An Immunoproteomic Survey of the Antibody Landscape: Insights and Opportunities Revealed by Serological Repertoire Profiling

Abstract

Immunoproteomics has emerged as a versatile tool for analyzing the antibody repertoire in various disease contexts. Until recently, characterization of antibody molecules in biological fluids was limited to bulk serology, which identifies clinically relevant features of polyclonal antibody responses. The past decade, however, has seen the rise of mass-spectrometry-enabled proteomics methods that have allowed profiling of the antibody response at the molecular level, with the disease-specific serological repertoire elucidated in unprecedented detail. In this review, we present an up-to-date survey of insights into the disease-specific immunological repertoire by examining how quantitative proteomics-based approaches have shed light on the humoral immune response to infection and vaccination in pathogenic illnesses, the molecular basis of autoimmune disease, and the tumor-specific repertoire in cancer. We address limitations of this technology with a focus on emerging potential solutions and discuss the promise of high-resolution immunoproteomics in therapeutic discovery and novel vaccine design.

Keywords: Ig-Seq; autoimmunity; cancer; infectious disease; proteomics; serological antibody repertoire.

Figure 1

Quantitative and qualitative profiling of antibody repertoires using the Ig-Seq pipeline. Antibodies sampled from biological fluids are subject to affinity purification against an antigen of interest and profiled by mass spectrometry (top pathway). A donor-specific reference database generated from BCR-Seq (bottom pathway) is used to match peptide spectra with antibody sequences. Relative antibody abundances are profiled in detail and can be tracked longitudinally. Ig-Seq enables detailed longitudinal profiling of antibody repertoires (1), identification of convergent responses (2), functional characterization of antibody specificity (3) and affinity (4), as well as delineation of the in vitro neutralization (5) and in vivo protection (6) conferred by abundant antibodies. Insights from the repertoire’s behavior after antigenic exposure, and the protective features of expressed mAbs, inform the design of diagnostics, vaccination strategies, and therapeutics.