8, 9 The complementarity-determining regions (CDRs), CDR1, CDR2 and CDR3, as well as the surrounding framework regions, together form the antigen-binding site of the antibody. This Review provides an overview of technologies for large-scale sequencing of antibody repertoires, and discusses how these technologies can be applied to characterize immune responses and identify antibodies of therapeutic, diagnostic or mechanistic relevance to autoimmune diseases, including rheumatic diseases.Īntibodies are comprised of an immunoglobulin heavy chain (IgH) and light chain (IgL), each containing an antigen-binding domain that is generated by the recombination, junctional diversification and somatic hypermutation of variable (V), joining (J) and/or diversity (D) gene segments during B-cell development. 4, 6, 7 A challenge in understanding, as well as in diagnostically and therapeutically harnessing, antibody responses is the identification of antibodies that underlie functional immune responses, that is, antibodies that directly contribute to an immune outcome, such as neutralizing a microbial pathogen or mediating autoimmune tissue injury. 1, 2, 3 In infectious diseases, in which antibody responses are usually protective, there is growing interest in isolating antibodies that could be developed as novel therapeutic agents 4, 5 and in using microbial antigens and epitopes targeted by antibody responses to develop vaccines. In autoimmune diseases, including autoimmune rheumatic diseases, antibody characterization has enabled the identification of autoantigens and has provided insights into the underlying mechanisms of disease furthermore, detection of autoantibodies has become a cornerstone of modern diagnostics. Analysis of these antibody repertoires, particularly those contributing to functional immune responses, can provide important information on protective and pathogenic immunity. In response to microbial infection, vaccination, autoimmune disease or cancer, the immune system generates distinct antibody repertoires. We anticipate that antibody repertoire sequencing will provide next-generation biomarkers, diagnostic tools and therapeutic antibodies for a spectrum of diseases, including rheumatic diseases.Īntibodies are a major component of the adaptive immune system and have critical roles in protective and pathogenic immune responses. Sequencing antibody repertoires is transforming our understanding of immune responses to autoimmunity, vaccination, infection and cancer. Integrated analysis of coexpressed functional genes provides the potential to further pinpoint the most important antibodies and clonal families generated during an immune response. 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. ![]() ![]() 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. 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. 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.
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