Recombinantly expressed clones (mainly IgG) have become a major class of therapeutics, used to fight multiple types of pathologies such as cancers and various infectious diseases. Nevertheless, it has been assumed that the actual repertoire of circulating Igs is extremely large and diverse ( Briney et al., 2019 Soto et al., 2019). Not all theoretically possible Ig clones will be expressed in the human body, since the number of B cells in a human body is several orders of magnitude lower (1–2 × 10 11) ( Apostoaei and Trabalka, 2012). Each unique combination of mature chains is called an Ig clone.Ĭonsidering the genes encoding the variable domain sections and the known genomic rearrangements, somatic hypermutations, and post-transcriptional processes that join these sections-resulting into the ultimate protein products-it has been estimated that in humans the theoretical molecular Ig diversity may extend beyond 10 15 ( Schroeder, 2006). The circulating antibodies, thus, consist of the fully matured heavy- and light-chain variable domain sequences that harbor the CDRs, joined by generally less sequence-variable framework regions (FR). The best antigen binders, modified through somatic recombination and hypermutation of numerous coding gene segment variants, give rise to the mature IgG secreting plasma B cells that produce the antibodies that end up in our circulation. The variable regions of the antibody, in particular the CDRs, are optimized to recognize antigens by a process known as affinity maturation. They are enclosed in the two fragment antigen-binding (Fab) arms of the antibody, consisting of the light chain and the N-terminal parts of the heavy chain (Fd). On the other hand, for both heavy and light chain, the sequence of the N-terminal Ig domains is hypervariable and contains the recognition-determining parts, better known as complementarity-determining regions (CDRs), of the molecule. Similar to the heavy chain, the C-terminal domain of the light chain is constant. The heavy chains possess three (IgG, IgA, and IgD) to four (IgM and IgE) immunoglobulin domains with large, conserved regions, which play a role in receptor binding and complement activation. Ig molecules consist of two identical heavy chains and two identical light chains, held together by a network of disulfide bridges. Immunoglobulins (Igs) represent some of the most important molecules in the human immune system. A detailed molecular view of these plasma components is crucial to understanding how they affect each individual’s immune response. The immune response in health and disease is crucially dependent on each person’s repertoire of immune cells, antibodies, and other circulating plasma proteins. The human immune system protects us not only from threats posed by pathogens but also cancer and various other diseases. A record of this paper’s transparent peer review process is included in the supplemental information. This IgG1 clone emerged at the onset of a septic episode and exhibited a high mutation rate (13%) compared with the closest matching germline DNA sequence, highlighting the importance of de novo sequencing at the protein level. We introduce an integrative protein- and peptide-centric approach to obtain and validate a full sequence of an individual plasma IgG1 clone de novo. We observe that each individual donor exhibits a unique serological IgG1 repertoire, which remains stable over time but can adapt rapidly to changes in physiology. Here, we combined several mass-spectrometry-based approaches to reveal that the circulating IgG1 repertoire in human plasma is dominated by a limited number of clones in healthy donors and septic patients. Although humans can produce billions of IgG1 variants through recombination and hypermutation, the diversity of IgG1 clones circulating in human blood plasma has largely eluded direct characterization.
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