During embryonic development, females randomly inactivate one of their two X chromosomes. Because BTK is required for Blymphocyte development, only cells in which the normal allele of BTK is active develop into mature B cells. Thus, in all B cells in female carriers of a mutant BTK gene, the active X chromosome is the normal one and the abnormal X chromosome is inactivated. This fact allowed female carriers of XLA to be identified even before the nature of the BTK protein was known. In contrast, the active X chromosomes in the T cells and macrophages of carriers are an equal mixture of normal and BTK mutant X chromosomes. Nonrandom Xinactivation only in B cells shows conclusively that the BTK gene is required for the development of B cells but not the other cell types, and that BTK must act in the B cells themselves rather than in stromal or other cells required for Bcell development (Fig. 13.4).
Autosomal recessive deficiencies in other components of the preBCR also block early Bcell development and cause severe Bcell deficiency and congenital agammaglobulinemia similar to that of XLA. These disorders are much rarer than XLA, and include mutations in the genes that encode the μ heavy chain (IGHM), which is the second most common cause of agammaglobulinemia; λ5 (IGLL1); and Igα (CD79A) and Igβ (CD79B) (see Fig. 13.2). Mutations that cripple the Bcell receptor signaling adaptor, Bcell linker protein (encoded by BLNK), also cause the arrest of early Bcell development that results in selective Bcell deficiency.
Patients with pure Bcell defects resist many pathogens other than pyogenic bacteria. Fortunately, the latter can be suppressed with antibiotics and with monthly infusions of human immunoglobulin collected from a large pool of donors. Because there are antibodies against many common pathogens in this pooled immunoglobulin, it serves as a fairly successful shield against infection.
T-cell activation and function that lead to abnormal antibody responses.
After their development in the bone marrow or thymus, B and T cells require antigendriven activation and differentiation to mount effective immune responses. Analogous to defects in early Tcell development, defects in Tcell activation and differentiation that occur after thymic selection have an impact on both cellmediated immunity and antibody responses (Fig. 13.5). Defects specific to the activation and differentiation of B cells can impair their ability to undergo class switching to IgG, IgA, and IgE while leaving cellmediated immunity largely intact. Depending on where in the process of T or Bcell differentiation these defects occur, the characteristics of the immune deficiency that results can be either profound or relatively circumscribed.
A common feature of patients with defects that affect Bcell class switching is hyperIgM syndrome (see Fig. 13.5). These patients have normal Band Tcell development and normal or high serum levels of IgM, but make very limited antibody responses against antigens that require Tcell help. Thus immunoglobulin isotypes other than IgM and IgD are produced only in trace amounts. This renders these patients highly susceptible to infection with extracellular pathogens. Several causes for hyperIgM syndromes have been distinguished, and these have helped to elucidate the pathways that are essential for normal classswitch recombination and somatic hypermutation in B cells. Defects have been found in both Tcell helper function and in the B cells themselves.