The disease usually does not become apparent until about 6 months of age, as maternal antibodies that were transported via the placenta are depleted. In most cases, recurrent bacterial infections of the respiratory tract, such as acute and chronic pharyngitis, sinusitis, otitis media, bronchitis, and pneumonia, call attention to the underlying immune defect. Almost always, the causative organisms are Haemophilus influenzae, Streptococcus pneumoniae, or Staphylococcus aureus, organisms that are normally opsonized by antibodies and cleared by phagocytosis. Because antibodies are important for neutralizing certain infectious viruses, individuals with this disease also are susceptible to some viral infections, especially those caused by enteroviruses. These viruses infect the gastrointestinal tract, and from there they can disseminate to the nervous system via the blood. Thus, immunization with live poliovirus carries the risk for paralytic poliomyelitis, and infections with echovirus can cause fatal encephalitis. For similar reasons, Giardia lamblia, an intestinal protozoan that is normally resisted by secreted IgA, causes persistent infections in individuals with this disorder. Many intracellular viral, fungal, and protozoal infections are handled quite well by the intact T cell–mediated immunity. For unclear reasons, autoimmune diseases (such as rheumatoid arthritis and dermatomyositis) occur in as many as 35% of patients with this disease.
The treatment of X-linked agammaglobulinemia is replacement therapy with intravenous immunoglobulin (IVIG) from pooled human serum.
DiGeorge syndrome is caused by a congenital defect in thymic development resulting in deficient T-cell maturation. T cells are absent in the lymph nodes, spleen, and peripheral blood, and infants with this defect are extremely vulnerable to viral, fungal, and protozoal infections. Patients also are susceptible to infection with intracellular bacteria, because of defective T cell–mediated immunity. B cells and serum immunoglobulins are generally unaffected.
The disorder is a consequence of a developmental malformation affecting the third and fourth pharyngeal pouches, structures that give rise to the thymus, parathyroid glands, and portions of the face and aortic arch. Thus, in addition to the thymic and T-cell defects, there may be parathyroid gland hypoplasia, resulting in hypocalcemic tetany, as well as additional midline developmental abnormalities. In 90% of cases of DiGeorge syndrome, there is a deletion affecting chromosomal region 22q11, discussed in Chapter 7. Transplantation of thymic tissue has successfully treated some affected infants. In patients with partial defects, immunity may improve spontaneously with age.
This disease is characterized by the production of normal (or even supranormal) levels of IgM antibodies and decreased levels of the IgG, IgA, and IgE isotypes; the underlying defect is an inability of T cells to activate B cells. As discussed earlier, many of the functions of CD4+ helper T cells require the engagement of CD40 on B cells, macrophages, and dendritic cells by CD40L (also called CD154) expressed on antigen-activated T cells. This interaction triggers Ig class switching and affinity maturation in the B cells, and stimulates the microbicidal functions of macrophages. Approximately 70% of individuals with hyper-IgM syndrome have the X-linked form of the disease, caused by mutations in the gene encoding CD40L located on Xq26. In the remaining patients, the disease is inherited in an autosomal recessive pattern caused by loss-offunction mutations involving either CD40 or an enzyme called activation-induced cytidine deaminase (AID), a DNA-editing enzyme that is required for Ig class switching and affinity maturation.