Specificity and overlap in gene segment-defined antibody repertoires.
BACKGROUND
To date several studies have sought to catalog the full suite of antibodies that humans naturally produce against single antigens or other specificities (repertoire). Here we analyze the properties of all sequenced repertoires in order to better understand the specificity of antibody responses. Specifically, we ask whether the large-scale sequencing of antibody repertoires might provide a diagnostic tool for detecting antigen exposure. We do this by examining the overlap in VH-, D-, and JH- segment usage among sequenced repertoires.


RESULTS
We find that repertoire overlap in VH-, D-, and JH-segment use is least for VH segments and greatest for JH segments, consistent with there being more VH than JH segments in the human genome. We find that for any two antigens chosen at random, chances are 90 percent that their repertoires' VH segments will overlap by less than half, and 98 percent that their VDJH combinations will overlap by < or =10 percent. We ran computer simulations to test whether enrichment for specific VDJH combinations could be detected in "antigen-exposed" populations, and found that enrichment is detectable with moderate-to-high sensitivity and high specificity, even when some VDJH combinations are not represented at all in some test sets.


CONCLUSIONS
Thus, as large-scale sequencing becomes cost-effective for clinical testing, we suggest that sequencing an individual's expressed antibody repertoire has the potential to become a useful diagnostic modality.
Arnaout
Ramy A
RA
Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA. rarnaout@partners.org
D000465:Algorithms; D000916:Antibody Diversity; D000941:Antigens / Q000737:chemistry; D003198:Computer Simulation; D019992:Databases as Topic; D000939:Epitopes; D015321:Gene Rearrangement; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D005803:Genes, Immunoglobulin; D016678:Genome; D015894:Genome, Human; D006801:Humans; D007133:Immunoglobulin Joining Region; D007135:Immunoglobulin Variable Region; D015233:Models, Statistical; D019151:Peptide Library; D011948:Receptors, Antigen, T-Cell / Q000737:chemistry / Q000276:immunology; D011995:Recombination, Genetic; D012680:Sensitivity and Specificity
D000941:Antigens; D000939:Epitopes; D007133:Immunoglobulin Joining Region; D007135:Immunoglobulin Variable Region; D019151:Peptide Library; D011948:Receptors, Antigen, T-Cell