The expression of long HCDR3 intervals is constrained by both genetic and somatic mechanisms during human B-cell ontogeny

Due to the greater range of lengths available to the third complementarity determining region of the H chain (HCDR3), the human antibody repertoire includes larger antigen binding site structures than those seen in first and second trimester fetal tissues. Transition to a steady state range of HCDR3 lengths is not complete until the infant reaches two months of age. Fetal constraints on length result from a genetic predilection for use of short DH and JH gene segments, and from DH-specific limitations in N addition. Superimposed upon these genetic mechanisms is a process of somatic selection that appears to ensure expression of a restricted range of HCDR3 lengths. A similar selection for a restricted range of HCDR3 intervals occurs in the neonatal mouse. Human cells expressing antibodies with "inappropriate" lengths appear to be eliminated when they first express IgM on their cell surface. Modeling studies suggest that increasing the length of HCDR3 creates "knob-like" antigen binding site structures not seen in the mouse. In human, the restriction in the range of HCDR3 lengths serves as a marker for an immature antibody repertoire and may contribute to the immunodeficiency state of the neonate.