The first description of an immunodeficiency disease was Ogden C. Bruton’s account, in 1952, of the failure of a male child to produce antibody. Because inheritance of this condition is Xlinked and is characterized by the absence of immunoglobulin in the serum (agammaglobulinemia), it was called Bruton’s Xlinked agammaglobulinemia (XLA) (see Fig. 13.2). Since then, autosomal recessive variants of agammaglobulinemia have been described. Infants with these diseases are usually identified as a result of recurrent infections with pyogenic bacteria, such as Streptococcus pneumoniae, and enteroviruses. In this regard, it should be noted that normal infants have a transient deficiency in immunoglobulin production in the first 3–12 months of life. The newborn infant has antibody levels comparable to those of the mother because of the transplacental transport of maternal IgG (see Section 1017). As this IgG is catabolized, antibody levels gradually decrease until the infant begins to produce significant amounts of its own IgG at about 6 months (Fig. 13.3). Thus, IgG levels are quite low between the ages of 3 months and 1 year. This can lead to a period of heightened susceptibility to infection, especially in premature babies, who begin with lower levels of maternal IgG and also reach immune competence later after birth. Because of the transient protection afforded
Fig. 13.3 Immunoglobulin levels in newborn infants fall to low levels at about 6 months of age. Babies are born with high levels of maternal igG, which is actively transported across the placenta from the mother during gestation. after birth, the production of igM starts almost immediately; the production of igG, however, does not begin for about 6 months, during which time the total level of igG falls as the maternally acquired igG is catabolized. thus, igG levels are low from about the age of 3 months to 1 year, which can lead to susceptibility to disease.
newborn infants by maternal antibodies, XLA is typically detected several months after birth, when maternal antibody levels in the infant have declined.
The defective gene in XLA encodes a protein tyrosine kinase called BTK (Bruton’s tyrosine kinase), which is a member of the Tec family of kinases that transduce signals through the preBcell receptor (preBCR; see Section 720). As discussed in Section 83, the preBcell receptor is composed of successfully rearranged μ heavy chains complexed with the surrogate light chain composed of λ5 and VpreB, and with the signaltransducing subunits Igα and Igβ. Stimulation of the preBcellreceptor recruits cytoplasmic proteins, including BTK, which convey signals required for the proliferation and differentiation of preB cells. In the absence of BTK function, Bcell maturation is largely arrested at the preBcell stage (see Fig. 13.2; see also Section 83), resulting in profound Bcell deficiency and agammaglobulinemia. Some B cells do mature, however, perhaps as a result of compensation by other Tec kinases.