CD21^−/lo naive B cells express autoreactive BCRs. (A) A majority of CD21^−/lo B cells from RA and CVID patients express IgM and IgD. Dot plots show IgM and IgD expression gated on CD19⁺CD21⁺(left) and CD19⁺CD21^−/lo (right) CD27-depleted B cells. (B) Most CD21^−/lo naive B cells express autoreactive antibodies. Antibodies cloned from single CD21⁺CD27⁻CD10⁻ and CD21^−/loCD27⁻CD10⁻ B cells from 2 healthy donors (HD10 and 11), 3 RA, and 3 CVID patients were tested by ELISA for reactivity against HEp-2 lysates. Dotted lines show ED38-positive control.²⁴  Horizontal lines show cutoff OD₄₀₅ for positive reactivity. For each B-cell population, the frequency of HEp-2–reactive and non–HEp-2–reactive clones is summarized in pie charts, with the number of antibodies tested indicated in the centers. The frequency of HEp-2–reactive B cells was higher in CD21^−/lo than in CD21⁺ B cells in all persons. (C) CD21^−/lo B cells express highly autoreactive antibodies. The frequency of highly HEp-2–reactive antibodies, arbitrarily defined by ELISA OD₄₀₅ > 2, expressed by CD21⁺ and CD21^−/lo B cells from HD, RA, and CVID patients is represented. A large fraction of CD21^−/lo B cells from most persons was highly HEp-2 reactive. P values calculated using a paired t test are indicated when significant. (D) A majority of highly autoreactive antibodies from CD21^−/lo B cells express kappa light chains. The frequency of highly HEp-2–reactive CD21^−/lo B cells from HD, RA, and CVID patients is represented subdivided among kappa and lambda clones. Many highly HEp-2–reactive CD21^−/lo B cells express kappa light chains, suggesting that receptor editing using lambda light chains was not induced to silence these clones.