Lineage Structure of the Human Antibody Repertoire in Response to Influenza Vaccination

Jiang, Ning; He, Jiankui; Weinstein, Joshua A.; Penland, Lolita; Sasaki, Sanae; He, Xiao; Dekker, Cornelia L.; Zheng, Nai Ying; Huang, Min; Sullivan, Molly; Wilson, Patrick C.; Greenberg, Harry B.; Davis, Mark M.; Fisher, Daniel S.; Quake, Stephen R.

doi:10.1126/scitranslmed.3004794

Cited by 312 publications

(356 citation statements)

References 29 publications

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“…TIV is known to trigger a strong hemagglutinin inhibition (HAI) antibody response, IgG plasmablast release, and isotype class switching, whereas the effects of LAIV are less pronounced (8,17,18). We showed that TIV vaccination indeed strongly increases numbers of abundant IgG lineages (Fig.…”

Section: Resultsmentioning

confidence: 74%

“…In a recent study, we outlined the age-dependent differential effects of TIV and LAIV vaccines on the IGH repertoire, showing that overall TIV causes a stronger class switch response than LAIV (8). Focusing on the analysis of the abundant lineages in the present study enabled us to create an even more detailed fingerprint of the B-cell response to influenza vaccine TIV, in which tens of highly abundant B-cell clones are accompanied by hundreds of moderately abundant B-cell clones.…”

Section: Discussionmentioning

confidence: 99%

“…This approach has been used to investigate a variety of phenomena, including effects of influenza vaccination, residual disease in leukemia, effects of immune suppression, and differences between memory and naive B-cell compartments (5)(6)(7)(8)(9)(10)(11).…”

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confidence: 99%

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Genetic measurement of memory B-cell recall using antibody repertoire sequencing

Vollmers

Sit

Weinstein

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Annual influenza vaccinations aim to protect against seasonal infections, and vaccine strain compositions are updated every year. This protection is based on antibodies that are produced by either newly activated or memory B cells recalled from previous encounters with influenza vaccination or infection. The extent to which the B-cell repertoire responds to vaccination and recalls antibodies has so far not been analyzed at a genetic level-which is to say, at the level of antibody sequences. Here, we developed a consensus read sequencing approach that incorporates unique barcode labels on each starting RNA molecule. These labels allow one to combine multiple sequencing reads covering the same RNA molecule to reduce the error rate to a desired level, and they also enable accurate quantification of RNA and isotype levels. We validated this approach and analyzed the differential response of the antibody repertoire to live-attenuated or trivalent-inactivated influenza vaccination. Additionally, we analyzed the antibody repertoire in response to repeated yearly vaccinations with trivalentinactivated influenza vaccination. We found antibody sequences that were present in both years, providing a direct genetic measurement of B-cell recall.E very year, influenza viruses cause the deaths of an average of 36,000 individuals in the United States alone (1). Although the immunological memory created through vaccination can confer decade-long protection against a particular viral strain, antigenic drift in the original strain and the occurrence of distinct viral strains can enable the virus to evade the immune system (2). As a result, influenza vaccination formulations have to be reevaluated, adjusted, and administered annually to best match the annual influenza strain. Vaccine-induced immunity against influenza is primarily antibody-based, and as such, it relies on the activation of naive B cells or the reactivation (recall) of memory B cells to produce high levels of antibody specific to the vaccine strain. Prior studies approached recall memory responses by measuring plasma antibody levels and specificity or sequencing antibody loci of isolated B cells, with one study concluding that the response to influenza vaccination is pauciclonal (i.e., composed of only a few distinct clones) (3, 4). However, this study and others were limited in the number of B cells that they were able to analyze and not able to show that the same clone recurs during recall. The strength of the recall response, the isotype distribution, and the clonal relationship to others have been unclear.Recently, methods to sequence antibody repertoires of whole organisms and human blood samples were developed and applied to investigate several features of B-cell repertoires (5, 6). This approach has been used to investigate a variety of phenomena, including effects of influenza vaccination, residual disease in leukemia, effects of immune suppression, and differences between memory and naive B-cell compartments (5-11).Analyzing vaccine recall response requires ...

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Section: Resultsmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

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Genetic measurement of memory B-cell recall using antibody repertoire sequencing

Vollmers

Sit

Weinstein

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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231

321

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“…We have explored the relationship of local sequence context to the frequency of AID-induced mutations in the human IGHV3-23*01 in vivo, in vitro, and in Ramos B cells to gain a better understanding of how the V region sequence has evolved to generate antibody diversity and protective antibodies. We selected IGHV3-23*01 because it is one of the most highly used human V regions (41)(42)(43) and because a published database (45,46) had a large subset of mutated V regions that were nonproductive and would reflect the inherent activity of AID and its associated factors in the absence of antigen selection. The most highly mutated sites in IGHV3-23*01 were overlapping AGCT and AGCA hotspot motifs (46,61), which are found in CDR1 and CDR2 and at one location in the beginning of FW1 (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…The IGVH3 family represents about half of the functional genomic human V regions (40), and IGVH3-23 is particularly interesting because it is the most commonly used V region during normal immune responses (41)(42)(43), as well as in some B-cell malignancies (44). Fortunately, there is a large database available for bioinformatic analysis with independently mutated productive and nonproductive human IGHV3-23*01 sequences (45,46).…”

Section: Significancementioning

confidence: 99%

Overlapping hotspots in CDRs are critical sites for V region diversification

Wei

Chahwan

Wang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Activation-induced deaminase (AID) mediates the somatic hypermutation (SHM) of Ig variable (V) regions that is required for the affinity maturation of the antibody response. An intensive analysis of a published database of somatic hypermutations that arose in the IGHV3-23*01 human V region expressed in vivo by human memory B cells revealed that the focus of mutations in complementary determining region (CDR)1 and CDR2 coincided with a combination of overlapping AGCT hotspots, the absence of AID cold spots, and an abundance of polymerase eta hotspots. If the overlapping hotspots in the CDR1 or CDR2 did not undergo mutation, the frequency of mutations throughout the V region was reduced. To model this result, we examined the mutation of the human IGHV3-23*01 biochemically and in the endogenous heavy chain locus of Ramos B cells. Deep sequencing revealed that IGHV3-23*01 in Ramos cells accumulates AID-induced mutations primarily in the AGCT in CDR2, which was also the most frequent site of mutation in vivo. Replacing the overlapping hotspots in CDR1 and CDR2 with neutral or cold motifs resulted in a reduction in mutations within the modified motifs and, to some degree, throughout the V region. In addition, some of the overlapping hotspots in the CDRs were at sites in which replacement mutations could change the structure of the CDR loops. Our analysis suggests that the local sequence environment of the V region, and especially of the CDR1 and CDR2, is highly evolved to recruit mutations to key residues in the CDRs of the IgV region.A fter an encounter with antigen and subsequent migration into the germinal centers of the secondary lymphoid organs, B cells undergo a regulated cascade of mutational events that occur at a very high frequency and are largely restricted to the variable (V) and switch (S) regions of the Ig heavy chain locus and the V region of the light chain locus. These mutagenic events are responsible for the somatic hypermutation (SHM) of the V regions and the class switch recombination of the constant (C) regions that are required for protective antibodies (1, 2). Both SHM and class switch recombination are initiated by activationinduced deaminase (AID) that preferentially deaminates the dC residues in WRC (W = A/T, R = A/G) hotspot motifs at frequencies 2-10-fold higher than SYC (S = G/C; Y = C/T) cold spots (3-7). During V region SHM, the resulting dU:G mismatch can then be replicated during S-phase to produce transition mutations, be processed by uracil-DNA glycosylase 2 and apurinic/ apyrimidinic endonucleases through the base excision repair pathway to produce both transitions and transversions (8-10), or be recognized by MutS homolog (MSH)2/MSH6 of the mismatch repair (MMR) complex that recruits the low-fidelity polymerase eta (Polη) to generate additional mutations at neighboring A:T residues (11).The specificity of AID targeting to the Ig gene has been under intense investigation. Studies have shown that AID deamination and mutagenesis targets single-stranded DNA substrates generated during ...

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CDR3 sequences in IgA nephropathy are shorter and exhibit reduced diversity

Zhang

Zeng²,

Tong

et al. 2020

FEBS Open Bio

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IgA nephropathy (IgAN) is the most common glomerulonephritis, which is characterized by the deposition of IgA antibody in the glomerulus. Systematic dissection of immune composition may contribute to a better understanding of the alternations in the immune system in IgAN. To this end, here we applied immune repertoire sequencing technology for parallel analysis of the CDR3 region of all B cell receptors, including all five antibody subtypes (IgA, IgG, IgM, IgE and IgD), in 13 IgAN patients and 7 healthy individuals. A significant decrease in CDR3 length was observed in the IgAN group. In particular, the JH6 family was significantly increased in IgAN. Amino acid usage was also altered in IgAN. Shannon, Simpson, Gini, and D50 indices also revealed significant differences in the diversity of IgG, IgM and IgA antibodies as compared to controls. The proportion of IgA and IgG were increased whereas IgM was decreased in IgAN. Moreover, a greater number of CDR3 sequences were shared between IgAN patients. These findings suggest that the BCR immune repertoire is dramatically altered in IgAN, as characterized by shortened CDR3 length as well as decreased overall diversity of CDR3.

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Lineage Structure of the Human Antibody Repertoire in Response to Influenza Vaccination

Cited by 312 publications

References 29 publications

Genetic measurement of memory B-cell recall using antibody repertoire sequencing

Genetic measurement of memory B-cell recall using antibody repertoire sequencing

Overlapping hotspots in CDRs are critical sites for V region diversification

CDR3 sequences in IgA nephropathy are shorter and exhibit reduced diversity

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