer can be carefully documented. Immunization with living organisms should be avoided since immunodeficient patients may develop life-threatening infections with these organisms. DETECTION OF B LYMPHOCYTES. (1) Histologic Studies of Lymphoid Tissues. These studies, though of interest in the study of immunodeficient patients, are not usually possible and perhaps are not necessary in many cases. Plasma cells, follicles, and germinal centers are often diminished in these patients. Immunofluorescent studies of these tissues are helpful in detecting immunoglobulin producing cells. (2) Complement Receptor Lymphocytes. Circulating B lymphocytes with receptors for C3 can be detected by the binding of human erythrocytes (E) complexed to antibodies (A) which have bound complement (C).30 These EAC-rosetting cells comprise about 20 to 25 per cent of . the total peripheral blood lymphocytes. (3) Lymphocytes Bearing Surface Immunoglobulins. Immunoglobulin bearing cells can be detected by staining with fluorescent antisera to human immunoglobulins. 18,28 About 15 to 20 per cent of the blood lymphocytes are found to be B cells by this technique. (4) Immunoglobulin Synthesis and Secretion by Blood Lymphocytes. The production of immunoglobulins by blood lymphocytes in vitro is increased after stimulation with pokeweed Initogen. 28,32,49 The nascent immunoglobulin can be detected by fluorescent or radioassay techniques. The ability of the cells to secrete and produce immunoglobulins can be determined by measuring the immunoglobulins in the superna tent of the cultured cells and in disrupted cells. The technique appears to be especially helpful in examining the interaction between B cells and T lymphocytes which enhance or suppress immunoglobulin synthesis. By co-culturing the patient's lymphocytes with normal immunoglobulin-producing cells, the mechanisms underlying the defects in immunoglobulin production may be further elucidated. These investigations have been of particular value in demonstrating abnormal suppression of immunoglobulin production by T lymphocytes from some patients with common variable immunodeficiency.49 PHYSICAL-CHEMICAL CHARACTERISTICS OF IMMUNOGLOBULINS. In special circumstances it may be indicated to seek further information concerning the special properties and structure of the immunoglobulins. These include the electrophoretic mobilities of the proteins, their molecular weight, carbohydrate content, and antigenic components.

MANAGEMENT There are five main points in the management of these patients. The first point, the accurate diagnosis of the type of immunodeficiency, was covered in the preceding section. It should be recognized that hypo-yglobulineInia may be due not only to primary disorders of B lymphocytes

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but also to hypercatabolic states such as nephrotic syndrome or exudative enteropathy or to viral infections such as congenital rubella syndrome41 ,42 or infectious mononucleosis. 33 In those situations treatment of the underlying disease will correct the immunologic abnormality. The second major point is the use of parenterally injected human immunoglobulins in the prophylactic treatment of the patients. Two types of preparations are currently in use, immune serum globulin (pooled human y-globulin) and human plasma. Immune serum globulin contains about 160 mg of protein per ml, 90 per cent of which is IgG. Since the quantities of other immunoglobulins are very low, immune serum globulin is applicable only for the treatment of IgG deficiencies. Immune serum globulin is given intramuscularly or subcutaneously in a dosage of 0.6 to 0.8 ml per kg every three to four weeks. This treatment should raise the serum IgG level by 100 to 200 mg per dl, if the catabolic rate of IgG is normal. The disadvantages of intramuscular administration ofimmune serum globulin are: (1) large volumes are required; (2) absorption from the muscle tissue may be erratic; (3) proteolysis may occur at the injection site; and (4) the injections are usually painful. Unfortunately, presently available preparations of immune globulin should not be given intravenously to patients with hypo-y-globulinemias because of the high risk of anaphylactoid reactions due to intravascular activation of complement by IgG aggregates. 21 Attempts have been made to modify IgG in order to eliminate its complement activating properties. So far, a preparation which is safe, yet effective, has not been developed for intravenous use. 21 Human plasma infusions have been advocated as a substitute for immune serum globulin,6 particularly in the following circumstances: (1) when large amounts of immune serum globulin are required; (2) when the patient becomes sensitized to the commercial preparation of immune serum globulin; and (3) when the immune serum globulin seems ineffective. IgA and IgM levels are raised for some days after plasma infusion. In addition, higher IgG levels can be obtained with plasma. The risk of viral hepatitis is, however, increased with plasma and the spectrum of antibodies to microbial pathogens provided by plasma from a single donor may not be sufficient. Fresh frozen plasma obtained by plasmapheresis may allow a patient to receive plasma from a single donor, thus reducing the risk of hepatitis. The dosage of plasma is about 15 ml per kg of body weight. This quantity is administered every three weeks or more often if clinically indicated. Hyperimmune plasma should be considered for those patients with known infections who are not responding to conventional therapy. The third point in the management of these patients is the rapid identification of infecting organisms and the prompt institution of appropriate antibiotic therapy. Other measures, such as bronchial toilet and drainage of infected sinuses, may be required. The fourth point in management is screening the family for immunodeficiency disorders in those cases which are of genetic origin. For example, in the case of x-linked hypo-y-globulinemia, all male siblings, young brothers of the mother, and male children of maternal aunts should be screened for the disease.

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The fifth point is genetic counseling. For instance, in x-linked immunodeficiencies, the parents of an affected male should be told that the risk of having an affected child is one chance in four for each pregnancy. The parents may wish to explore the possibility of determining the sex of their unborn child by amniocentesis for the purpose of planned abortion of potentially affected males. This will depend upon the seriousness of the defect as well as the attitudes of the parents. Other family members may wish also to avail themselves of genetic counseling, particularly poten tial female carriers.

SUMMARY Patients with primary disorders of B lymphocytes and immunoglobulins usually display increased susceptibility to bacterial infections but atopic, autoimmune, and malignant disorders are also more common in these patients. The spectrum of these disorders ranges from a virtual absence of B cells and immunoglobulins to selective deficiencies of immunoglobulin subclasses. The diagnosis is dependent upon the demonstration of the immunologic deficits by specialized laboratory procedures which include the quantitation of immunoglobulins, the formation of antibodies in vivo and in vitro and the demonstration of B cells in the tissues or the peripheral blood. There are five major points in the management of these patients: (I) the delineation of the immunologic defects by laboratory testing, (2) the use of parenterally injected human immunoglobulins, (3) the rapid identification of infecting organisms and the prompt institution of appropriate antibiotic therapy, (4) screening the family for immunodeficiency in those cases which are of genetic origin, and (5) genetic counseling.

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