Deficiencies in Immunoglobulins and Cell-Mediated Immunity Part 1

Immunoglobulin Deficiency Syndromes

Insufficient production of one or more kinds of antibodies characterizes the immunoglobulin deficiency syndromes [see Table 1].1,2 Patients with these deficiencies are subject to recurrent pyogenic infections, such as otitis media, sinusitis, and pneumonia. Repeated episodes of pneumonia can lead to chronic obstructive pulmonary disease. For many of these deficiencies, the genetic basis has now been defined. The primary care physician’s role in these disorders is to suspect the diagnosis under the appropriate clinical circumstances—often, unusual susceptibility to certain infections in a patient with a family history of the same—and to order the preliminary laboratory studies. Definitive diagnosis and management is typically the responsibility of the immunologist. Control of the infections to which these patients are susceptible is principally managed by the intravenous administration of large doses of y-globulin.

X-linked agammaglobulinemia

X-linked agammaglobulinemia, also known as congenital agammaglobulinemia or Bruton disease, was the first immunodeficiency disorder to be described, in 1952.

Genetics and Pathogenesis

The gene responsible for X-linked agammaglobulinemia is located on the long arm of the X chromosome (Xq21.33-q22).35 This gene, termed btk, is a member of the src family of oncogenes and encodes a unique tyrosine kinase.48 It probably plays a critical role in the maturation of B cells: pre-B cells are present in normal numbers in the bone marrow of males with X-linked agam-maglobulinemia, but they do not develop into mature B cells.2 Because the genes governing the structure of immunoglobulins are on autosomal chromosomes, the mechanism of the disorder must also involve a defect in a regulatory gene.

In patients with X-linked agammaglobulinemia, the lym-phoid organs are characterized by a lack of germinal follicles, B cells, and plasma cells. On bone marrow studies, pre-B cells (which contain immunoglobulin ^ heavy chains in their cytoplasm and therefore can be identified by immunofluorescence staining with antiserum to the ^ chain) are present in normal numbers.


Clinical manifestations Because infants are born with IgG from their mother in their blood, boys who have X-linked agam-maglobulinemia do not start to show the effects of the disorder until 6 to 15 months of age.

Table 1 Primary Specific Immunodeficiencies Involving Antibodies

Usual Phenotypic Expression

Presumed Level of Basic Cellular Defect

Known or Presumed Pathogenetic Mechanism



Antibody Deficiencies

Cellular Abnormalities

X-linked agamma-globulinemia

All immuno-globulins


Pre-B cells

Mutations in the gene for Bruton’s X-linked tyrosinase (btk)


Common variable immunodeficiency

All immuno-globulins

Faulty B cell maturation

Immaturity of B cells

i Helper T cell function Intrinsic B cell defect Underproduction of B cells

Autoantibodies to B cells


Selective IgA deficiency



Terminal differentiation of IgA+ B cells impaired


Usually unknown (autosomal recessive more common than autosomal dominant); frequent in families of patients with common variable immunodeficiency

Ig deficiencies, with increased IgM

IgG, IgA, and IgE


Failure of immuno-globulin class switching

X-linked form: mutations in the gene for the CD40 ligand Autosomal recessive form: activation-induced cytidine deaminase

X-linked, autosomal recessive, or unknown

Selective deficiency of IgG subclasses

One or more IgG isotypes





k-Chain deficiency




Point mutation at 2p11

Autosomal recessive

Transient hypogam-maglobulinemia of infancy

IgG and IgA


Impaired terminal differentiation of B cells

i Helper T cells

Frequent in heterozygous individuals in families with various severe combined immunodeficiencies


When an immunoelectrophoretic pattern of agammaglobulinemic serum is compared with 6a normal serum pattern, the absence of IgA, IgM, and IgG—characteristic of the disorder—is clearly demonstrated.

Figure 1 When an immunoelectrophoretic pattern of agammaglobulinemic serum is compared with 6a normal serum pattern, the absence of IgA, IgM, and IgG—characteristic of the disorder—is clearly demonstrated.

They then demonstrate unusual susceptibility to infections by pyogenic organisms (e.g., otitis media, sinusitis, and pneumonia from Haemophilus influenzae, pneumo-cocci, streptococci, staphylococci, and meningococci). Those infections are more frequent and more severe in boys with X-linked agammaglobulinemia than in normal children, and recurrent infection by the same organism is common. Frequently, the infections are slow to respond to antibiotics. Recurrent pulmonary infections often lead to bronchiectasis and pulmonary insufficiency. Affected males have normal resistance to the common viral diseases, fungi, and most gram-negative organisms, but some have developed polio after receiving oral polio vaccine. About one third of patients have symptoms that resemble rheumatoid arthritis, including swollen and painful joints. A severe late complication is a fatal syndrome similar to dermato-myositis but with central neurologic involvement, as well. This syndrome is gradual in onset, usually starting in the second or third decade of life. In several patients with this syndrome, echo-viruses have been cultured from the blood, stool, and cerebro-spinal fluid.9

Laboratory testing Diagnosis begins with measuring the serum level of each class of immunoglobulin [see Figure 1]. Patients with X-linked agammaglobulinemia usually have less than 100 mg/dl of IgG (normal levels are 614 to 1,295 mg/dl), and they have levels of IgA, IgM, IgD, and IgE that are extremely low or undetectable. Such findings should prompt referral of the patient to an immunologist.

In patients with X-linked agammaglobulinemia, analysis of white blood cells by flow cytometry reveals a lack of B cells. These patients are unable to mount an antibody response to antigen challenge, such as routine diphtheria-pertussis-tetanus (DPT) or H. influenzae vaccination, and they cannot neutralize the toxin in a Schick test (intradermal injection of diphtheria toxin). In contrast, cell-mediated immune functions, such as delayed hyper-sensitivity-mediated skin reactions and graft rejection, are essentially normal, and the T cells respond in vitro to phytohemagglu-tinin and produce lymphokines normally.

Screening All subsequent male offspring of the mother or maternal aunts of a patient with X-linked agammaglobulinemia should be screened for mutations of the btk gene. Because the defect is limited to B cells, female carriers of the gene can be detected by analysis of X-chromosome inactivation in B cells.10,11 In female carriers, pre-B cells in which the X chromosome bearing the normal gene has been inactivated will not develop into B cells; therefore, all mature B cells will bear an active X chromosome containing only the normal gene.


Preparations of 5% or 10% y-globulin solution are now used as replacement therapy for agammaglobulinemia. Parents can be reassured that these preparations pose no risk of transmitting HIV or other viral infection. Intravenous administration of these preparations is well tolerated; large doses can be given without discomfort or pain. Infants do not require permanent intravenous access.

Dosages of y-globulin are adjusted according to the patient’s health. The minimal effective dosage of intravenous y-globulin is 300 mg/kg a month; however, higher doses, such as 500 mg/kg a month, are usually optimal.12 Dividing the monthly dosage of y-globulin and administering it at 1-week or 2-week intervals is preferable, because it maintains higher immuno-globulin levels. The y-globulin is infused at a rate of 3 ml/min or slower. Side effects may include headache, shaking chills, flank pain, fever, and hypotension. These can be ameliorated by giving an antihistamine or methylprednisolone before the infusion.

Bacterial infections in patients with X-linked agammaglobu-linemia require vigorous antibiotic treatment. Antibiotics should be given in prolonged courses (e.g., 2 weeks) at full doses.

Prognosis The prognosis is very good for patients whose condition is diagnosed and treated early. A recent study of 31 patients with X-linked agammaglobulinemia found that early and prolonged y-globulin replacement therapy is effective in preventing bacterial infections and pulmonary insufficiency. Viral infections still developed, however, and one patient died of enteroviral meningoencephalopathy.13

Common variable immunodeficiency

Common variable immunodeficiency (CVID) is so called because it accounts for over 50% of cases of immunodeficiency and because patients present with variable clinical manifestations and somewhat inconsistent laboratory findings; disease course varies, as well.

Etiology and Pathogenesis

The cause of CVID is unknown. CVID does not appear to be genetically transmitted—apparently the germ cells are not involved—although some family clusters have been seen. CVID affects males and females equally.

A variety of pathogenetic mechanisms underlie CVID.2 These include (1) B cells that do not respond to stimulatory signals from T cells, (2) B cells that can synthesize but cannot secrete im-munoglobulins, (3) the absence of helper T cells (required for normal B cell function), and (4) the presence of autoantibodies to B cells. In a few cases of CVID, B cells cannot be detected. All patients show markedly low serum levels of all immunoglobulins.


Clinical manifestations Onset of CVID can occur at any age, but it usually occurs after puberty. Patients have the same heightened vulnerability to infections as those with X-linked agammaglobulinemia; also, there is chronic involvement of the sinuses and respiratory tract.

CVID is associated with several autoimmune diseases, such as rheumatoid arthritis, idiopathic thrombocytopenia, hemolytic anemia, neutropenia, and, predominantly, pernicious anemia. Infectious diarrhea and malabsorption syndrome are common. CVID is also associated with severe malabsorption syndrome caused by gluten-sensitive enteropathy. It is unclear whether CVID is a cause or an effect of these disorders. Chronic lung disease that produces bronchiectasis is common in CVID; this condition should be differentiated from cystic fibrosis, chronic allergy, and a1-antitrypsin deficiency. In contrast to X-linked agammaglobulinemia, CVID is often marked by considerable enlargement of regional lymph nodes and splenomegaly.

Laboratory tests IgG levels in patients with CVID are generally lower than 250 mg/dl, and other immunoglobulins are also markedly decreased. B cells are usually present, but they do not mature normally into plasma cells, which synthesize and secrete immunoglobulins. Tests of cell-mediated immunity also demonstrate defects.

Lymphoid hyperplasia may occur in the gut of patients with CVID. This can be visualized by barium contrast x-ray of the upper GI tract, which is indicated in CVID patients with GI symptoms.


Treatment of CVID is essentially the same as that of X-linked agammaglobulinemia: replacement y-globulin therapy and vigorous use of antibiotics during acute infections. Diarrhea in these patients is frequently caused by Giardia lamblia infection, which can be rapidly controlled with quinacrine hydrochloride or metronidazole.11 Special care must be taken if steroids are used as therapy for the associated autoimmune diseases, because these agents may heighten susceptibility to infection.


Patients with CVID can have a normal life span. Women with the disease can carry a normal pregnancy to term and have normal babies. Although those babies will lack maternal IgG and the passive immunity it confers in the first months of life, they do well without treatment with y-globulin.

Selective immunoglobulin deficiencies

Selective IgA Deficiency

Epidemiology Selective IgA deficiency is one of the most common immunodeficiencies in whites, occurring in one in 600 to 800 persons in this population. It does not occur in Africans and almost never occurs in Asians.

Genetics and pathogenesis The genetics of IgA deficiency are unclear. Data on inheritance are conflicting, with some suggesting autosomal dominant inheritance and others suggesting autosomal recessive inheritance.

A few patients lacking serum IgA have secretory IgA, and some patients have monomeric IgM in their secretions. B cells bearing surface IgA are present, indicating that the defect is probably in the terminal differentiation of IgA-secreting cells. In vitro, IgA-bearing cells can be stimulated by mitogens to produce IgA.14

Diagnosis Many patients with IgA deficiency are surprisingly healthy. Nevertheless, IgA deficiency is associated with many clinical syndromes. Patients most often come to medical attention because of recurrent sinus and pulmonary infection by bacteria and viruses. These patients also show a higher incidence of autoimmune, GI, allergic, connective tissue, and malignant diseases. Some patients with IgA deficiency produce antibodies to bovine proteins, suggesting that IgA in the gut normally helps prevent absorption of foreign antigens. IgA deficiency is found in about 70% of patients with ataxia-telangiectasia (see below).

The serum IgA level is less than 5 mg/dl (normal, 60 to 309 mg/dl). Other immunoglobulin levels are normal. Although patients with IgA deficiency usually also have defects in T cell function, most of these patients have normal cell-mediated immunity.

Treatment There is currently no satisfactory means of supplying adequate levels of IgA. Sinus and pulmonary infections in IgA-deficient patients are treated by standard means.

Complications In extremely rare instances, patients with IgA deficiency produce IgE antibodies to IgA and will have ana-phylactic reactions when given immunoglobulin.15 Immunoglo-bulin replacement therapy should be avoided in such patients; blood transfusion can also precipitate an anaphylactic reaction. Patients who require blood should receive red cells from an IgA-deficient donor because anaphylactic reactions may occur even if the red blood cells are washed three times.

Immunoglobulin Deficiency with Elevated IgM

The combination of markedly elevated IgM levels and deficiency of other immunoglobulins is termed the hyper-IgM syndrome. The IgM in these patients is heterogeneous; thus, it is polyclonal and does not emerge from malignant cells.

In 70% of hyper-IgM cases, the syndrome is X-linked; in the remainder, it is autosomal recessive and affects both males and females. The X-linked form of the hyper-IgM syndrome results from a genetic defect in the CD40 ligand, which is found on the surface of activated T cells.16-18 Normally, this ligand interacts with the CD40 molecule on the B cell surface, inducing isotype switching. The autosomal recessive form of the hyper-IgM syndrome results from a genetic defect in an enzyme called activation-induced cytidine deaminase (AID).19 This enzyme is involved in RNA editing, but its precise role in immunoglobulin class switching is unknown.

Diagnosis Patients with hyper-IgM syndrome show increased susceptibility to infection similar to that seen in X-linked agammaglobulinemia (see above). Immunoglobulin assays show an elevated level of IgM (350 to 1,000 mg/dl); the IgD level may also be elevated. IgA is usually undetectable, and the IgG level is normally less than 100 mg/dl. Many plasma cells, as well as lymphocytoid and plasmacytoid cells structurally similar to those of Waldenstrom macroglobulinemia, are seen in the gut, lymphoid organs, and blood. These plasma cells stain with fluo-rescein-labeled antibodies to IgM. In the X-linked form of hyper-IgM syndrome, lymph nodes are small and contain no germinal centers. In AID deficiency, lymph nodes are enlarged and contain germinal centers. Lymph node biopsy is not usually obtained for clinical diagnosis, however.

Treatment Treatment for hyper-IgM syndrome is the same as that for X-linked agammaglobulinemia (see above).

Selective Deficiencies of IgM or the Subclasses of IgG

Selective IgM deficiency is rare. This deficiency may precede the onset of CVID. Patients with selective deficiencies of the IgG subclasses have a decrease in total IgG, the degree of which depends on the subclass involved. The decrease is most profound in the case of IgG1 deficiency because almost three quarters of IgG molecules belong to this subclass. Some patients with IgG deficiency are unable to mount an antibody response to certain antigens. Patients with IgG2 deficiency are especially prone to infection by bacteria with a large amount of surface polysaccha-ride, such as pneumococci and H. influenzae. The diagnosis is confirmed by quantitation of the IgG subclasses and administration of a polysaccharide-antigen vaccine (typically, pneumococ-cal vaccine); patients with IgG deficiency will fail to produce antibodies in response to vaccination. Patients with selective deficiencies of the IgG subclasses respond to intravenously administered y-globulin.

Deficiencies of Cell-Mediated Immunity

Extreme susceptibility to opportunistic infection is the most important clinical feature of deficiencies of cell-mediated immunity, or T cell deficiencies. Such deficiencies, which manifest as impairment in delayed hypersensitivity, may be inherited or may be secondary to another disorder [see Table 2]. The acquired immunodeficiency syndrome is discussed elsewhere [see 7:XXXIII HIV and AIDS].

Table 2 Conditions Associated with Impaired Delayed Hypersensitivity

Primary deficiencies of cell-mediated immunity [see Table 3]

Chromosomal abnormalities: Bloom syndrome, Down syndrome, Fanconi syndrome

Infections: HIV (AIDS), lepromatous leprosy, Epstein-Barr virus (X-linked lymphoproliferative syndrome), chronic mucocuta-neous candidiasis, secondary syphilis, and many other viral and parasitic diseases

Neoplasms: thymoma, Hodgkin disease and other lymphomas, any advanced malignant disease

Connective tissue diseases: systemic lupus erythematosus, advanced rheumatoid arthritis

Physical agents: burns, x-irradiation

Other conditions: sarcoidosis, malnutrition, aging, inflammatory bowel disease, intestinal lymphangiectasia

Iatrogenic causes: chemotherapy, postsurgery, x-irradiation therapy

In general, patients with T cell deficiencies have more frequent and more severe infections than do patients who have pure B cell deficiencies [see Table 3].2 Patients with deficiencies of cell-mediated immunity cannot cope with a number of ordinarily innocuous organisms, such as Candida albicans and Pneumocys-tis carinii, and are especially susceptible to enteric bacteria, viruses, and fungi. Live attenuated vaccines are dangerous in these patients: vaccination for smallpox or administration of bacillus Calmette-Guerin (BCG) has led to rapid death.

Determining the defects of cell-mediated immunity requires testing in a specialized immunology laboratory. An extensive array of tests is available at such laboratories [see Table 4]. The choice of tests and the order in which they are performed depend on the particular case.

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