ACP medicine, 3rd Edition

Immunology/Allergy

Deficiencies in Immunoglobulins and Cell-Mediated Immunity

Fred S. Rosen M.D.1

1James L. Gamble Professor of Pediatrics, Harvard Medical School, President, Center for Blood Research, Boston

The author has no commercial relationships with manufacturers of products or providers of services discussed in this subsection.

April 2003

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 γ-globulin.

Table 1 Primary Specific Immunodeficiencies Involving Antibodies

Designation

Usual Phenotypic Expression

Presumed Level of Basic Cellular Defect

Known or Presumed Pathogenetic Mechanism

Inheritance

Antibody Deficiencies

Cellular Abnormalities

X-linked agammaglobulinemia

All immunoglobulins

↓ B cells

Pre-B cells

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

X-linked

Common variable immunodeficiency

All immunoglobulins

Faulty B cell maturation

Immaturity of B cells

↓ Helper T cell function Intrinsic B cell defect Underproduction of B cells
Autoantibodies to B cells

Unknown

Selective IgA deficiency

IgA

↓ IgA plasma cells
± IgA+ B cells

Terminal differentiation of IgA+ B cells impaired

Unknown

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

↓ IgG and IgA plasma cells
↑ IgM and IgD plasma cells
± ↑ IgM+ B cells

Failure of immunoglobulin 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

↓ Plasma cells
±↓ T cells

Unknown

Unknown

Unknown

κ-Chain deficiency

IgG(κ)

↓ κ+ B cells

Unknown

Point mutation at 2p11

Autosomal recessive

Transient hypogammaglobulinemia of infancy

IgG and IgA

↓ Plasma cells
B cells normal

Impaired terminal differentiation of B cells

↓ Helper T cells

Frequent in heterozygous individuals in families with various severe combined immunodeficiences

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).3,4,5 This gene, termed btk, is a member of the src family of oncogenes and encodes a unique tyrosine kinase.4,5,6,7,8 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 agammaglobulinemia, 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 lymphoid organs are characterized by a lack of germinal follicles, B cells, and plasma cells. On bone marrow studies, pre-B cells (which contain immunoglobulin µ heavy chains in their cytoplasm and therefore can be identified by immunofluorescence staining with antiserum to the µ chain) are present in normal numbers.

Diagnosis

Clinical manifestations

Because infants are born with IgG from their mother in their blood, boys who have X-linked agammaglobulinemia do not start to show the effects of the disorder until 6 to 15 months of age. They then demonstrate unusual susceptibility to infections by pyogenic organisms (e.g., otitis media, sinusitis, and pneumonia from Haemophilus influenzae, pneumococci, 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 dermatomyositis 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, echoviruses have been cultured from the blood, stool, and cerebrospinal 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.

 

Figure 1. Comparison of Agammaglobulinemic Serum with Normal Serum

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.

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 hypersensitivity-mediated skin reactions and graft rejection, are essentially normal, and the T cells respond in vitro to phytohemagglutinin 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.

Treatment

Preparations of 5% or 10% γ-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 γ-globulin are adjusted according to the patient's health. The minimal effective dosage of intravenous γ-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 γ-globulin and administering it at 1-week or 2-week intervals is preferable, because it maintains higher immunoglobulin levels. The γ-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 agammaglobulinemia 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 γ-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 immunoglobulins, (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.

Diagnosis

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 α1-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

Treatment of CVID is essentially the same as that of X-linked agammaglobulinemia: replacement γ-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.

Prognosis

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 γ-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 anaphylactic reactions when given immunoglobulin.15 Immunoglobulin 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.16,17,18 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).19This 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 Waldenström macroglobulinemia, are seen in the gut, lymphoid organs, and blood. These plasma cells stain with fluorescein-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 polysaccharide, such as pneumococci and H. influenzae. The diagnosis is confirmed by quantitation of the IgG subclasses and administration of a polysaccharide-antigen vaccine (typically, pneumococcal 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 γ-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's syndrome, Down's syndrome, Fanconi's syndrome
Infections: HIV (AIDS), lepromatous leprosy, Epstein-Barr virus (X-linked lymphoproliferative syndrome), chronic mucocutaneous candidiasis, secondary syphilis, and many other viral and parasitic diseases
Neoplasms: thymoma, Hodgkin's 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 Pneumocystis 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-Guérin (BCG) has led to rapid death.

Table 3 Classification of Primary Specific Immunodeficiencies Involving Cell-Mediated Immunity

Designation

Usual Phenotypic Expression

Presumed Level of Basic Cellular Defect

Known or Presumed Pathogenetic Mechanism

Inheritance

Main Associated Features

Functional Deficiencies

Cellular Abnormalities

Congenital thymic hypoplasia (DiGeorge syndrome)

CMI, impaired antibody

↓ T cells

Thymocytes

Embryopathy of third and fourth pharyngeal pouch areas

Usually not familial

Hypoparathyroidism Abnormal facies Cardiovascular abnormalities

Severe combined immunodeficiency

CMI, antibody

- T cells, + B cells

LSC

Mutation in γ chain of IL-2R, IL-4R, IL-7R, IL-11R, IL-15R, or JAK3 or IL-7 receptor α chain

X-linked or autosomal recessive

- T cells, - B cells

Mutation in RAG1 or RAG2

Autosomal recessive

Adenosine deaminase (ADA) deficiency

CMI antibody

↓ T cells, ± B cells

LSC or early T cells

Metabolic effects of ADA deficiency

Autosomal recessive

Purine nucleoside phosphorylase (PNP) deficiency

CMI ± antibody

↓ T cells

T cells

Metabolic effects of PNP deficiency

Autosomal recessive

Hypoplastic enemia

Reticular dysgenesis

CMI, antibody, phagocytes

↓ T cells, ↓ B cells, ↓phagocytes

HSC

Unknown

Autosomal recessive

Neutropenia

Wiskott-Aldrich syndrome

Antibody to certain antigens (mainly polysaccharides), CMI (progressive)

↓ T cells, ↑ B cells (progressive)

HSC

Mutations inWASP gene

X-linked

Thrombocytopenia
Eczema
Lymphoreticular cancers

Immunodeficiency with ataxia-telangiectasia

CMI, antibody (partial)

↓ T cells, ↓plasma cells (mainly those cells producing IgA, IgE, ±IgG)

Defective check points in T and B cell division

Mutations in ATM gene

Autosomal recessive

Cerebellar ataxia
Telangiectasia
Chromosomal abnormalities
Raised serum α-fetoprotein levels

MHC class II deficiency

CMI ± antibody

None

T cells, B cells, and antigen-presenting cells

Defects of promoter proteins

Autosomal recessive

Intestinal malabsorption

CD3 deficiency

CMI

None

T cells

Mutations in CD3-ε or CD3-γ

Autosomal recessive

CD8 deficiency

CMI

↓ CD8+ T cells, normal number of CD4+ cells

Early T cells

Mutations in ZAP genes

Autosomal recessive

CMI—cell-mediated immunity  LSC—lymphocytic stem cell  HSC—hematopoietic stem cell

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.

Table 4 Laboratory Tests Used to Determine Deficiencies of Cell-Mediated Immunity

Skin test: 24- to 48-hr reaction to Candida, Trichophyton, PPD
Response to nonspecific mitogens: phytohemagglutinin, concanavalin A, pokeweed mitogen
Response to specific mitogens: diphtheria, tetanus, Candida
Response to alloantigens: mixed lymphocyte reaction
When responses to alloantigens and nonspecific and specific mitogens are negative: repeat tests while stimulating cells with IL-2
Enumerate T cells with monoclonal antibody to CD3, with or without a cell sorter
Enumerate T cell subsets with monoclonal antibody to CD4 for helper T cells and with monoclonal antibody to CD8
Enumerate T cells positive for Ia (class II) antigens (which measures the number of activated T cells)
Quantitate IL-2 receptors with monoclonal antibody TAC
Quantitate IL-2 and interferon-gamma synthesis
Enumerate NK cells with monoclonal antibodies Leu-7 and Leu-11
Assay NK cell activity using cell line K-562
Assay cytotoxic T cell activity using cell lines of cloned T cells
Enumerate monocytes with monoclonal antibody Mo-1
Assay for IL-1 production by stimulated monocytes
Determine serum level of anti-T cell antibodies
Determine if antibody to HIV is present
HLA typing
Assay erythrocytes for adenosine deaminase and purine nucleoside phosphorylase activity
Detect thymus shadow on x-ray
Note: all patients with defects in cell-mediated immunity should receive all tests listed, except the last three, for optimal examination. The last three tests are for patients suspected of having severe combined immunodeficiency or congenital thymic hypoplasia. HLA typing is needed for prospective recipients of bone marrow transplants.
IL-1—interleukin-1 IL-2—interleukin-2 PPD—purified protein derivative of tuberculin NK—natural killer HIV—human immunodeficiency virus

CONGENITAL THYMIC HYPOPLASIA

Pathogenesis

Congenital thymic hypoplasia (DiGeorge syndrome) results from the lack of normal development of the third and fourth brachial, or pharyngeal, pouches, which leads to abnormality in the great vessels and to the absence of the thymus and the parathyroids. Congenital thymic hypoplasia is not inherited; rather, it is thought to result from an intrauterine accident occurring before the eighth week of pregnancy. The absence of the thymus leads to deficiency in cell-mediated immunity.

Diagnosis

Clinical manifestations

Patients with congenital thymic hypoplasia have distinctive facial features, including low-set ears, a shortened philtrum, and ocular hypertelorism. Hypocalcemia from associated parathyroid deficiency is a universal finding and often results in neonatal tetany. There can be a right-sided aortic arch or tetralogy of Fallot or many other cardiac malformations.

Laboratory tests

The T cell defect in children with congenital thymic hypoplasia varies from mild to profound. Severely affected children do not exhibit delayed hypersensitivity reactions; their lymphocytes do not respond to mitogens or antigens in vitro, nor do they produce lymphokines. The lymph nodes lack paracortical lymphocytes. Plasma cells are present, however, and immunoglobulin levels are normal. Although patients with congenital thymic hypoplasia produce specific antibodies when they are immunized with various antigens, the antibody response is not quite normal, because secondary responses are lacking.

As the patient ages, T cell function improves; and usually by the time the child is 5 years of age, skin testing reveals no abnormality in cell-mediated immunity. However, the abnormal T cell phenotype—as indicated by a higher than normal ratio of CD4+ to CD8+ T cells—persists for life. Karyotyping reveals microdeletions at chromosome 22q11 in approximately 90% of patients.

Treatment

Thymus transplantation should be undertaken in those infants with congenital thymic hypoplasia who experience frequent infections. Transplantation of fetal thymus results in rapid acquisition of normal T cell function, which is thought to be secondary to production of a thymic hormone secreted by the thymic epithelium. Rejection appears not to be a problem.

SEVERE COMBINED IMMUNODEFICIENCY

Severe combined immunodeficiency disease (SCID) is characterized by marked depletion of cells that mediate both humoral and cellular immunity—B cells and T cells, respectively. SCID is fatal if left untreated.

Several variants of SCID have been identified. They are designated as T-B- or T-B+, depending on whether B cells are normal or increased (B+) or absent (B-). In addition to the extent of B cell involvement, the variants also differ in the site of the basic cellular defect, the pathogenetic mechanism, and the mode of inheritance [see Table 3].

Genetics and Pathogenesis

T-B+ SCID may be transmitted as either an X-linked or an autosomal recessive trait. The specific genetic defect responsible for the X-linked form of T-B+ SCID results from mutations in the γ chain of the interleukin-2 receptor (IL-2R),20 whose gene is localized to the long arm of the X chromosome at Xq13.21 This γ chain is also found in the receptors for IL-4, IL-7, IL-11, and IL-15.22 Engagement of the IL-7 receptor by IL-7 is required for T cell maturation, so precursor T cells in these patients do not mature.

When any of those receptors, or IL-2R, are engaged by its ligands, a cytoplasmic tyrosine kinase (Janus-family tyrosine kinase, or JAK3) bound to the γ chain is activated. The gene encoding JAK3 is on an autosome, not the X chromosome. Thus, autosomal recessive T-B+ SCID is caused by mutations in the JAK3 gene.23,24

T-B- SCID is inherited in an autosomal recessive manner. About half of the cases are caused by a deficiency in the enzyme adenosine deaminase (ADA),25 and another large fraction results from mutations in the recombination-activating genes RAG-1 and RAG-2.26 These recombinase enzymes are required for the gene rearrangements that occur before T cell receptor or immunoglobulin synthesis. Other patients with autosomal recessive T-B- SCID lack the enzyme purine nucleoside phosphorylase (PNP).27

ADA deficiency leads to an accumulation of adenosine, adenosine triphosphate (ATP), and deoxy-ATP (dATP). It has been shown that dATP poisons ribonucleotide reductase, an enzyme required for DNA synthesis. Thus, lymphocytes lacking ADA cannot divide until the dATP overload is decreased or removed. In a similar manner, lymphocytes that lack PNP accumulate guanosine, guanosine triphosphate (GTP), and deoxy-GTP, causing metabolic abnormalities that resemble those seen in ADA deficiency. SCID caused by ADA or PNP deficiency can be diagnosed prenatally by amniocentesis because fibroblasts in the amniotic fluid also show the enzymatic defect.

CD8 deficiency is a rare form of SCID that results from mutations in the ZAP-70 gene.28,29 ZAP-70 is a tyrosine kinase that binds to the CD3 chain and is involved in signal transduction from the T cell receptor (the TCR-CD3 complex). CD8+ T cells fail to mature, and mature CD4+ T cells fail to function as a result of the mutations in ZAP-70.

Another variant of SCID is reticular dysgenesis, a severe combined immunodeficiency with a generalized granulocyte deficiency. Newborns with this disease lack granulocytes in the blood and bone marrow and die of infection within the first few days of life.

Diagnosis

Clinical manifestations

Chronic pulmonary infections, diarrhea, moniliasis, and failure to thrive are the most common manifestations of SCID. The lymph nodes are small to absent despite chronic infections, which usually begin at 3 to 6 months of age.

Laboratory tests

Complete blood counts show a low number of lymphocytes. There is absence of a thymic shadow on chest x-ray. (Autopsy in fatal cases has revealed an embryonic thymus that resembles the thymus at 6 weeks of gestation, before invasion with lymphocytes.) Tests for cutaneous delayed hypersensitivity and contact sensitization and in vitro assays of blood lymphocytes are negative, demonstrating the absence of T cells, a phytohemagglutinin response, and lymphokine production. Antibody levels are usually low, although occasionally the IgM level is normal; and sometimes, a myeloma component is seen.

Treatment

Hundreds of cases of SCID have been successfully treated by transplantation of bone marrow cells.30 By 3 to 8 months after receiving the bone marrow, these patients show normal delayed hypersensitivity and T cell function and are no longer abnormally susceptible to infection.

Immunologic reconstitution with bone marrow cells should be attempted only in specialized centers where comprehensive histocompatibility typing and intensive 24-hour care can be given. If the donor and the recipient are not exceedingly well matched, fatal graft versus host disease (GVHD) will ensue. Even an HLA-mismatched blood transfusion can produce fatal GVHD in such patients: the patient is immunocompromised and thus cannot reject the injected cells, but the histoincompatible cells that have been administered recognize the patient's cells as foreign and react against them.

The manifestations of GVHD include fever, diarrhea, depression of the bone marrow, splenomegaly, and an erythematous rash on the face, trunk, and extremities. The reaction eventually leads to death. GVHD can be avoided by irradiating the blood before transfusion.

It is possible to establish grafts of half-matched (haploidentical) parental marrow in infants with SCID. GVHD can be avoided in those cases if the parental marrow is depleted of T cells before transplantation by passage over lectin columns or by treatment with anti-T cell monoclonal antibody plus complement.

Patients with ADA deficiency have also been treated successfully with infusions of purified adenosine deaminase modified with polyethylene glycol. The ADA gene has been cloned and inserted into a retroviral vector.31 In a few ADA-deficient children, this vector has been transfected into peripheral blood lymphocytes, which were then reinfused. This gene therapy procedure has corrected the immunodeficiency in these patients, although it must be repeated periodically.32 Successful gene therapy has also been carried out in X-linked SCID by transducing a Maloney virus vector bearing the gene for the common γ chain into bone marrow cells. Sustained responses have been reported in four of these patients: T cell number and function normalized in these patients, as did B cell function, and infusions of γ globulin were no longer required.33

WISKOTT-ALDRICH SYNDROME

An X-linked recessive disease, Wiskott-Aldrich syndrome (WAS), results from a mutation that has been mapped to the Xp11.3-p11.22 region of the X chromosome. The WAS gene has been cloned.34,35

The lymphoid system of a patient with WAS appears anatomically intact at birth. Starting in the first months of life, however, there is a decrease in T cells in the paracortical areas of the lymph nodes and a polyclonal expansion of B cells. The T cells in these patients respond poorly to mitogens. The protein encoded by the WAS gene appears to be involved in signal transduction that leads to reorganization of the cytoskeleton when lymphocytes are stimulated, which results in defective collaboration between T cells and B cells. Lymphocytes have a markedly abnormal appearance when visualized by scanning electron microscopy. Platelets are abnormally small and few in number.36Certain missense mutations in the WAS gene lead to a mild disease called X-linked thrombocytopenia.37

Diagnosis

Clinical manifestations

WAS is characterized by eczema, easy bruising, increased susceptibility to infection (both pyogenic and opportunistic), and bloody diarrhea. These manifestations appear in the first months of life. An increased incidence of hematopoietic malignancies is seen, starting in the second or third decade of life.

Laboratory testing

Patients with WAS have normal levels of IgG, high levels of IgE and IgA, and low levels of IgM. Severe thrombocytopenia is universal. Tests of cell-mediated immunity [see Table 4] show a variety of abnormalities: WAS patients lack isohemagglutinins and are unable to make antibodies to polysaccharides. They respond to some protein antigens but not to others; in addition, they may exhibit anergy and may not display positive results to skin tests for the usual bacterial or fungal antigens.

Treatment

WAS patients have been treated with marrow transplantation after receiving irradiation or busulfan and antilymphocyte serum to destroy residual lymphocytes; they have then shown normal immune and platelet functions. In WAS patients who do not receive a bone marrow transplant and who experience severe bleeding from thrombocytopenia, splenectomy may be considerably beneficial.38

IMMUNOLOGIC DEFICIENCY WITH ATAXIA-TELANGIECTASIA

Ataxia-telangiectasia (A-T) is a disease associated with defects in cell-mediated immunity and with immunoglobulin deficiencies. It is inherited as an autosomal recessive trait. The gene for A-T (ATM for A-T mutated) maps to the chromosomal region 11q22.3.39,40 Normally, the gene appears to function in repair of breaks in double-stranded DNA. Patients with A-T have a disorder of the cell-cycle checkpoint pathway that results in an extreme hypersensitivity to ionizing radiation. Consequently, frequent chromosomal breaks, inversions, and translocations are observed. Postmortem examination may disclose abnormalities in the thymus, which is small and deficient in lymphocytes. There also may be an abnormality in lymph node structure.

Diagnosis

Clinical manifestations

A-T presents as a progressive neurologic disease that begins in early childhood. It is characterized by cerebellar ataxia, starting at 18 months of age, followed by increasing tremor and deterioration of mental function. By 5 years of age, progressive telangiectasia is seen in the vessels of the bulbar conjunctiva and is later visible on the skin. The immune deficiencies in these patients leads to recurrent sinus and bronchial infections and subsequent bronchiectasis. An unusually high incidence of lymphoid malignant disorders has been reported in patients with A-T.41

Laboratory testing

About 70% of patients with A-T have a severe deficiency in IgA. On tests of cell-mediated immunity [see Table 4], some A-T patients are anergic and fail to show delayed hypersensitivity responses to common microbial antigens. They may also have abnormal in vitro cell-mediated immune responses and may tolerate allografts.

Treatment and Prognosis

No satisfactory treatment for A-T is currently available. Persons with A-T who survive into their second decade may fail to mature sexually. A-T patients usually die of lymphoid malignancies or other causes by the end of their second decade.

References

  1. Rosen FS, Wedgwood RJ, Eibl M, et al: Primary immunodeficiency diseases: report of a WHO Scientific Group. Clin Exp Immunol 109(suppl 1):1, 1997
  2. Rosen FS, Cooper MD, Wedgwood RJP: The primary immunodeficiencies. N Engl J Med 333:431, 1995
  3. Kwan SP, Terwilliger J, Parmley R, et al: Identification of a closely linked DNA marker, DXS178, to further refine the X-linked agammaglobulinemia locus. Genomics 6:238, 1990
  4. Vetrie D, Vorechovsky I, Sideras P, et al: The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases. Nature 361:226, 1993
  5. Tsukada S, Saffran DC, Rawlings DJ, et al: Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia. Cell 72:279, 1993
  6. Hagemann TL, Chen Y, Rosen FS, et al: Genomic organization of the Btk gene and exon scanning for mutations with X-linked agammaglobulinemia. Hum Mol Genet 3:1743, 1994
  7. Zhu Q, Zhang M, Winkelstein J, et al: Unique mutations of Bruton's tyrosine kinase in fourteen unrelated X-linked agammaglobulinemia families. Hum Mol Genet 3:1899, 1994
  8. Conley ME, Fitch-Hilgenberg ME, Cleveland GL, et al: Screening of genomic DNA to identify mutations in the gene for tyrosine kinase. Hum Mol Genet 3:1751, 1994
  9. Misbah SA: Chronic enteroviral meningoencephalitis in agammaglobulinemia: case report and literature review. J Clin Immunol 12:266, 1992
  10. Fearon ER, Winkelstein JA, Civin CI, et al: Carrier detection in X-linked agammaglobulinemia by analysis of X-chromosome inactivation. N Engl J Med 316:427, 1987
  11. Conley ME, Brown P, Pickard AR, et al: Expression of the gene defect in X-linked agammaglobulinemia. N Engl J Med 315:564, 1986
  12. Buckley RH, Schiff RI: The use of intravenous immune globulin in immunodeficiency diseases. N Engl J Med 325:110, 1991
  13. Quartier P, Debre M, De Blic J, et al: Early and prolonged intravenous immunoglobulin replacement therapy in childhood agammaglobulinemia: a retrospective survey of 31 patients. J Pediatr 134:589, 1999
  14. Conley ME, Cooper MD: Immature IgA B cells in IgA-deficient patients. N Engl J Med 305:495, 1981
  15. Burks AW, Sampson HA, Buckley RH: Anaphylactic reactions after gamma globulin administration in patients with hypogammaglobulinemia: detection of IgE antibodies to IgA. N Engl J Med 314:560, 1986
  16. Fuleihan R, Ramesh N, Loh R, et al: Defective expression of the CD40 ligand in X chromosome-linked immunoglobulin deficiency with normal or elevated IgM. Proc Natl Acad Sci USA 90:2170, 1993
  17. Korthauer U, Graf D, Mages HW, et al: Defective expression of T-cell CD40 ligand causes X-linked immunodeficiency with hyper-IgM. Nature 361:539, 1993
  18. Mayer L, Kwan S-P, Thompson C, et al: Evidence for a defect in “switch” T cells in patients with immunodeficiency and hyperimmunoglobulin M. N Engl J Med 314:409, 1986
  19. Revy P, Muto T, Levy Y, et al: Activation-induced deaminase (AID) deficiency causes the autosomal recessive form of the hyper-IgM syndrome (HIGM2). Cell 102:565, 2000
  20. Noguchi M, Yi H, Rosenblatt HM, et al: Interleukin 2 receptor γ chain mutation results in X-linked severe combined immunodeficiency in humans. Cell 73:147, 1993
  21. Puck JM, Conley ME, Bailey LC: Refinements of linkage of human severe combined immunodeficiency (SCDX1) to polymorphic markers in Xq13. Am J Hum Genet 53:176, 1993
  22. Puel A, Ziegler SF, Buckley RH, Leonard WJ: Defective IL7R expression in T(-)B(+)NK(+) severe combined immunodeficiency. Nat Genet 20:394, 1998
  23. Macchi P, Villa A, Gillani S, et al: Mutations of Jak 3 gene in patients with autosomal recessive combined immune deficiency (SCID). Nature 377:65, 1995
  24. Russell SM, Tayebi N, Nakajima H, et al: Mutation of Jak3 in a patient with SCID: essential role of Jak3 in lymphoid development. Science 270:797, 1995
  25. Hirschhorn R: Adenosine deaminase deficiency. Immunodefic Rev 2:175, 1990
  26. Schwarz K, Gauss GH, Ludwig L, et al: RAG mutations in human B cell-negative SCID. Science 274:97, 1996
  27. Markert ML: Purine nucleoside phophorylase deficiency. Immunodef Rev 3:45, 1991
  28. Arpaia E, Shahar M, Dadi H, et al: Defective T cell receptor signaling and CD8+ thymocyte selection in humans lacking Zap-70 kinase. Cell 76:947, 1994
  29. Chan AC, Kadlecek TA, Elder ME, et al: ZAP-70 deficiency in autosomal recessive form of severe combined immunodeficiency. Science 264:1599, 1994
  30. Buckley RH, Schiff RI, Schiff SE, et al: Human severe combined immunodeficiency: genetic, phenotypic, and functional diversity in one hundred eight infants. J Pediatrics 130:378, 1997
  31. Williams DA, Lemischka IR, Nathan DG, et al: Introduction of new genetic material into pluripotent hematopoietic stem cells of the mouse. Nature 310:476, 1984
  32. Blaese RN, Culver KW, Miller AD, et al: T-lymphocyte-directed gene therapy for ADA deficiency SCID: initial trial results after 4 years. Science 270:470, 1995
  33. Hacein-Bey-Abina S, Le Deist F, Carlier F, et al: Sustained correction of X-linked severe combined immunodeficiency by ex vivo gene therapy. N Engl J Med 346:1185, 2002
  34. Derry JMJ, Ochs HD, Francke U: Isolation of a novel gene mutated in Wiskott-Aldrich syndrome. Cell 78:635, 1994
  35. Kwan S-P, Hagemann T, Radke BE, et al: Identification of mutations in the gene responsible for the Wiskott-Aldrich syndrome and characterization of a polymorphic dinucleotide repeat at the DXS 6940 locus adjacent to the disease gene. Proc Natl Acad Sci USA 92:4706, 1995
  36. Remold-O'Donnell E, Rosen FS, Kenney DM: Defects in Wiskott-Aldrich syndrome blood cells. Blood 87:2621, 1996
  37. Villa A, Notarangelo L, Macchi P, et al: X-linked thrombocytopenia and Wiskott-Aldrich syndrome are allelic diseases with mutations in the WASP gene. Nat Genet 9:414, 1995
  38. Mullen CA, Anderson KD, Blaese RM: Splenectomy and/or bone marrow transplantation in the management of Wiskott-Aldrich syndrome: long term follow-up of 62 cases. Blood 82:2961, 1993
  39. Gatti RA, Berkel I, Boder E, et al: Localization of an ataxia-telangiectasia gene to chromosome 11q22–23. Nature 336:577, 1988
  40. Savitsky K, Barshira A, Gilad S, et al: A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science 268:1749, 1995
  41. Swift M: Genetic aspects of ataxia-telangiectasia. Immunodefic Rev 2:67, 1990

Editors: Dale, David C.; Federman, Daniel D.