- Nonoyama S,
- Tsukada S,
- Yamadori T,
- et al.
Purpose of the Study
X-linked agammaglobulinemia (XLA) is classically described as a pure humoral immunodeficiency in which boys fail to produce mature B cells and as a consequence, make no immunoglobulin. With the advent of genetic testing for this disorder, it has become clear that there are boys with XLA who have small numbers of peripheral blood B cells and small amounts of antibody. This study evaluated the function of the peripheral blood B cells in boys with XLA.
Five of 9 patients with XLA had detectable peripheral blood B cells. Four of the 5 patients had missense mutations of Btk identified. In the fifth patient, absence of Btk protein was demonstrated by Western blot.
B cell function was evaluated using CD40 crosslinking and interleukin (IL)-4 stimulation. Proliferation, immunoglobulin E (IgE) production, and upregulation of CD23 were measured. In addition, patients were immunized to øX174.
Proliferation, CD23 expression, and IgE production were all normal in the B cell cultures from XLA patients. Although antibody titers after immunization were not normal, XLA patients were capable of responding to the immunization and demonstrated an enhanced response after a secondary immunization suggesting immunologic memory is intact. Significantly, the patients did not undergo isotype switching to IgG on secondary immunization.
CD40-mediated B cell function in XLA patients appears to be relatively normal. The authors suggest that this bypass strategy could be used as a potential therapy for XLA.
The function of Btk is incompletely understood. Analysis has been complicated by the fact that murine models of XLA exhibit significant differences from the human disease. This study demonstrates that B cells from patients with Btk mutations are not intrinsically dysfunctional. This implies that Btk may be important in B cell maturation but is dispensible for some functions after maturation. This study also implies that there is a Btk bypass pathway that allows some B cells to mature. Using a Btk bypass therapeutic strategy would have significant theoretical risks but is certainly an approach worth consideration.