Population-wide diversity and stability of serum antibody epitope repertoires against human microbiota

Vogl, Thomas; Klompus, Shelley; Leviatan, Sigal; Kalka, Iris; Weinberger, Adina; Wijmenga, Cisca; Fu, Jingyuan; Zhernakova, Alexandra; Weersma, Rinse K.; Segal, Eran

doi:10.1038/s41591-021-01409-3

Cited by 50 publications

(134 citation statements)

References 63 publications

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“…reported a PhIP-Seq analysis of 997 healthy individuals using a 244,000 peptide library that includes surface and secreted proteins from commensal, pathogenic and probiotic bacterial species, as well as the Virulence Factor Database and additional controls from IEDB. 22 Similar to our findings, the Vogl study detected antibodies to many public and personal epitopes from both pathogenic and commensal bacteria. These reactivities were stable over time and correlated weakly with metagenomic sequencing of the same individuals.…”

Section: Discussionsupporting

confidence: 89%

“…These latter reactivities most likely reflect previous shigellosis in these specific individuals. In agreement with findings reported recently, 22 S. flexneri seropositive individuals were significantly older than seronegative individuals (Mann-Whitney U Test, p=0.031). The highly seroprevalent peptides clustering at the bottom of In order to better understand homology shared between the observed immunoprevalent peptides and clusters, we used a network graph-based approach in which peptides (nodes) are linked (by an edge) if they share sequence similarity by blastp alignment (Fig.…”

Section: Toxscan Antibody Profiles In a Cross-sectional Healthy Cohortsupporting

confidence: 92%

Section: Toxscan Antibody Profiles In a Cross-sectional Healthy Cohortsupporting

confidence: 92%

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Prevalence, persistence, and genetics of antibody responses to protein toxins and virulence factors

Angkeow

Monaco

Chen

et al. 2021

Preprint

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Microbial exposures are crucial environmental factors that impact healthspan by sculpting the immune system and microbiota. Antibody profiling via programmable Phage ImmunoPrecipitation Sequencing (PhIP-Seq) provides a high-throughput, cost-effective approach for multiplexed detection of exposure and response to thousands of microbial protein products. Here we designed and constructed a library of 95,601 56 amino acid peptide tiles spanning a subset of environmental proteins more likely to be associated with immune responses: those with "toxin" or "virulence factor" keyword annotations. PhIP-Seq was used to profile the circulating antibodies of ~1,000 individuals against this "ToxScan" library of 14,430 toxins and virulence factors from 1,312 genera of organisms. In addition to a detailed analysis of six commonly encountered human commensals and pathogens, we study the age-dependent stability of the ToxScan profile and use a genome-wide association study (GWAS) to find that the MHC-II locus modulates the selection of bacterial epitopes. We detect previously described anti-flagellin antibody responses in a Crohn's disease cohort and identify a novel association between anti-flagellin antibodies and juvenile dermatomyositis (JDM). PhIP-Seq with the ToxScan library provides a new window into exposure and immune responses to environmental protein toxins and virulence factors, which can be used to study human health and disease at cohort scale.

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Section: Discussionsupporting

confidence: 89%

Section: Toxscan Antibody Profiles In a Cross-sectional Healthy Cohortsupporting

confidence: 92%

Section: Toxscan Antibody Profiles In a Cross-sectional Healthy Cohortsupporting

confidence: 92%

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Prevalence, persistence, and genetics of antibody responses to protein toxins and virulence factors

Angkeow

Monaco

Chen

et al. 2021

Preprint

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“…enzyme-linked immunosorbent assays [ELISAs] or peptide arrays) do not allow for such large-scale measurements and are usually limited to parallel measurements of only a few hundreds to thousands of antigens. Moreover, although B-cell receptor sequencing (BCR-seq) methods report on the clonal diversity of the BCR DNA sequences that underlie antibody specificity, the exact nature of the antigens bound and their associations with IBD remain incompletely addressed (Vogl et al, 2021; Sterlin et al, 2020; Fadlallah et al, 2019). Phage-displayed immunoprecipitation sequencing (PhIP-seq) is a high-throughput technology that now allows for systematic investigation of hundreds of thousands of antigens simultaneously, and it has been successfully applied in both healthy populations and in the context of viral infections, although there is little data available on immune-mediated diseases (Vogl et al, 2021; Mohan et al, 2018; Zeevi et al, 2015; Larman et al, 2013; Mina et al, 2019; Xu et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

In-depth characterization of the serum antibody epitope repertoire in inflammatory bowel disease using phage-displayed immunoprecipitation sequencing

Bourgonje

Andreu‐Sánchez

Vogl

et al. 2021

Preprint

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Inflammatory bowel diseases (IBD), e.g. Crohn's disease (CD) and ulcerative colitis (UC), are chronic immune-mediated inflammatory diseases. A comprehensive overview of an IBD-specific antibody epitope repertoire is, however, lacking. We leveraged a high-throughput phage-displayed immunoprecipitation sequencing (PhIP-seq) workflow to identify antibodies against 344,000 antimicrobial, immune and food antigens in 497 IBD patients as compared to 1,326 controls. IBD was characterized by 373 differentially abundant antibodies (202 overrepresented and 171 underrepresented), with 17% shared by both IBDs, 55% unique to CD and 28% unique to UC. Antibodies against bacterial flagellins dominated in CD and were associated with ileal involvement, fibrostenotic disease and anti-Saccharomyces cerevisiae antibody positivity, but not with fecal microbiome composition. Antibody epitope repertoires accurately discriminated CD from controls (AUC=0.89), and similar discrimination was achieved when using only ten antibodies (AUC=0.87). IBD patients thus show a distinct antibody repertoire against selected peptides, allowing patient stratification and discovery of immunological targets.

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“…At the same time, the gut microbiome also plays a pivotal role in shaping systemic immune responses and is known to influence the efficacy of immune checkpoint inhibitors [35,36]. Despite the knowledge of the influence of sex, age and diet on the gut microbiome, little is known to what extent these parameters can affect the response to immunotherapy [37,38].…”

Section: Discussionmentioning

confidence: 99%

Distinctive Role of the Systemic Inflammatory Profile in Non-Small-Cell Lung Cancer Younger and Elderly Patients Treated with a PD-1 Immune Checkpoint Blockade: A Real-World Retrospective Multi-Institutional Analysis

Nardone

Giannicola

Giannarelli

et al. 2021

Life

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An immune checkpoint blockade with mAbs to PD-1 and PD-L1 is an expanding therapeutic option for mNSCLC patients. This treatment strategy is based on the use of mAbs able to restore the anti-tumor activity of intratumoral T cells inhibited by PD-1 binding to PD-L1/2 on tumor and inflammatory cells. It has been speculated that a chronic status of systemic inflammation as well as the immunosenescence physiologically occurring in elderly patients may affect the efficacy of the treatment and the occurrence of irAEs. We performed a multi-institutional retrospective study aimed at evaluating the effects of these mAbs (nivolumab or atezolizumab) in 117 mNSCLC patients younger (90 cases) and older (27 cases) than 75 years in correlation with multiple inflammatory parameters (NLR, CRP, ESR, LDH and PCT). No differences were observed when the cohorts were compared in terms of the frequency of PFS, OS, inflammatory markers and immune-related adverse events (irAEs). Similarly, the occurrence of irAEs was strictly correlated with a prolonged OS survival in both groups. On the contrary, a negative correlation between the high baseline levels of inflammatory markers and OS could be demonstrated in the younger cohort only. Overall, PD-1/PD-L1-blocking mAbs were equally effective in young and elderly mNSCLC patients; however, the detrimental influence of a systemic inflammation at the baseline was only observed in young patients, suggesting different aging-related inflammation immunoregulative effects.

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Population-wide diversity and stability of serum antibody epitope repertoires against human microbiota

Cited by 50 publications

References 63 publications

Prevalence, persistence, and genetics of antibody responses to protein toxins and virulence factors

Prevalence, persistence, and genetics of antibody responses to protein toxins and virulence factors

In-depth characterization of the serum antibody epitope repertoire in inflammatory bowel disease using phage-displayed immunoprecipitation sequencing

Distinctive Role of the Systemic Inflammatory Profile in Non-Small-Cell Lung Cancer Younger and Elderly Patients Treated with a PD-1 Immune Checkpoint Blockade: A Real-World Retrospective Multi-Institutional Analysis

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