X-Linked Agammaglobulinemia of Bruton
X-linked agammaglobulinemia is one of the more common forms of primary immunodeficiency. It is characterized by the failure of B-cell precursors (pro-B cells and pre-B cells) to
mature into B cells. During normal B-cell maturation in the bone marrow, the immunoglobulin heavy-chain genes are rearranged first, followed by rearrangement of the light chain genes.
In X-linked agammaglobulinemia, B-cell maturation stops after the rearrangement of heavy chain genes. Because light chains are not produced, the complete immunoglobulin molecule
(which contains heavy and light chains) cannot be assembled and transported to the cell membrane. Free heavy chains can be found in the cytoplasm. This block in differentiation is due to
mutations in a cytoplasmic tyrosine kinase, called B-cell tyrosine kinase (Btk). Btk is a protein tyrosine kinase associated with the antigen receptor complex of pre-B and mature B cells.
It is needed to transduce signals from the antigen receptor that are critical for driving maturation. When it is mutated, the pre-B cell receptor cannot deliver signals, and maturation stops at
this stage. The BTK gene maps to the long arm of the X chromosome at Xq21.22.
Figure 6-42Scheme of lymphocyte development and sites of block in primary immunodeficiency diseases. The affected genes are indicated in parentheses for some of the disorders. ADA,
adenosine deaminase; CD40L, CD40 ligand; SCID, severe combined immunodeficiency.
Figure 6-43Schematic illustration of an HIV-1 virion. The viral particle is covered by a lipid bilayer that is derived from the host cell.
Figure 6-44HIV proviral genome. Several viral genes and their corresponding functions are illustrated. The genes outlined in red are unique to HIV; others are shared by all retroviruses.
Figure 6-45Pathogenesis of HIV-1 infection. Initially, HIV-1 infects T cells and macrophages directly or is carried to these cells by Langerhans cells. Viral replication in the regional
lymph nodes leads to viremia and widespread seeding of lymphoid tissue. The viremia is controlled by the host immune response (not shown), and the patient then enters a phase of clinical
latency. During this phase, viral replication in both T cells and macrophages continues unabated, but there is some immune containment of virus (not illustrated). There continues a gradual
erosion of CD4+ cells by productive infection (or other mechanisms, not shown). Ultimately, CD4+ cell numbers decline, and the patient develops clinical symptoms of full-blown AIDS.
Macrophages are also parasitized by the virus early; they are not lysed by HIV-1, and they may transport the virus to tissues, particularly the brain.
Figure 6-46Mechanism of HIV entry into host cells. Interactions with CD4 and CCR5 coreceptor are illustrated. (Adapted with permission from Wain-Hobson S: HIV. One on one meets
two. Nature 384:117, 1996. Copyright 1996, Macmillam Magazines Limited.)
Figure 6-47The life cycle of HIV. The steps from viral entry to production of infectious virions are illustrated.
Figure 6-48Mechanisms of CD4 cell loss in HIV infection.
Figure 6-49HIV infection showing the formation of giant cells in the brain. (Courtesy of Dr. Dennis Burns, Department of Pathology, University of Texas Southwestern Medical School,
TABLE 6-12-- Major Abnormalities of Immune Function in AIDS
Predominantly due to selective loss of the CD4+ helper-inducer T-cell subset; inversion of CD4:CD8 ratio
Date: 2016-04-22; view: 492