Understanding the human antibody repertoire

Abstract

The origins of the various elements in the human antibody repertoire have been and still are subject to considerable uncertainty. Uncertainty in respect of whether the various elements have always served a specific defense function or whether they were co-opted from other organismal roles to form a crude naïve repertoire that then became more complex as combinatorial mechanisms were added. Estimates of the current size of the human antibody naïve repertoire are also widely debated with numbers anywhere from 10 million members, based on experimentally derived numbers, to in excess of one thousand trillion members or more, based on the different sequences derived from theoretical combinatorial calculations. There are questions that are relevant at both ends of this number spectrum. At the lower bound it could be questioned whether this is an insufficient repertoire size to counter all the potential antigen-bearing pathogens. At the upper bound the question is rather simpler: How can any individual interrogate such an astronomical number of antibody-bearing B cells in a timeframe that is meaningful? This review evaluates the evolutionary aspects of the adaptive immune system, the calculations that lead to the large repertoire estimates, some of the experimental evidence pointing to a more restricted repertoire whose variation appears to derive from convergent 'structure and specificity features', and includes a theoretical model that seems to support it. Finally, a solution that may reconcile the size difference anomaly, which is still a hot subject of debate, is suggested.

Keywords: Antibody repertoire; adaptive immunity; infinite repertoire theorem; naïve repertoire; variable region assembly.

Figure 1.

Cartoons of the combinatorial assembly process by which heavy-chain variable domains (Figure 1(a)) and light chain variable domains (Figure1(b)) are assembled in the B-cell. The relationship between the framework regions and the CDRs is shown in Figure 1(c). Figure 1(a,c) is adapted from Figure 5 in reference 4.

Figure 2.

The molecular surface of neuraminidase showing elements of the interacting surfaces in the x-ray structures of its complex with antibody NC10 (pdb: 1NMB) and antibody NC41 (pdb: 1NCA). The epitope residues on neuraminidase common to the binding of antibodies NC10 and NC41 are shown in purple while those epitope residues only bound in NC10 are in red and for NC41 in cyan. The enzyme active site is shown in green. Reconstructed from Figure 5 in reference 58 using Adobe Illustrator.

Figure 3.

The epitopes (top) and paratopes (bottom) from the crystal structures of the two VHH-HEWL (hen-egg lysozyme) complexes, D2-L19, and cAb.Lys2. The contacting regions (within 5 Å of the other protein in the complex) are colored blue. The amino acid Thr47 in the light chain is labeled and colored red and its binding pocket within the paratope is indicated with an arrow. Reproduced from Figure 1(c) in reference 59 with permission from CCC Market Place. The original figure was kindly supplied by the authors.

Figure 4.

A surface epitope region (red) consisting of 12 different amino acids selected from the exposed surface of the protein, PCSK9 (PDB: 2PMW). An outline of each residue side-chain is indicated by a yellow circle or oval. The epitope region is used to calculate the combinations of each unique residue set from 1 to 12 residues that could be addressed by different antibodies. The surface region is redrawn from the PDB structure (2PMW; reference 75) using Adobe Illustrator See text for explanation.