Agammaglobulinemia results from the absence or defective function of B cells with subsequent severe decrease in immunoglobulin levels and a total absence of specific antibody. X-linked agammaglobulinemia affects males and is characterized by a profound deficiency of B cells, severe hypogammaglobulinemia, and absence of lymphoid tissue (Table 73-1; see Fig. 73-1). The defect is caused by mutations in a gene encoding the tyrosine kinase Btk on chromosome Xq22 that is involved in a signaling of the pre-B-cell receptor and the B-cell antigen receptor. Autosomal recessive agammaglobulinemiaresults from a variety of defects in the pre-B-cell and B-cell antigen receptor complexes and includes mutations in the μ heavy chain gene, λ5, Igα, Igβ, and BLNK. X-linked agammaglobulinemia is more common than the autosomal recessive forms.
Patients with agammaglobulinemia usually present during the first 6 to 12 months of life as maternally derived antibodies wane, although patients can present years later. These patients develop infections with Streptococcus pneumoniae, Haemophilus influenzae type b, Staphylococcus aureus, and Pseudomonas, organisms for which antibody is an important opsonin. They also have increased susceptibility to giardiasis and enteroviral infections, leading to chronic enteroviral meningoencephalitis and vaccine-associated poliomyelitis (if immunized with oral live, attenuated poliovirus vaccine).
Common variable immunodeficiency (CVID) is a heterogeneous disorder characterized by hypogammaglobulinemia developing after an initial period of normal immune function, most commonly in the second and third decades of life (see Table 73-1). Serum IgG levels are less than 500 mg/dL (usually <300 mg/dL) with IgA levels less than 10 mg/dL and/or low IgM levels. Antibody titers to protein antigens, suchas tetanus and diphtheria, and to polysaccharide antigens,such as pneumococcus, are low or absent. T-cell numbersand function are highly variable, and B-cell numbers can be normal or low. Patients exhibit normal-sized or enlargedtonsils and lymph nodes and may have splenomegaly. Theyare susceptible to frequent respiratory tract infections due to Streptococcus pneumoniae, Haemophilus influenzae type b, and Mycoplasma. Gastrointestinal infections with Giardia, Campylobacter, Salmonella, Helicobacter, and enteroviruses are common. Autoimmune hemolytic anemia and thrombocytopenia occur frequently, and granulomatous diseaseaffecting the gastrointestinal tract, liver, and lungs leadsto significant morbidity. Cancer, especially lymphoma, is amajor cause of mortality.
Common variable immunodeficiency Defects in T cell & B cell development T− B− SCID Defects in T cell activation and function Differentiation Pre–B cell Mature B cellB LYMPHOCYTE LINEAGEIsotype Switching/ Somatic Hypermutation IgA Stem cell T LYMPHOCYTE LINEAGEThymus Mature T cell Effector helper, functions Effector cytotoxic, functions DiGeorge syndrome /MHC deficiency Agammaglobulinemia Defects in T cell development T− B+ SCID PROLIFERATION PROLIFERATION CD8+ CD4+ CD34+ Plasma cells IgG Bone marrow X-linked hyper IgM Hyper IgMSelective Ig isotype deficiencies Memory cell
Figure 73-1 Sites of cellular abnormalities in congenital immunodeficiencies. In primary immunodeficiency diseases, the maturation or activation of B or T lymphocytes may be blocked at different stages.