X. Disorders of Lymphocytes (Figure 15-2)

Abnormalities of B cells and T cells may lead to deficiencies of antibody production, T-cell function, or both. Whereas pure B-cell defects are uncommon, hypogammaglobulinemia is a feature of most disorders involving lymphocyte function. Thus, 75% of all primary immunodeficiency diseases involve abnormalities of antibody concentration or function.

A.IgA deficiency

1.Definition. Selective IgA deficiency is characterized by serum IgA concentrations <7 mg/dL but usually normal levels of other immunoglobulin isotypes. However, IgA deficiency may be associated with other defects in many patients. Fifty percent of

patients with IgA deficiency have IgG deficiency and 20–30% have IgG2 and IgG4 subclass deficiencies.

2.Epidemiology. IgA deficiency is the most common immune deficiency, with a prevalence of 1 in 500–1000.

3.Etiology. A genetic basis for IgA deficiency is sometimes present, but for most patients, the precise cause is usually unclear.

4.Clinical features

a.Respiratory infections, such as sinusitis, pneumonia, and otitis media

b.GI manifestations, such as chronic diarrhea and infection with Giardia lamblia

c.Autoimmune and rheumatic diseases, such as systemic lupus erythematosus, juvenile rheumatoid arthritis, and celiac disease may be associated with IgA deficiency.

d.Atopic diseases, such as allergic rhinitis, eczema, urticaria, and asthma, may occur in up to 50% of patients with IgA deficiency.

5.Diagnosis. Quantitative measurement of serum immunoglobulins, which reveals the deficiency of IgA (<7 mg/dL), is the basis of diagnosis.

6.Management. IgA cannot be replaced; thus management of infections and other complications are the mainstays of therapy. Intravenous immune globulin (IVIG) is not indicated (it contains almost all IgG). Patients with IgA deficiency can mount an antibody reaction to IgA and therefore should receive blood transfusions without IgA.

B.Common variable immunodeficiency

1.Definition. This heterogeneous group of disorders is characterized by hypogammaglobulinemia. Most patients have normal numbers of B and T cells but have variable degrees of T-cell dysfunction. Most commonly diagnosed in patients who present with infections occurring after infancy when the protective maternal antibodies decrease. This is unlike severe combined immunodeficiency disease (SCID) which usually presents in the first few months of life [see section X.C].

2.Epidemiology. Most cases are sporadic, with prevalence between 1 in 10,000 and 1 in 100,000.

3.Etiology. A variety of defects in B-cell function or in B cell–T cell interaction can produce the clinical picture of common variable immunodeficiency. The genetic basis of this disorder is largely unknown, but a number of genetic defects have recently been elucidated.

4.Clinical features

a.Respiratory infections (frequently caused by Haemophilus influenzae, Moraxella catarrhalis, and Streptococcus pneumoniae) and GI infections accompanied by chronic diarrhea (often caused by G. lamblia and Campylobacter jejuni)

b.Autoimmune disorders, such as rheumatoid arthritis, autoimmune thyroiditis, autoimmune thrombocytopenia, and autoimmune hemolytic anemia

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c.Increased risk of malignancy

5.Diagnosis

a.Quantitative immunoglobulin measurement shows decreased serum immunoglobulin concentrations.

b.Diminished antibody function may be assessed by measuring titers generated in response to childhood immunizations (i.e., diphtheria, tetanus, and pneumococcus).

c.T-cell proliferation to mitogens (nonspecific stimulators of lymphocyte production) may be diminished.

6.Management

a.Monthly IVIG replacement

b.Aggressive management of infections with antibiotics

c.Chronic diarrhea management including nutritional support

C.SCID

1.Definition. SCID is a group of inherited disorders characterized by profoundly defective

T-cell and B-cell function.

2.Etiology. More than 12 distinct genetic abnormalities that produce SCID have been identified.

a.X-linked SCID, caused by deficiency of the common gamma chain of the receptor for cytokines interleukin (IL)-2, IL-4, IL-7, IL-9, and IL-15, accounts for about 50% of all cases of SCID.

b.Autosomal recessive SCID is caused by a variety of genetic defects involving T-cell ontogeny or function. Adenosine deaminase deficiency accounts for approximately 30% of cases of autosomal recessive SCID.

3.Clinical features

a.Increased susceptibility to infection within the first few months of life with common pathogens and with opportunistic organisms, such as Candida albicans and

Pneumocystis jirovecii

b.Chronic diarrhea and failure to thrive are common.

4.Diagnosis

a.Persistent lymphopenia (<1500 lymphocytes/mL) is a nearly constant feature in patients with SCID.

b.Enumeration of lymphocyte populations by flow cytometry shows decreased numbers of T-cells.

c.Quantitative measurement of serum immunoglobulins shows severe hypogammaglobulinemia.

d.T-cell responses to mitogens and antigens are severely depressed.

5.Management

a.Supportive care with appropriate antibiotics, nutritional interventions, and psychosocial support is necessary.

b.Blood products should be irradiated to prevent graft-versus-host disease.

c.Monthly IVIG replacement is administered to maintain a normal serum IgG level.

d.P. jirovecii pneumonia (PCP) prophylaxis with trimethoprim–sulfamethoxazole is indicated.

e.Bone marrow transplant can be curative. Complications include graft-versus-host disease, infection, and medication toxicity. Other options include cord blood stem cell or peripheral blood stem cell transplant.

f.Gene therapy is a potential future cure.

D.Ataxia telangiectasia

1.Definition. Ataxia telangiectasia is an autosomal recessive disorder characterized by combined immunodeficiency, cerebellar ataxia, oculocutaneous telangiectasias, and

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predisposition to malignancy.

2.Etiology. Ataxia telangiectasia results from a mutation of a gene on the long arm of chromosome 11. The gene product is involved in cell cycle control, DNA recombination, and cellular responses to DNA damage.

3.Clinical features

a.Variable degrees of immunodeficiency that most commonly manifests as chronic sinopulmonary infections

b.Severe progressive cerebellar ataxia that results in a need for wheelchair assistance by early adolescence in most patients

c.Telangiectasias that appear on the bulbar conjunctiva between 2 and 5 years of age and later on exposed skin and areas of trauma

d.High risk of malignancy, particularly lymphoma and carcinoma, owing to defects in DNA repair

e.Other clinical features such as café-au-lait spots, vitiligo, prematurely gray hair, and multiple endocrine abnormalities

4.Diagnosis

a.Quantitative measurement of serum immunoglobulins reveals IgG deficiency in 85% of patients and IgA deficiency in 75% of patients.

b.Evaluation of T-cell function may reveal skin test anergy and diminished T-cell proliferation to mitogens.

5.Management

a.Treat the neurologic complications

b.Aggressively treat infections

c.Monitor for malignancies

d.Avoid ionizing radiation, which exacerbates DNA breakage and repair, thus increasing the risk of malignancy.

E.DiGeorge syndrome is a congenital immunodeficiency syndrome characterized by cardiac defects, abnormal facies, thymic hypoplasia, cleft palate, and hypocalcemia because of a submicroscopic deletion on chromosome arm 22q11 (mnemonic: CATCH-22). See , section IV.D.1.

F.Wiskott–Aldrich syndrome

1.Definition. Wiskott–Aldrich syndrome is an X-linked disorder characterized by combined immunodeficiency, eczema, and congenital thrombocytopenia with small platelets.

2.Etiology. Wiskott–Aldrich syndrome is caused by the mutation of a gene on the short arm of the X chromosome. The gene product is important in T-cell receptor signaling and cytoskeletal organization.

3.Clinical features

a.Susceptibility to infections with encapsulated organisms, such as H. influenzae and S. pneumoniae, because patients do not produce antibodies to polysaccharide antigens.

b.Thrombocytopenia characterized by small defective platelets. Bleeding episodes are frequent and are associated with a risk of intracranial hemorrhage.

c.Eczema, which predisposes to skin infections

4.Diagnosis

a.Complete blood count reveals thrombocytopenia and small platelets.

b.Decreased IgM is demonstrated by measurement of immunoglobulins.

c.Antibody response to polysaccharide antigens (i.e., polysaccharide vaccines) is diminished.

d.Cellular immune function is defective and anergy is present. Patients have near-

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normal numbers of T cells, but they respond poorly to antigens and do not develop antigen-specific cytotoxic T cells.

5.Management

a.Human leukocyte antigen (HLA)—matched bone marrow transplantation is the therapy of choice.

b.IVIG is administered for hypogammaglobulinemia.

c.Splenectomy cures the thrombocytopenia in more than 90% of patients. Quality of life is improved, and medical management is simplified. Prophylactic antibiotics or

IVIG must be administered regularly after splenectomy.

G.X-linked (Bruton) agammaglobulinemia

1.Definition. X-linked agammaglobulinemia is characterized by severe hypogammaglobulinemia and a paucity of mature B cells (<1% B cells in peripheral blood) with normal T-cell number and function.

2.Etiology. X-linked agammaglobulinemia is due to mutations in the Bruton tyrosine kinase (BTK) gene on the X chromosome. The BTK gene is critical to normal B-cell ontogeny. Mutations lead to a block in the development from pre–B cell to mature B cell.

3.Clinical features. Increased susceptibility to infections with encapsulated bacteria (S. pneumoniae, H. influenzae, S. aureus) and chronic enteroviral infection may occur.

4.Diagnosis

a.Quantitative immunoglobulin measurement reveals profound decreases in all immunoglobulin isotypes.

b.B cells are absent or greatly diminished.

c.T cells are present, and cell-mediated functions are preserved.

d.Mutations in the BTK gene are demonstrated by mutation analysis.

5.Management. Treatment includes monthly IVIG replacement to prevent infection.

FIGURE 15-2 Disorders of lymphocytes.

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