Lossius a immune repertoire2/7/2024 The findings are consistent with an increasing body of literature that reports commonalities in the sequence of immunoglobulins targeting a particular antigen ( 9– 14). We previously found evidence for common features between antigen-specific immune sera. The techniques were already combined successfully in the past, and can help provide unique but not always consistent views on the repertoire ( 4– 8). In this way, we can obtain a more comprehensive picture of the differences but also similarities that exist between individuals after an immune response to a particular antigen. For these reasons, we here study the immune repertoire with a combination of proteomics and NGS. Antibody proteins can be collected from serum and affinity-enriched in order to study an antigen-specific subset of molecules. However, antibodies that are produced as a result of an immune response will generally end up in the circulation regardless of the site of production. The timing and location of the sampling sites are likely to affect the immune repertoire that is observed, and not all sites are easily accessible, especially in human subjects. ![]() The immune response is a compartmentalized process that takes place in circulating blood, in the interstitial space of (inflamed) tissues, and in lymphoid organs, such as lymph nodes, the spleen, or bone marrow. Another challenge is the tissue niche that is sampled for obtaining sequence information. Distinctions have been found between the B-cell receptor repertoire and the plasma cell repertoire that drives immunoglobulin expression ( 3). One challenge is that not all cells with a rearranged immunoglobulin locus express immunoglobulin protein. Yet, it is challenging to obtain a sample for sequencing that properly reflects the repertoire of antibody proteins that is present in the serum, and even more the repertoire of an antigen-specific subset of sequences. Research groups have started using and refining such tools to understand the development of immune responses, and envision potential applications of information on the immune repertoire. The high-throughput sequencing methods that are available allow researchers to obtain a listing of the repertoire of sequences that make up the antibodies or T-cell receptors that mediate the adaptive immune response. Yet, it is only in recent years that technology has advanced sufficiently to study the population of sequences that results from this recombination process and the subsequent mutation and selection pressures for the formation of mature immunoglobulins ( 2). The basic understanding of the molecular biology that leads to diversity in the adaptive immune response emerged around 1980 ( 1), an effort that was awarded with a Nobel prize for Physiology and Medicine for Tonegawa. With additional research, this may enable interesting applications in biotechnology and clinical diagnostics. Thus, data from different analysis methods and different experimental platforms show that the immunoglobulin repertoires of immunized animals have overlapping and converging features. Also, similar mutation patterns were found in branches of the phylogenetic tree that were associated with antigen-specific immunoglobulins through proteomics data. A phylogenetic analysis on the NGS reads showed that reads from different individuals immunized with the same antigen populated distinct branches of the phylogram, an indication that the repertoire had converged. However, the number of shared sequences decreased in a log-linear fashion relative to the number of animals that share them, which may affect future applications. It was found that the immune repertoires resulting from each antigen had many similarities that allowed samples to cluster together, and that mutated immunoglobulin peptides were shared among animals with a response to the same antigen significantly more than for different antigens. Both methods contributed complementary information in the characterization of the immune repertoire. Proteomics and NGS data on the repertoire are in qualitative agreement, but did show quantitative differences that may relate to differences between the biological niches that were sampled for these approaches. ![]() Using both proteomic and NGS approaches, we characterized the immune repertoires in groups of rats after immunization with purified antigens. During B-cell development, VDJ recombination and somatic mutations generate diversity, whereas selection processes remove it. The immune system produces a diverse repertoire of immunoglobulins in response to foreign antigens. 2Erasmus Center for Biomics, Erasmus MC, Rotterdam, Netherlands.1Department of Neurology, Erasmus MC, Rotterdam, Netherlands.
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