The histologic findings in SCID depend on the underlying defect. In the two most common forms (γc mutation and ADA deficiency), the thymus is small and devoid of lymphoid cells. In X-linked SCID, the thymus contains lobules of undifferentiated epithelial cells resembling fetal thymus, whereas in SCID caused by ADA deficiency, remnants of Hassall’s corpuscles can be found. In both diseases, other lymphoid tissues are hypoplastic as well, with marked depletion of T cell areas and in some cases both T cell and B cell zones.
Currently, HSC transplantation is the mainstay of treatment. X-linked SCID is the first disease in which gene therapy has been successful. For gene therapy, a normal γc gene is expressed using a viral vector in HSCs taken from patients, and the cells are then transplanted back into the patients. The clinical experience is small, but some patients have shown reconstitution of their immune systems for several years after therapy. Unfortunately, however, about 20% of patients receiving a first-generation viral vector developed T cell acute lymphoblastic leukemia (T-ALL), highlighting the dangers of this particular approach to gene therapy. The uncontrolled T-cell proliferation is likely the result of the virus integrating into the genome close to an oncogene, leading to the activation of the oncogene, and possibly also because of the growth advantage conferred by the introduced normal γc gene. Current trials are using new vectors with safety features built in. Patients with ADA deficiency also have been treated with HSC transplantation and, more recently, with administration of the enzyme or gene therapy involving the introduction of a normal ADA gene into T-cell precursors.
X-linked agammaglobulinemia (XLA), or Bruton disease, is characterized by the failure of pre–B cells to differentiate into mature B cells and, as the name implies, a resultant absence of antibodies (gamma globulin) in the blood.
It is one of the more common forms of primary immunodeficiency, occurring at a frequency of about 1 in 100,000 male infants. During normal B-cell maturation, immunoglobulin (Ig) heavy chain genes are rearranged first, followed by light chain genes. At each stage, signals are received from the expressed components of the antigen receptor that drive maturation to the next stage; these signals act as quality controls, to ensure that the correct receptor proteins are being produced. In XLA, B-cell maturation stops after the initial heavy chain gene rearrangement because of mutations in a tyrosine kinase that is associated with the pre–B-cell receptor and is involved in pre-B-cell signal transduction. This kinase is called Bruton tyrosine kinase (BTK). When BTK is nonfunctional, the pre– B-cell receptor cannot signal the cells to proceed along the maturation pathway. As a result, Ig light chains are not produced, and the complete Ig molecule containing heavy and light chains cannot be assembled and transported to the cell membrane, although free heavy chains can be found in the cytoplasm. Because the BTK gene is on the X chromosome, the disorder is only seen in males. Sporadic cases with the same features have been described in females, possibly due to mutations in other genes that function in the same pathway.
Classically, the disease is characterized by a profound reduction in the number of B cells in the blood and secondary lymphoid organs and an absence of germinal centers and plasma cells in these organs. T-cell numbers and responses may be normal.