Phage display sequencing reveals that genetic, environmental, and intrinsic factors influence variation of human antibody epitope repertoire

Andreu‐Sánchez, Sergio; Bourgonje, Arno R.; Vogl, Thomas; Kurilshikov, Alexander; Leviatan, Sigal; Ruiz-Moreno, Angel J.; Hu, Shixian; Sinha, Trishla; Vila, Arnau Vich; Klompus, Shelley; Kalka, Iris; Leeuw, Karina de; Arends, Suzanne; Jonkers, Iris; Withoff, Sebo; Sandovici, Maria; Weinberger, Adina; Wijmenga, Cisca; Segal, Eran; Weersma, Rinse K.; Fu, Jingyuan; Zhernakova, Alexandra

doi:10.1016/j.immuni.2023.04.003

Cited by 9 publications

(29 citation statements)

References 129 publications

(166 reference statements)

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“…By combining epitope-level and AVARDA analyses, we first investigated the effects of age and sex on the anti-viral antibody repertoire, including antibody levels against 2,608 public peptides and 150 viruses. Regression modeling indicated that antibody reactivity against a wide range of viruses is strongly associated with age, in line with previous studies (Figure 2A) 4,5 . Antibodies against 565 epitopes significantly increased with age, primarily those targeting herpesviruses, as well as the Orthopneumovirus RSV, which infect the human host continuously throughout a lifetime.…”

Section: Resultssupporting

confidence: 91%

“…The number of enriched peptides (STAR Methods) per subject was normally distributed, with an average of 881 and 1,044 peptides for MI and EIP subjects, respectively, owing to cohort differences in age, sex and/or ancestry (Figures 1D and S1C). When estimating antibody reactivity from peptide scores, we found that most peptides are enriched in only a few individuals, reflecting individual-specific immune responses (so-called private epitopes) or false positives (Figures 1E and S1D), in line with previous PhIP-seq studies 4,22,24 . Within the MI and EIP cohorts, 2,608 and 3,210 epitopes were public , hereby defined as peptides significantly enriched in >5% of subjects for at least two peptides from the same virus.…”

Section: Resultssupporting

confidence: 88%

“…For two out of four loci, associated peptides originated from multiple viruses, indicating that candidate variants have pleiotropic effects on anti-viral humoral immunity (Figure 6B). The HLA locus showed the strongest associations, in line with previous work demonstrating its major effects on humoral responses against EBV, IAV, HSV-1, VZV, JC polyomavirus, and MCV 2,4,10–13 . Here, we found a significant association between HLA variants and antibody response against 99 peptides from 12 viruses.…”

Section: Resultssupporting

confidence: 87%

“…For example, women have higher titers against human papillomavirus (HPV) 1 and Epstein-Barr virus (EBV) 1,2 and generally generate more robust vaccine responses than men 3 . Population immunity against some herpesviruses, such as HSV-1 and cytomegalovirus (CMV), tends to increase over time due to accumulated exposure 1,2,4,5 . In contrast, viruses that are more prevalent in children (such as respiratory syncytial virus (RSV) and varicella-zoster virus (VZV)) or are a part of childhood immunization schedules (such as measles, mumps, and rubella viruses) tend to be present at high levels in most adults 1,2 .…”

Section: Introductionmentioning

confidence: 99%

“…In contrast, viruses that are more prevalent in children (such as respiratory syncytial virus (RSV) and varicella-zoster virus (VZV)) or are a part of childhood immunization schedules (such as measles, mumps, and rubella viruses) tend to be present at high levels in most adults 1,2 . Other non-genetic factors associated with serostatus include socioeconomic status 1,2 and smoking 4 .…”

Section: Introductionmentioning

confidence: 99%

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A systematic investigation into the non-genetic and genetic factors affecting the human anti-viral antibody repertoire

Olin,

Jaquaniello,

Tan

et al. 2023

Preprint

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SummaryImmunoglobulins are among the most important anti-viral effectors of the human immune system. The biological mechanisms underlying antibody production and maintenance are relatively well understood. However, a broader model of how host intrinsic factors and external processes influence humoral responses to viral infections is lacking. Here, we investigate how age, sex, genetics, health-related habits, and immune factors relate to the anti-viral antibody repertoire of healthy humans. We used VirScan, a high-throughput technology based on phage-display immunoprecipitation sequencing (PhIP-seq), to characterize antibody reactivity against more than 90,000 viral epitopes in 1,212 healthy adults of European and African descent. By comparing VirScan with various serological assays, we first show that PhIP-seq-based antibody repertoires recapitulate expected serostatuses and uncover considerable variation in epitope-specific reactivity. In addition to age and sex effects, we find that the antibody repertoire is strongly associated with active smoking, which results in increased antibody levels against rhinoviruses. We provide evidence that individuals born in Central Africa and Europe differ in antigenic reactivity to common herpesviruses by targeting different viral proteins. By comparing antibody repertoires to 169 immune cell parameters, we find that HLA-DR expression in circulating dendritic cells is associated with increased reactivity against EBV. Finally, we conducted a GWAS of antibody binding against more than 2,600 viral peptides. We confirmed a strong effect ofHLAandIGHloci and theFUT2gene and identified new associations between variants in these genes and antibodies against adenoviruses and saliviruses. These findings highlight the determinants of human variation in the humoral response to viruses and broaden perspectives on how the antibody repertoire is generated and maintained.

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Section: Resultssupporting

confidence: 91%