The Human Antibody Repertoire

The human antibody naïve repertoire is formed by the combinatorial assembly of heavy and light chains from a number of gene segments. For each heavy chain a complete sequence derives from selection and joining together (with imprecision) of one each from a number of different germline VH, DH, and JH sequences. A similar process occurs during light chain assembly involving two gene sequences, a VL and JL sequence both of which can be either a kappa or lambda type. Estimates of the theoretical number of antibody sequences based on all possible combinatorial sequence assemblies have been in the range of 1015 to 1018 different antibody sequences for the naïve repertoire. Clearly these numbers cannot be made by an individual never mind sampled (there are only 1013 cells in the human body of all types). However, its proposed existence has become an idée fixe on the actual repertoire size without consideration of the evolutionary cost of such a largely inaccessible repertoire, or its practical use. Given that the observed numbers of B cells in the naïve repertoire is in the range 107-109, an astronomical difference from the theoretical calculations, serious questions arise about whether the combinatorial process is genetically regulated, whether the repertoire has extensive sequence redundancy, or perhaps whether a small naïve repertoire followed by an efficient hypermutation and selection process is sufficient to cover all antigen space.

Recent works suggested that the repertoire may be ‘sequence redundant’ whereby many different sequences may have the same or highly similar structural features that are key to determining the antibody specificity. Again, the assumption in the theoretical calculations is that each gene segment and/or combination of gene segments, has an equal probability of being represented in the repertoire, that is there is no regulatory preference at work during the selection process. The presence of ‘public clonotypes’ in the responses to pathogens from widely different geographical and racial groups supports the notion of redundancy but more work needs to be done to determine if sequence redundancy can bridge the theoretical and practical repertoire gap.

hoped will attempt to uncover how the naïve antibody repertoire is actually built, how diverse it is from the perspective of antigen recognition not simply on the basis of sequence variation but by examining paratope structural commonality among different sequences, and what if any regulatory/selection mechanisms may be at work to condense the actual repertoire into a manageable and useful immunity defense system.

We are interested in Original Research, Review, and Mini Review articles, focusing on B cell repertoires, but not limited to the following areas:

- B-cell repertoire theory: how large is large enough?
- Germ line gene usage: is it random?
- Novel approaches and strategies applied to study B-cell receptor repertoires;
- B-cell receptor repertoire sequencing analysis to gain insights into the adaptive immune response in healthy/non-healthy individuals;
- How common is repertoire sequence redundancy in relation to paratope structure; methods of analysis?
- Repertoire ‘holes’ and their consequences for immunity
- Lessons from the mouse repertoire

Keywords: antibodies repertoire, immune system, B-cell repertoire, B-cells, The antigen receptor repertoires of B-cells, antigen receptor repertoire, antibodies, immunoglobulin germline genes

Important Note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.