IgA deficiency is the most common of all immunodeficiencies. Depending on the country, the incidence is between 1:400 and 1:3000. There is an increased incidence oflgA deficiency in subjects with defects in chromosome 18, connatal rubellasyndrome, andataxia telangiectasia(Mietens, 1983). Associatedwith the deficiency are recurrent bacterial infections, bronchitis, sinusitis, pneumonia, allergies, and autoimmune diseases (Schaffer etal., 1991). B-cell differentiation arrest preventing isotypic switching from IgG to IgA is the central defect in the immunodeficiency.
Table 2. Familial SyndromesAssociated with Hypogammaglobulinemia
Common variable immunodeficiency
Immunodeficiency with hyper-lgM
Partial albinism and immunodeficiency
Modified fromPediatricReseorch, Stiehm, 1993. 33:S2-7, with permission of Pediatric Research.
CVID is a major antibody immunodeficiency characterized by recurrent upper, lower respiratory tract infections and, in a few patients, granulomatous disease (Cunningham-Rundles, 1994). Over 20% of the patientpopulations also develop autoimmune diseases (Vetrie etal., 1993).
Based on the number and function of B cells in the peripheral blood, patients can be segregated into three groups. A small group of patients lacks B cells in the blood and has only scattered bone marrow B cells. These subjects are classified as Bruton's type X-linked agammaglobulinemia (XLA). The major phenotypic defect is a mutation in the Bruton's kinase gene (Btk). Over 120 point mutations of Btk have been described (Vihinen et al., 1995).
Btk is activated following cross-linking of surface immunoglobulin. A pleckstrin-homology domain binds to G-protein subunits and the proline-rich portion binds to the src homology domains ofthe src protein family. In addition to controlling isotypic switching, the Btk gene controls other critical functions such as light chain VDJ rearrangements and differentiation of B cells.
The second patient group has reduced numbers of B cells and defects in the synthesis of IgG and IgM. These patients present with granulomatous disease resembling sarcoid. Granulomata may be found in the spleen, lymph nodes, lungs, skin, and brain. The histology is characteristic ofnoncaseating epithelial granuloma (Spickett et al., 1990).
A third group of patients are categorized as hyper-lgM (HIM). Subjects have recurrent upper and lower respiratory infection, otitis, diarrhea, and ulcers. Patients do not respond to normal vaccines (Notarangelo et al., 1992). From a mechanistic perspective, HIM results from mutations in the CD40L (gp39) that preclude interactions with CD40.
B cells from these patients do not produce either IgG or IgA. IgM can be produced in vitro but not in vivo. Because only IgM can be produced, there are recurrent upper respiratory infections and infections with opportunistic pathogens such as Cryptosporidium or Pneumocystis carinii. Moreover, some IgMs are autoantibodies reacting with host red cells, leukocytes, and platelets. The destruction of these blood cells leads to secondary immunodeficiencies and reduced resistance to infections (Fischer and Arnaiz-Villena, 1995).
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