Many rare cases of lymphocyte activation defects have been described that affect antigen receptor signaling and various biochemical pathways. Defects in TH1 responses are associated with atypical mycobacterial infections, and defective TH17 responses are the cause of chronic mucocutaneous candidiasis as well as bacterial infections of the skin (a disorder called Job syndrome).
In some inherited systemic disorders, immune deficiency is a prominent clinical problem. Two representative examples of such diseases are described next.
Wiskott-Aldrich syndrome is an X-linked disease characterized by thrombocytopenia, eczema, and a marked vulnerability to recurrent infection that results in early death. The thymus is normal, at least early in the disease course, but there is progressive loss of T lymphocytes from the blood and the T cell zones (paracortical areas) of lymph nodes, with variable defects in cellular immunity. Patients do not make antibodies to polysaccharide antigens, and the response to protein antigens is poor. IgM levels in the serum are low, but levels of IgG are usually normal and, paradoxically, IgA and IgE are often elevated. The syndrome is caused by mutations in an X-linked gene encoding Wiskott-Aldrich syndrome protein (WASP). WASP belongs to a family of signaling proteins that link membrane receptors, such as antigen receptors, to cytoskeletal elements. The WASP protein is involved in cytoskeleton-dependent responses, including cell migration and signal transduction, but how this contributes to the functions of lymphocytes and platelets is unclear. The only treatment is HSC transplantation.
Ataxia telangiectasia is an autosomal-recessive disorder characterized by abnormal gait (ataxia), vascular malformations (telangiectases), neurologic deficits, increased incidence of tumors, and immunodeficiency. The immunologic defects are of variable severity and may affect both B cells and T cells. The most prominent humoral immune abnormalities are defective production of isotype-switched antibodies, mainly IgA and IgG2. The T-cell defects are usually less pronounced, and may be associated with thymic hypoplasia. Patients experience upper and lower respiratory tract bacterial infections, multiple autoimmune phenomena, and increasingly frequent cancers, particularly lymphoid tumors, with advancing age. The gene responsible for this disorder encodes a protein called ATM (ataxia telangiectasia mutated), a sensor of DNA damage that activates cell cycle checkpoints and apoptosis in cells with damaged DNA. Lack of ATM also leads to abnormalities in antigen gene recombination (and therefore defects in the generation of antigen receptors) and abnormal antibody isotype switching.
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Inherited defects in the early innate immune response typically affect leukocyte functions or the complement system and lead to increased vulnerability to infections ( 5.13 ). Some defects whose molecular bases are defined are summarized next.
Leukocyte adhesion deficiencies (LADs) stem from inherited defects in adhesion molecules that impair leukocyte recruitment to sites of infection, resulting in recurrent bacterial infections. LAD1 is caused by defects in the β2 chain that is shared by the integrins LFA-1 and Mac-1, while LAD2 is caused by a defect in a fucosyl transferase that is required to synthesize functional sialyl-Lewis X, the ligand for Eand P-selectins.
Chronic granulomatous disease results from inherited defects in the genes encoding components of phagocyte oxidase, the phagolysosomal enzyme that generates ROS such as superoxide (O2 • ), resulting in defective bacterial killing and susceptibility to recurrent bacterial infection. The name of this disease comes from the macrophage-rich chronic inflammatory reaction that