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Chapter: Medical Immunology: Primary Immunodeficiency Diseases

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Infantile Agammaglobulinemia (Bruton-Janeway Syndrome)

This is the prototype of “pure” B-cell deficiency. The disease is predominately transmitted as an X-linked trait.

Infantile Agammaglobulinemia (Bruton-Janeway Syndrome)

This is the prototype of “pure” B-cell deficiency. The disease is predominately transmitted as an X-linked trait. The defective gene is located on Xq21.2–22, the locus coding for the B-cell progenitor kinase or Bruton’s tyrosine kinase (Btk). Patients may have mutations at different sites within the locus resulting either in the lack of synthesis of the kinase or in the synthesis of an inactive form of the kinase.

Btk plays an important role in B-cell differentiation and maturation and is also part of the group of tyrosine kinases involved in B-cell signaling in adult life. Most mutations affecting Btk are associated with infantile agammaglobulinemia, but some patients with similar mutations have mild forms of immunodeficiency with variable levels of im-munoglobulin production. These findings suggest that B-cell differentiation may depend on additional, not yet identified cofactors.

Some forms of autosomal recessive infantile agammaglobulinemia have deletions of genes encoding parts of either the V region or of the Cµ region. Such deletions are associ-ated with a total lack of differentiation of B lymphocytes, similar to the defect seen in pa-tients with Btk deficiency.

1. Clinical Presentation

 

Infectious symptoms usually begin early in infancy as maternally acquired IgG disappears. The patients most commonly suffer from repeated infections caused by common pyogenic bacteria (Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae) of the sinopulmonary system. Pyoderma, purulent conjunctivitis, pharyngitis, purulent arthritis, otitis media, sinusitis, and bronchitis are common clinical findings. Severe life-threatening infections, such as pneumonia, empyema, meningitis, and septicemia, are also frequently seen. Chronic obstructive lung disease and bronchiectasis develop as a conse-quence of repeated bronchopulmonary infections in untreated older patients. Chronic diar-rhea and malabsorption caused by infections with Giardia lamblia are seen more frequently in these patients than in the general population. Arthritis of the large joints develops in about 30–35% of the cases and is sometimes associated with infection by Ureaplasma ure-alyticum. Agammaglobulinemic patients are at risk of developing paralytic polio after vac-cination with the attenuated polio vaccine. They also are at risk of developing chronic vi-ral meningoencephalitis, usually caused by echovirus.

2. Diagnosis

 

The diagnosis of agammaglobulinemia requires the quantitative assay of immunoglobulin levels. The serum levels for the three major immunoglobulins (IgG, IgA, and IgM) are greater than 2 SD below the normal level for children of the same age, although in infants low levels of IgG may be masked by the presence of maternal antibody. Usually the sum of the three major immunoglobulin isotypes is less than 100 mg/dL and electrophoresis fails to show a gamma globulin peak.

Definitive diagnosis requires at least one of the following: (1) detection of Btk mu-tations, (2) absence of Btk mRNA on Northern blot analysis of neutrophils or monocytes, (3) lack of Btk protein in monocytes or platelets, or (4) maternal male relatives with less than 2% CD19+ B cells.

The lack of B lymphocytes in peripheral blood ( <2% of the circulating lymphocytes are CD 19+ ) is one of the most important laboratory features of the disease, not shared by the most frequent cases of hypogammaglobulinemia, common variable immunodeficiency . Histological examination of lymphoid tissues shows lack of germinal centers and secondary follicles in lymph nodes and peri-intestinal lymphoid tissues. Plasma cells are absent both from peripheral lymphoid tissues and from bone marrow. Adenoids, ton-sils, and peripheral lymph nodes are hypoplastic. The thymus has normal structure, and the T-cell–dependent areas in peripheral lymphoid organs are normally populated. Normal numbers of B-cell precursors can be demonstrated in the bone marrow, indicating that the basic defect is a maturation block, restricted to B-cell development. Peripheral blood lym-phocyte counts are usually normal, T-lymphocyte counts are normal or elevated, T-lym-phocyte subsets are normal, and T-lymphocyte function is also normal.

Predictably, B-cell function is depressed. Isohemagglutinins are undetectable and the patients fail to produce antibodies after active immunization. Live, attenuated vaccines should be avoided in these patients.

3. Therapy

 

The primary strategy in therapy of infantile agammaglobulinemia is the prevention of in-fections. These children should not receive immunizations containing live, attenuated viruses (polio, measles, mumps, rubella, and varicella). Infections should be treated early and aggressively with antibiotics. Infections are best prevented by regular (monthly) infu-sions of intravenous gammaglobulin (IVIg). IVIg consists of purified polyclonal human IgG obtained from the pooled plasma of healthy blood donors. IgA and IgM, which can cause anaphylactoid reactions, are removed. Viruses that can be transmitted by blood transfusions are inactivated by detergent to minimize the risks of infection. IVIg penetrates mucosal sur-faces and crosses the blood-brain barrier poorly. Infections of the gastrointestinal tract some-times require the use of human or bovine colustrum or oral gamma globulin. Viral infections in the central nervous system may require infusions with intraventricular gamma globulin.

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