Impaired antibody affinity maturation process characterizes a subset of patients with common variable immunodeficiency

Common variable immunodeficiency (CVID) is an heterogeneous syndrome charac terized by decreased levels of serum Ig and recurrent bacterial infection. Here, we were interested to study whether a qualitative defect of the affin ity Ab maturation process could be combined to the low level of serum Ig in a cohort of 38 CVID patients. For this, we designed a novel and rapid scre ening test for the detection of hypomutated V gene expressed by memory B ce lls, This test delineated a subset of 9/38 (23%) CVID patients with an abno rmal pattern of Ig V gene mutation. The mean frequency of V gene mutation o f this subset was significantly lower (1.74%) compared with other CVID pati ents (5.46%) and normal donors (6.5%) (p < 0.0001). The mean age of this su bgroup was significantly higher than other hypogammaglobulinemic patients w ith normal levels of V gene mutation (p < 0.02), whereas no difference in t he duration of symptoms was noted between the two groups. This suggests tha t hypomutation characterizes patients who began CVID late in life. Recently , it was shown that non-Ig sequences, such as the intronic BCL-6 gene, coul d be the target of the somatic hypermutation process in normal memory B cel ls. Our finding of a normal mutation frequency of the BCL-6 gene in two hyp omutated CVID point to a defect of the Ig targeting of hypermutation machin ery in these cases.