in X-linked agammaglobulinemia (Xla), a protein tyrosine kinase of the tec family called BtK, which is encoded on the X chromosome, is defective. in normal individuals, B-cell development proceeds through a stage in which the pre-B-cell receptor, consisting of μλ5:VpreB (see Section 8-3), transduces a signal via BtK, triggering further B-cell development. in males with Xla, no signal can be transduced and, although the pre-B-cell receptor is expressed, the B cells develop no further. in female mammals, including humans, one of the two X chromosomes in each cell is permanently inactivated early in development. Because the choice of which chromosome to inactivate is random, half of the pre-B cells in a carrier female will have inactivated the chromosome with the wild-type BTK gene, meaning that they can express only the defective BTK gene and cannot develop further. therefore, in the carrier, mature B cells always have the nondefective X chromosome active. this is in sharp contrast to all other cell types, which have the nondefective X chromosome active in only half of their cells. nonrandom X-chromosome inactivation in a particular cell lineage is a clear indication that the product of the X-linked gene is required for the development of cells of that lineage. it is also sometimes possible to identify the stage at which the gene product is required, by detecting the point in development at which X-chromosome inactivation develops bias. using this kind of analysis, one can identify carriers of X-linked traits such as Xla without needing to know the nature of the mutant gene.
Fig. 13.5 Defects in T-cell and B-cell activation and differentiation cause immunodeficiencies. the pathways leading to activation and differentiation of naive t cells and B cells are shown here. the protein products of genes known to be mutated in the relevant human immunodeficiency diseases are indicated in red boxes. BCR, B-cell receptor; CViDs, common variable immunodeficiencies; tCR, t-cell receptor. note that the defect in cytoskeletal function in Wiskott–aldrich syndrome (WaS) affects immune-cell function at many steps in this schema, and is not included in the figure for the sake of clarity.
Fig. 13.6 Patients with CD40 ligand deficiency are unable to activate their B cells fully. lymphoid tissues in patients with CD40 ligand deficiency, which manifests as a hyper-igM syndrome, are devoid of germinal centers (top panel), unlike a normal lymph node (bottom panel). B-cell activation by t cells is required both for isotype switching and for the formation of germinal centers, where extensive B-cell proliferation takes place. Photographs courtesy of R. Geha and a. Perez-atayde.
TCRCD4 activated CD4 T cell mature B cell plasma cells AID, UNG, TACI, CD19, ICOS resting macrophage activated macrophage lgA lgE lgG IL-12, intracellular killing CD40L, NEMO CD40 mutated genes not known BCR IgD B-cell intrinsic hyper-IgM syndromes or CVIDs IgA defciency X-linked hyper-IgM syndromes hyper-IgM syndromes