Sequencing the functional antibody repertoire—diagnostic and therapeutic discovery

• Published in: Nature reviews. Rheumatology Vol. 11; no. 3; pp. 171 - 182
• Main Author: Robinson, William H.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2015; Nature Publishing Group
• Subjects: 631/1647/664; 631/1647/664/2229; 631/208/514/2254; 631/250/38; Antibodies; Antibodies - classification; Antibodies - genetics; Antigens; Arrays; Autoimmune diseases; Biomarkers; Cancer; Computational Biology - methods; DNA sequencing; Genes; Genetic aspects; High-Throughput Nucleotide Sequencing - methods; Humans; Immune response; Immune system; Immunoglobulin Heavy Chains - genetics; Immunoglobulins; Infections; Infectious diseases; Medicine & Public Health; Methods; Nucleotide sequencing; Peptides; Prevention; review-article; Rheumatic diseases; Rheumatology
• ISSN: 1759-4790; 1759-4804
• DOI: 10.1038/nrrheum.2014.220

Key Points The development of high-throughput DNA sequencing has enabled large-scale analysis of antibody repertoires and responses Critical parameters for characterization of functional antibody repertoires include the methodology, the B-cell population characterized, clinical characteristics of the individuals analysed and the bioinformatic analysis High-fidelity analysis of full-length paired heavy and light chains expressed by individual B cells is critical for the characterization of functional antibody repertoires Analysis of coexpressed functional genes can identify antibodies that contribute to functional immune responses Sequencing antibody repertoires is transforming our understanding of pathogenic and protective immune responses in autoimmunity, infection, vaccination and cancer Antibody repertoire sequencing should lead to the generation of biomarkers, diagnostic tools and therapeutic antibodies for various diseases, including rheumatic diseases Next-generation sequencing is at the forefront of the identification and characterization of clonal families of antibodies that are involved in immune responses to infection, cancer and autoimmune disease. In this article, cutting-edge antibody repertoire sequencing technologies are described as a means of paving the way forward for research and discovery in rheumatology. The development of high-throughput DNA sequencing technologies has enabled large-scale characterization of functional antibody repertoires, a new method of understanding protective and pathogenic immune responses. Important parameters to consider when sequencing antibody repertoires include the methodology, the B-cell population and clinical characteristics of the individuals analysed, and the bioinformatic analysis. Although focused sequencing of immunoglobulin heavy chains or complement determining regions can be utilized to monitor particular immune responses and B-cell malignancies, high-fidelity analysis of the full-length paired heavy and light chains expressed by individual B cells is critical for characterizing functional antibody repertoires. Bioinformatic identification of clonal antibody families and recombinant expression of representative members produces recombinant antibodies that can be used to identify the antigen targets of functional immune responses and to investigate the mechanisms of their protective or pathogenic functions. Integrated analysis of coexpressed functional genes provides the potential to further pinpoint the most important antibodies and clonal families generated during an immune response. Sequencing antibody repertoires is transforming our understanding of immune responses to autoimmunity, vaccination, infection and cancer. We anticipate that antibody repertoire sequencing will provide next-generation biomarkers, diagnostic tools and therapeutic antibodies for a spectrum of diseases, including rheumatic diseases.