Shaping of Human Germline IgH Repertoires Revealed by Deep Sequencing

Department of Immunology, University of Washington, Seattle, WA 98195
The Journal of Immunology (Impact Factor: 4.92). 08/2012; 189(6):3221-30. DOI: 10.4049/jimmunol.1201303
Source: PubMed


To understand better how selection processes balance the benefits of Ig repertoire diversity with the risks of autoreactivity and nonfunctionality of highly variable IgH CDR3s, we collected millions of rearranged germline IgH CDR3 sequences by deep sequencing of DNA from mature human naive B cells purified from four individuals and analyzed the data with computational methods. Long HCDR3 regions, often components of HIV-neutralizing Abs, appear to derive not only from incorporation of long D genes and insertion of large N regions but also by usage of multiple D gene segments in tandem. However, comparison of productive and out-of-frame IgH rearrangements revealed a selection bias against long HCDR3 loops, suggesting these may be disproportionately either poorly functional or autoreactive. Our data suggest that developmental selection removes HCDR3 loops containing patches of hydrophobicity, which are commonly found in some auto-antibodies, and at least 69% of the initial productive IgH rearrangements are removed from the repertoire during B cell development. Additionally, we have demonstrated the potential utility of this new technology for vaccine development with the identification in all four individuals of related candidate germline IgH precursors of the HIV-neutralizing Ab 4E10.

Download full-text


Available from: Kevin Larimore, Jan 08, 2014
  • Source
    • "The great variability of antibody repertoire in a single individual and among different subjects is in all cases based on the use of a definite number of chromosomally encoded genes, known as antibody germlines [1]. As a result, the antigen-specific somatic hypermutation of only few germline genes allows the production of a virtually infinite number of different immunoglobulins [2] [3] [4]. This is particularly evident in cases when different individuals produce different immunoglobulins against the same pathogen, but all originating from a single antibody germline gene. "
    [Show abstract] [Hide abstract]
    ABSTRACT: It is known that even the adaptive components of the immune system are based on genetic traits common to all individuals, and that diversity is shaped by the lifelong contacts with different non-self antigens, including those found on infectious pathogens. Besides the individual differences, some of these common traits may be more prone to react against a given antigen, and this may be exploited by the infectious pathogens. Indeed, viral infections can deregulate immune response by subverting antibody (Ab) gene usage, leading to the overexpression of specific Ab subfamilies. This overexpression often results in a protective antiviral response but, in some cases, also correlates with a higher likelihood of developing humoral autoimmune disorders. These aspects of virus-induced autoimmunity have never been thoroughly reviewed, and this is the main purpose of this review. An accurate examination of virus specific Ab subfamilies elicited during infections may help further characterize the complex interplay between viruses and the humoral immune response, and be useful in the design of future monoclonal antibody (mAb)-based anti-infective prophylactic and therapeutic strategies. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Full-text · Article · Apr 2015 · Seminars in Immunology
  • Source
    • "Surprisingly, we find that simple competition between receptor clones can drive the population to the optimal composition for minimizing the cost of infections. New high throughput methods are making it possible to survey B-cell and T-cell receptor diversity in fish [3] [4], in mice [2] [5] and humans [6] [7] [8] [9]. As methods are developed to better characterize pathogenic landscapes and receptor cross-reactivity, predictions for the composition of optimal repertoires derived from our framework can be directly compared with experiments. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The repertoire of lymphocyte receptors in the adaptive immune system protects organisms from diverse pathogens. A well-adapted repertoire should be tuned to the pathogenic environment to reduce the cost of infections. We develop a general framework for predicting the optimal repertoire that minimizes the cost of infections contracted from a given distribution of pathogens. The theory predicts that the immune system will have more receptors for rare antigens than expected from the frequency of encounters; individuals exposed to the same infections will have sparse repertoires that are largely different, but nevertheless exploit cross-reactivity to provide the same coverage of antigens; and the optimal repertoires can be reached via the dynamics of competitive binding of antigens by receptors, and selective amplification of stimulated receptors. Our results follow from a tension between the statistics of pathogen detection, which favor a broader receptor distribution, and the effects of cross-reactivity, which tend to concentrate the optimal repertoire onto a few highly abundant clones. Our predictions can be tested in high throughput surveys of receptor and pathogen diversity.
    Full-text · Article · Jul 2014 · Proceedings of the National Academy of Sciences
  • Source
    • "It is now confirmed that even though it violates the 12/23 rule, direct joining of one D gene segment to another can occur in most species. In human B cells, D-D fusions are found in approximately 5% of genes that encode antibodies and are the major mechanism accounting for the unusually long CDR3 loops in heavy chains (Larimore et al., 2012; Meek et al., 1989; Murphy et al., 2007). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The characterization of the human T-cell receptor (TCR) repertoire has made remarkable progress, with most of the work focusing on the TCRβ chains. Here, we analyzed the diversity and complexity of both the TCRα and TCRβ repertoires of three healthy donors. We found that the diversity of the TCRα repertoire is higher than that of the TCRβ repertoire, whereas the usages of the V and J genes tended to be preferential with similar TRAV and TRAJ patterns in all three donors. The V-J pairings, like the V and J gene usages, were slightly preferential. We also found that the TRDV1 gene rearranges with the majority of TRAJ genes, suggesting that TRDV1 is a shared TRAV/DV gene (TRAV42/DV1). Moreover, we uncovered the presence of tandem TRBD (TRB D gene) usage in ~2% of the productive human TCRβ CDR3 sequences. Electronic supplementary material The online version of this article (doi:10.1007/s13238-014-0060-1) contains supplementary material, which is available to authorized users.
    Full-text · Article · May 2014 · Protein & Cell
Show more