agammaglobulinemia is a genetically determined immunodeficiency disease characterized by the inability to synthesize all classes of antibody. It was discovered in 1952 by O. C. Bruton in what is still regarded as an outstanding example of research in clinical immunology. Bruton's investigation involved a young boy who had mumps 3 times and experienced 19 different episodes of serious bacterial infections during a period ofjust over 4 years. Because pneumococcus bacteria were isolated from the child's blood during
10 of the episodes of bacterial infection, attempts were made to induce immunity to pneumococcus by immunization with pneumococcus vaccine. The failure of these efforts to induce antibody responses prompted Bruton to determine whether the patient could mount antibody responses when challenged with other antigens. Surprisingly, immunization with diphtheria and typhoid vaccine preparations did not raise humoral responses in this patient. Electrophoretic analysis of the patient's serum revealed that although normal amounts of albumin and other typical serum proteins were present, gamma globulin, the major antibody fraction of serum, was absent. Having traced the immunodeficiency to a lack of antibody, Bruton tried a bold new treatment. He administered monthly doses of human immune serum globulin. The patient's experience of a fourteen-month period free of bacterial sepsis established the usefulness of the immunoglobulin replacement for the treatment of immunodeficiency.
Though initially called Bruton's agammaglobulinemia, this hereditary immunodeficiency disease was renamed X-linked agammaglobulinemia, or X-LA, after the discovery that the responsible gene lies on the X chromosome. The disease has the following clinical features:
■ Because this defect is X-linked, almost all afflicted individuals are male.
■ Signs of immunodeficiency may appear as early as 9 months after birth, when the supply of
XLyn? Fyn? Others?
XLyn? Fyn? Others?
The B-cell coreceptor is a complex of three cell membrane molecules: TAPA-1 (CD81), CR2 (CD21), and CD19. Binding of the CR2 component to complement-derived C3d that has coated antigen captured by mIg results in the phosphorylation of CD19. The Src-family tyrosine kinase Lyn binds to phosphorylated CD19. The resulting activated Lyn and Fyn can trigger the signal-transduction pathways shown in Figure 11-8 that begin with phospholipase C.
complex serves to amplify the activating signal transmitted through the BCR. In one experimental in vitro system, for example, 104 molecules of mIgM had to be engaged by antigen for B-cell activation to occur when the coreceptor was not involved. But when CD19/CD2/TAPA-1 coreceptor was crosslinked to the BCR, only 102 molecules of mIgM had to be engaged for B-cell activation. Another striking experiment highlights the role played by the B-cell coreceptor. Mice were immunized with either unmodified lysozyme or a hybrid protein in which genetic engineering was used to join hen's egg lysozyme to C3d. The fusion protein bearing 2 or 3 copies of C3d produced anti-lysozyme responses that were 1000 to 10,000 times greater than those to lysozyme alone. Perhaps coreceptor phenomena such as these explain how naive B cells that often express mIg with low affinity for antigen are able to respond to low concentrations of antigen in a primary response. Such responses, even though initially of low affinity, can play a significant role in the ultimate generation of high-affinity antibody. As described later in this chapter, response to an antigen can lead to affinity maturation, resulting in higher average affinity of the B-cell population. Finally, two experimental observations indicate that the CD19 component of the B-cell coreceptor can play a role independent of CR2, the complement receptor. In normal mice, artifically crosslinking the BCR with anti-BCR antibodies results in the maternal antibody acquired in utero has decreased below protective levels.
■ There is a high frequency of infection by Streptococcus pneumoniae and Haemophilus influenzae; bacterial pneumonia, sinusitis, meningitis, or septicemia are often seen in these patients.
■ Although infection by many viruses is no more severe in these patients than in normal individuals, long-term antiviral immunity is usually not induced.
■ Analysis by fluorescence microscopy or flow cytometry shows few or no mature B cells in the blood.
Studies of this disease at the cellular and molecular level provide insights into the workings of the immune system. A scarcity of B cells in the periphery explained the inability of X-LA patients to make antibody. Studies of the cell populations in bone marrow traced the lack of B cells to failures in B-cell development. The samples displayed a ratio of pro-B cells to pre-B cells 10 times normal, suggesting inhibition of the transition from the proto the pre-B-cell stage. The presence of very few mature B cells in the marrow indicated a more profound blockade in the development of B cells from pre-B cells.
In the early 1990s, the gene responsible for X-LA was cloned. The normal counterpart of this gene encodes a protein tyrosine kinase that has been named Bru-ton's tyrosine kinase (Btk) in honor of the resourceful and insightful physician who discovered X-LA and devised a treatment for it. Parallel studies in mice have shown that the absence of Btk causes a syndrome known as xid, an immunodeficiency disease that is essentially identical to its human counterpart, X-LA. Btk has turned out to play important roles in B-cell signaling. For example, crosslinking of the
B-cell receptor results in the phosphoryla-tion of a tyrosine residue in the catalytic domain of Btk. This activates the protein-tyrosine-kinase activity of Btk, which then phosphorylates phospholipase C-72 (PLC-72); in vitro studies of cell cultures in which Btk has been knocked out show compromised PLC-72 activation. Once activated, PLC-72 hydrolyzes membrane phospholipids, liberating the potent second messengers IP3 and DAG. As mentioned earlier, IP3 causes a rise in intracellular Ca2+, and DAG is an activator of protein kinase C (PKC). Thus, Btk plays a pivotal role in activating a network of intracellular signals vital to the function of mature B cells and earlier members of the B-cell lineage. Research has shown that it belongs to a family of PTKs known as Tec kinases; its counterpart in T cells is Itk. The insights gained from studies of X-LA, xid, and Btk are impressive examples of how the study of pathological states can clarify the workings of normal cells.
stimulation of some of the signal-transduction pathways characteristic of B-cell activation. On the other hand, treatment of B cells from mice in which CD19 has been knocked out with anti-BCR antibody fails to induce these pathways. Furthermore, CD19 knockout mice make greatly diminished antibody response to most antigens.
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