VH Gene Research Articles

HIV-1 VRC01 Germline-Targeting Immunogens Select Distinct Epitope-Specific B Cell Receptors

Activating precursor B cell receptors of HIV-1 broadly neutralizing antibodies requires specifically designed immunogens. Here, we compared the abilities of three such germline-targeting immunogens against the VRC01-class receptors to activate the targeted B cells in transgenic mice expressing the germline VH of the VRC01 antibody but diverse mouse light chains. Immunogen-specific VRC01-like B cells were isolated at different time points after immunization, their VH and VL genes were sequenced, and the corresponding antibodies characterized. VRC01 B cell sub-populations with distinct cross-reactivity properties were activated by each immunogen, and these differences correlated with distinct biophysical and biochemical features of the germline-targeting immunogens. Our study indicates that the design of effective immunogens to activate B cell receptors leading to protective HIV-1 antibodies will require a better understanding of how the biophysical properties of the epitope and its surrounding surface on the germline-targeting immunogen influence its interaction with the available receptor variants invivo.

Bim establishes the B-cell repertoire from early to late in the immune response.

In T cell-dependent antibody responses, some of the activated B cells differentiate along extrafollicular pathways into low-affinity memory and plasma cells, whereas others are involved in subsequent germinal center (GC) formation in follicular pathways, in which somatic hypermutation and affinity maturation occur. The present study demonstrated that Bim, a proapoptotic BH3-only member of the Bcl-2 family, contributes to the establishment of the B-cell repertoire from early to late stages of immune responses to T cell-dependent antigens. Extrafollicular plasma cells grew in the spleen during the early immune response, but their numbers rapidly declined with the appearance of GC-derived progeny in wild-type mice. By contrast, conditional Bim deficiency in B cells resulted in expansion of extrafollicular IgG1+ antibody-forming cells (AFCs) and this expansion was sustained during the late response, which hampered the formation of GC-derived high-affinity plasma cells in the spleen. Approximately 10% of AFCs in mutant mice contained mutated VH genes; thus, Bim deficiency appears not to impede the selection of high-affinity AFC precursor cells. These results suggest that Bim contributes to the replacement of low-affinity antibody by high-affinity antibody as the immune response progresses.

CLL-132: Mutational Status of IGVH in Correlation with Genetic Abnormalities of Patients with Chronic Lymphocytic Leukemia in Macedonia - A Single-Centre Experience

Context B-cell chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease. One of the most important molecular predictors, the immunoglobulin VH gene mutational status, divides CLL into two prognostic groups, where unmutated U-CLL is associated with remarkably worse prognosis than mutated M-CLL. In many studies, multiple recurring chromosomal aberrations appear to be effective prognostic markers in CLL. Objective The aim of the study was first-time evaluation of rearrangement of IG genes and genetic abnormalities in Macedonian CLL patients. Design Prospective study of Macedonian patients with CLL at early and advanced stage of disease in a period of time from January 2011 to January 2019. The median follow-up was 48 months (1-96 months). Setting Mutational status and configuration of IGHV-IGHD-IGHJ rearrangements in 90 treatment-naive CLL patients were analyzed using reverse transcriptase-polymerase chain reaction (RT-PCR) and sequencing methodology. We used multiplex ligation-dependent probe amplification (MLPA) for detection of most common genetic abnormalities. Interventions We introduced prognostic markers like cytogenetic aberrations, and mutational status of immunoglobulin heavy chain in prognostic stratification of Macedonian patients with CLL. Results Our evaluation has shown that 54.7% patients belonged to the U-CLL subset, whereas 45.3% belonged to the M-CLL subset. The most frequently expressed IGHV subgroup was IGHV3 (40%), followed by IGHV4 (29%), IGHV1(27%), and IGHV5 (3%). The most frequent subgroup with 8% were IGHV1-69*13 and IGHV4-34*0. In the IGHD and IGHJ sets, most frequently expressed genes were IGHD3 (59.7%) and IGHJ6(53.1%), respectively. We found that 80% of IGHV1, 65.6% of IGHD3, and 83.3% of IGHJ6 genes were U-CLL (p=0.0005). Frequency of genetic aberrations by MLPA were 13q14 deletion (20%) followed by 11q deletion (14%), then trisomy 12 (13%) and 17p deletion (6.6%), multiple mutations (6.7%), and NOTCH mutation (5.3%). Conclusions Our evaluation of mutational status on IGVH, IGDH, and IGJH genes in Macedonian CLL patients resulted with data that are consubstantial to those from the Mediterranean area. Novel mutations discovered in this study must be validated through large cohort studies and may offer clues to the mechanisms underlying the difference in CLL survival. In the future, therapeutic strategies targeting these genes should be evaluated and considered.

Altered 3D chromatin structure permits inversional recombination at the IgH locus.

Immunoglobulin heavy chain (IgH) genes are assembled by two sequential DNA rearrangement events that are initiated by recombination activating gene products (RAG) 1 and 2. Diversity (DH) gene segments rearrange first, followed by variable (VH) gene rearrangements. Here, we provide evidence that each rearrangement step is guided by different rules of engagement between rearranging gene segments. DH gene segments, which recombine by deletion of intervening DNA, must be located within a RAG1/2 scanning domain for efficient recombination. In the absence of intergenic control region 1, a regulatory sequence that delineates the RAG scanning domain on wild-type IgH alleles, VH and DH gene segments can recombine with each other by both deletion and inversion of intervening DNA. We propose that VH gene segments find their targets by distinct mechanisms from those that apply to DH gene segments. These distinctions may underlie differential allelic choice associated with each step of IgH gene assembly.

Analysis of the Chinese Alligator TCRα/δ Loci Reveals the Evolutionary Pattern of Atypical TCRδ/TCRμ in Tetrapods.

Atypical TCRδ found in sharks, amphibians, birds, and monotremes and TCRμ found in monotremes and marsupials are TCR chains that use Ig or BCR-like variable domains (VHδ/Vμ) rather than conventional TCR V domains. These unconventional TCR are consistent with a scenario in which TCR and BCR, although having diverged from each other more than 400 million years ago, continue to exchange variable gene segments in generating diversity for Ag recognition. However, the process underlying this exchange and leading to the evolution of these atypical TCR receptor genes remains elusive. In this study, we identified two TCRα/δ gene loci in the Chinese alligator (Alligator sinensis). In total, there were 144 V, 154 Jα, nine Jδ, eight Dδ, two Cα, and five Cδ gene segments in the TCRα/δ loci of the Chinese alligator, representing the most complicated TCRα/δ gene system in both genomic structure and gene content in any tetrapod examined so far. A pool of 32 VHδ genes divided into 18 subfamilies was found to be scattered over the two loci. Phylogenetic analyses revealed that these VHδ genes could be related to bird VHδ genes, VHδ/Vμ genes in platypus or opossum, or alligator VH genes. Based on these findings, a model explaining the evolutionary pattern of atypical TCRδ/TCRμ genes in tetrapods is proposed. This study sheds new light on the evolution of TCR and BCR genes, two of the most essential components of adaptive immunity.

Grade I, II and III Follicular Lymphomas Express Ig VH Genes with Different Patterns of Somatic Mutation

Follicular lymphoma (FL) is an indolent, B-cell, non-Hodgkin’s lymphoma with varying cytological appearance and clinical behavior. The genetic hallmark of FL is the t(14;18) translocation, and as a germinal center derived entity it is also characterized by somatic hypermutation of the immunoglobulin heavy chain (IgH) gene. In an attempt to correlate this molecular signature with the cytological grading of FL, we have analyzed the IgH variable (IgVH), regions in all cytological grades of FL. Four FL cases showing t(14;18) translocation were classified into grade I-III categories according to the current WHO guidelines. The IgVH gene segments were PCR-amplified, sequenced, and compared to their respective germline IgVH sequences. The neoplastic cells of grade I and II FLs revealed clonally related, but highly divergent IgVH gene sequences indicating the ongoing nature of somatic hypermutation. Grade III FL also showed extensive presence of somatic hypermutation, but these mutations were not associated with intraclonal divergence. Thus, these results suggest that grade I-II and grade III FL may represent different biological entities. The presence of ongoing somatic hypermutation of IgVH sequences in grade I and II FLs is compatible with direct follicular origin of these tumor cells, contrasting the homogenous, stable clones of grade III FL resembling a post-follicular stage of B-cell development. Our findings demonstrate that contrary to the three tiered cytological grading, molecular features of IgH genes classify FL into two distinct subcategories. These studies also suggest that with progression FL gains post-follicular–like molecular features and becomes independent of the germinal center microenvironment.

Stereotyped B-cell response that counteracts antigenic variation of influenza viruses.

Influenza A subtypes are categorized into group 1 and group 2 based on the hemagglutinin (HA) sequence. Owing to the phylogenetic distance of HAs in different groups, antibodies that bind multiple HA subtypes across different groups are extremely rare. In this study, we demonstrated that an immunization with acid-treated HA antigen elicits germinal center (GC) B cells that bind multiple HA subtypes in both group 1 and group 2. The cross-group GC B cells utilized mostly one VH gene (1S56) and exhibited a sign of clonal evolution within GCs. The 1S56-lineage IgGs derived from GC B cells were able to bind to HA protein on the infected cell surface but not to the native form of HA protein, suggesting the cryptic nature of the 1S56 epitope and its exposure in infected cells. Finally, the 1S56-lineage IgGs provided protection against lethal infection in an Fc-dependent manner, independent of the virus-neutralizing activity. Thus, we identified 1S56-lineage antibodies as a unique stereotype for achieving cross-group influenza specificity. The antigens exposing the 1S56 epitope may be good candidates for broadly protective immunogens.

Intestinal Anti-tissue Transglutaminase2 Autoantibodies: Pathogenic and Clinical Implications for Celiac Disease.

Celiac disease (CD) is a systemic disease that primarily affects the small intestine. The presence of anti-tissue transglutaminase 2 (anti-TG2) antibodies in the serum, as well as the presence of autoimmune phenomena, account for the inclusion of CD among autoimmune diseases. Anti-TG2 autoantibodies are produced at intestinal level, where they are deposited even before they appear in circulation. The pathogenic events that lead to their production are still not completely defined, but a central role seems to be played by gliadin-specific T cells. Interestingly, limited somatic mutations have been observed in VH and VL genes in TG2-specific plasma cells, another important aspect being the biased use of a heavy chain encoded by the VH5 gene. Conflicting data have been produced over the years on the effect of anti-TG2 antibodies on TG2 function. Although the presence of anti-TG2 antibodies in serum is considered a hallmark of CD and relevant from a clinical viewpoint, the role of these autoantibodies in the development of the celiac lesion remains to be defined. In the years, different technical approaches have been implemented to detect and measure intestinal CD-associated autoantibody production. Two aspects can make intestinal anti-TG2 antibodies relevant: from a clinical viewpoint: the first is their proposed ability in potential coeliac patients to predict the development of a full-blown enteropathy; the second is their possible role in revealing a condition of reactivity to gluten in patients with no circulating CD-associated autoantibodies. In fact, the detection of CD-specific autoantibodies production in the intestine, in the absence of serum positivity for the same antibodies, could be suggestive of a very early condition of gluten reactivity; alternatively, it could be not specific for CD and merely attributable to intestinal inflammation. In conclusion, the role of mucosal anti-TG2 antibodies in pathogenesis of CD is unknown. Their presence, the modalities of their production, their gluten dependence render them a unique model to study autoimmunity.

Correlation of PI3K upregulation with NOTCH2 mutations in ibrutinib-resistant mantle cell lymphoma.

e20065 Background: PI3K dysregulation has been linked to ibrutinib resistance in mantle cell lymphoma (MCL); however, the investigation of PI3K signaling as an important ibrutinib resistance mechanism has been rarely assessed in clinical samples. Therefore, we sought to more fully characterize PI3K dysregulation in ibrutinib-sensitive and -resistant MCL clinical samples at the genomic and transcriptomic levels. Methods: Whole exome sequencing (WES; n = 41) and RNA-seq (n = 93) were performed on fresh peripheral blood, apheresis, or biopsy patient primary samples. All analysis was performed using the BostonGene automated pipeline. Results: To evaluate ibrutinib resistance in MCL, we compared the activity of 11 cellular pathways calculated by PROGENy between ibrutinib-sensitive and -resistant MCL. The PI3K pathway was the most differentially expressed between the two groups (q < 0.005; > 1 median absolute deviation in ibrutinib-resistant MCL). Increased PI3K pathway expression in the ibrutinib-resistant MCL tumors strongly correlated with hyperproliferation (r = 0.49; p = 6e-07). Both hyperproliferation and enriched PI3K expression associated with more frequent NOTCH2 somatic mutations (~22% ibrutinib-resistant MCL with high PI3K expression (p = 0.004) and hyperproliferation (p = 0.003)) that generate a premature stop codon in the PEST domain, likely resulting in hyperactive NOTCH2. Frequent TP53 mutations were identified in ibrutinib-resistant MCL tumors (58%; 3-fold greater vs ibrutinib-sensitive tumors; p = 0.02) based on our cohort and the Agarwal et al., 2019, Nature Medicine cohort. PI3K signaling is a known p53 activator, which may lead to a compensatory tumor suppressive mechanism, indicating that PI3K activation may induce mutational pressure on TP53 to promote MCL survival. VH gene usage variability of the B-cell receptor (BCR), the inducer of PI3K signaling, was not different between ibrutinib-sensitive and -resistant MCL, suggesting that diverse BCR expression does not underlie enriched ibrutinib-resistant MCL PI3K expression. Conclusions: PI3K inhibitors have resulted in underwhelming MCL clinical outcomes; yet, the advent of next-generation PI3K inhibitors such as copanlisib with potentially greater efficacy and less toxicity warrants the continued investigation of PI3K signaling in ibrutinib-resistant MCL. We identified a strong correlation between gain-of-function NOTCH2 mutations and enriched PI3K signaling, suggesting that dual inhibition of NOTCH and PI3K may overcome ibrutinib resistance in MCL.

The immune system of children: the key to understanding SARS-CoV-2 susceptibility?

The immune system of children: the key to understanding SARS-CoV-2 susceptibility?

Early AID expression in developing B cells marks a population with a restricted IgH repertoire favoring D-proximal VH gene usage

Abstract Activation-induced cytidine deaminase (AID) is well characterized in germinal center reactions as a driver of secondary antibody diversification through the processes of somatic hypermutation and class-switch recombination, but recent reports from clinical and murine studies suggest an additional role during primary diversification. Specifically, inhibition or knockout of AID activity during B cell development results in increased IgM autoantibody production. Furthermore, the expression of AID during development appears to be driven by B cell receptor mediated recognition of autoantigens, including RNA and dsDNA. To examine the pattern of early AID expression, we used lineage tracing in an AID-Cre x R26R-EYFP mouse model to identify a subpopulation of AID experienced (AID-exp) pre-B cells. Sequencing of the IgH repertoire from the AID-exp subpopulation reveals a stark reduction in the diversity of VH gene usage compared to AID-naïve pre-B cells. The reduction in diversity is accompanied by enrichment for specific VH genes, including D-proximal elements associated with B1 cells and autoantibodies. Thus, we discern skewing within the AID-exp repertoire suggestive of antigen-dependent selection in the bone marrow compartment. Our results support the hypothesis that AID is induced in pre-B cells carrying an autoreactive heavy chain and effects tolerization to specific self-antigens.

Altered 3D chromatin structure permits inversional recombination at the IgH locus

Abstract Immunoglobulin heavy chain (IgH) genes are assembled by two sequential DNA rearrangement events that are initiated by recombinase activating gene products (RAG) 1 and 2. Diversity gene segments (DH) rearrange first, followed by variable (VH) gene rearrangements. Here we provide evidence that each rearrangement step is guided by different rules of engagement between rearranging gene segments. DH gene segments, that recombine by deletion of intervening DNA, must be located within a RAG1/2 scanning domain for efficient recombination. In the absence of intergenic control region 1, a regulatory sequence that delineates the RAG scanning domain on WT IgH alleles, VH and DH gene segments can recombine with each other by both deletion and inversion of intervening DNA. We propose that VH gene segments find their targets by diffusion-controlled mechanisms. These distinct mechanisms may underlie differential allelic choice associated with each step of IgH gene assembly.

Persistence of HIV-1 Env-Specific Plasmablast Lineages in Plasma Cells after Vaccination in Humans

SummaryInduction of persistent HIV-1 Envelope (Env) specific antibody (Ab) is a primary goal of HIV vaccine strategies; however, it is unclear whether HIV Env immunization in humans induces bone marrow plasma cells, the presumed source of long-lived systemic Ab. To define the features of Env-specific plasma cells after vaccination, samples were obtained from HVTN 105, a phase I trial testing the same gp120 protein immunogen, AIDSVAX B/E, used in RV144, along with a DNA immunogen in various prime and boost strategies. Boosting regimens that included AIDSVAX B/E induced robust peripheral blood plasmablast responses. The Env-specific immunoglobulin repertoire of the plasmablasts is dominated by VH1 gene usage and targeting of the V3 region. Numerous plasmablast-derived immunoglobulin lineages persisted in the bone marrow >8 months after immunization, including in the CD138+ long-lived plasma cell compartment. These findings identify a cellular linkage for the development of sustained Env-specific Abs following vaccination in humans.

The human antibody repertoire genetically encodes for both productive and non-productive targeting solutions against the same broadly neutralizing antibody epitope on influenza virus

Abstract A major obstacle to universal influenza vaccine development centers on the ability to elicit high titer responses against functionally conserved but immunologically subdominant features of this virus. Using a transgenic mouse vaccine model wherein antibodies develop with human CDRH3 diversity but are constrained to user defined antibody V genes, we have recently demonstrated that the human VH gene IGHV1-69 encodes for germline B cell receptors (BCRs) that naturally engage a conserved broadly neutralizing epitope on the hemagglutinin (HA) stalk of Group 1 influenza A viruses (IAV). Importantly, this VH endowment enables elicitation of an immunodominant bnAb response against IAV following vaccination with an engineered HA vaccine nanoparticle. However, IGHV1-69 is polymorphic with ~15% of the global population homozygous for alleles that bear a single nucleotide polymorphism (SNP) in CDRH2 (F54L) which confers germline binding to the bnAb target. To test the consequences of this, we applied our transgenic vaccine model to compare the capacity of IGHV1-69 vs IGHV1-69 SNP to elicit bnAb responses following immunization with our HA nanoparticle. We found that while both VH forms endow germline BCR targeting solutions to the same IAV bnAb site, only the WT form is productive following immunization. Germline competition within heterozygous animals (F54/L54) suggests that the capacity for pathway expansion arises via differences in the germline-endowed affinity for the same bnAb target. While globally, most humans utilize at least one copy of IGHV1-69 and would be predicted to support a bnAb response to our vaccine antigen, certain ethnicities show heightened usage of IGHV1-69 SNP and may therefore be limited by non-productive responses.

IgM+IgD− B cells in Human GALT Harbor Characteristics of B1 B cells

Abstract During embryogenesis, B cell lymphopoiesis occurs in fetal liver (FL) and bone marrow (BM). B cells derived from these organs differ in their Ig VH gene usage, their morphological and functional characteristics, and they home to different organs in the mature fetus. Although in mice, FL-B cells are known to home to the peritoneum and GALT, little is known of these cells in humans. We identified a FL-like B cell population representing 10–20% of total B cells in human GALT (appendix and tonsil), but only 1–2% in peripheral blood. These cells express IgM, but not IgD on their surface, spontaneously secrete antibodies in culture, and preferentially class-switch to IgA upon LPS stimulation, three characteristics of FL-B cells. The GALT IgM+IgD− B cells are negative for immature B cell markers CD10 and CD5, plasma cell markers CD38hi and CD138, the activation marker CD43 and the transitional B cell marker CD24hi as expected for FL B cells. In infants and children less than 10 years of age, most (70%) of these IgM+IgD− cells are CD27- non-memory B cells. These data support the hypothesis that the GALT IgM+IgD− B cells are of FL origin. Consistent with this idea, approximately 50% of the B cells in an appendix from a 1-day-old neonate were IgM+IgD−. Deep BCR sequence analysis of these cells will establish their developmental origin.

Next-generation sequencing of the intrahepatic antibody repertoire delineates a unique B-cell response in HBV-associated acute liver failure.

Hepatitis B virus (HBV) is a major cause of acute liver failure (ALF) worldwide. While liver damage in classic acute hepatitis B is believed to be T-cell mediated, the pathogenesis of HBV-associated ALF remains largely unknown. Access to liver specimens from well-characterized patients with HBV-associated ALF provided us with the opportunity to perform next-generation sequencing (NGS) of the entire VH repertoires of IgM and IgG from the livers of four ALF patients, a control liver donor and a patient with chronic HBV infection. We found that ALF is not associated with expansion of specific B-cell lineages. However, NGS showed that the intrahepatic VH repertoires from ALF patients were characterized by the abundant presence of antibodies in germline configuration in contrast to their marginal prevalence in controls. Moreover, NGS identified a large number of VH genes in germline configuration with identical VDJ sequences in the IgM and IgG repertoires in all four ALF patients, indicating that isotype switch from IgM to IgG had occurred without somatic hypermutation. The results of this study indicate that the presence of intrahepatic antibodies in unmutated germline configuration is a broad phenomenon in the global antibody repertoire generated from total RNA derived from whole-liver tissue that is strongly associated with ALF, suggesting a major role of T cell-independent humoral immunity in the pathogenesis of ALF.

Characteristics of Plasmablast Repertoire in Chronically HIV-Infected Individuals for Immunoglobulin H and L Chain Profiled by Single-Cell Analysis.

Characterization of the diversified immunoglobulin (Ig) repertoire may provide insight into pathways that shape an efficient antibody (Ab) repertoire for immune response against human immunodeficiency virus (HIV) infection. This study aimed to profile characteristics of the plasmablast repertoire during chronic HIV infection. Ig variable regions of plasmablasts from both chronically HIV-infected donors (HIVDs) previously treated with antiretroviral therapy (ART) and healthy donors (HDs) were amplified by single-cell PCR to establish the basis for further repertoire analysis. We compared the plasmablast repertoires expressed in multiple chronically HIVDs after ART treatment cessation and HDs. We also examined the non-productive repertoire to identify the indication of the immediate products of the rearrangement machinery without an impact of selection during HIV infection. We found multiple differences between the productive repertoires of HIVD and HD subjects, including biased usages of VH3-49, VH1-2, VH3-33, VH3-74, and VH5-51 in VH and D1-7, D1-14, D1-20, and D5-5/18 in D segments in the HIVD group, as well as shorter and preferential glycine usages in CDRH3 regions. Gene selections were also detected in light chains. Notably, differences between productive rearrangements of HIVDs and HDs outnumbered those between productive and non-productive rearrangements within HIVDs. HIV infection may exert a dominant impact on the development of the plasmablast repertoire. The impact of selection is of limited significance in shaping the plasmablast repertoire. Overall, the data indicate that the environment in which the plasmablasts live can affect the distribution of the VH and VL genes in the repertoire and the amino acid compositions of the expressed Abs.

IL-7R Signalling Activates Widespread V <sub>H</sub> and D <sub>H</sub> Gene Usage to Drive Antibody Diversity in Bone Marrow B Cells

Generation of the primary antibody repertoire requires V(D)J recombination of hundreds of gene segments in the immunoglobulin heavy chain (Igh) locus. It has been proposed that interleukin-7 receptor (IL-7R) signalling is necessary for Igh recombination, but this has been challenging to partition from the receptor’s role in B cell survival and proliferation. By generating the first detailed description of the Igh repertoire of murine IL-7Rα-/- bone marrow B cells, we demonstrate that IL-7R signalling profoundly influences VH gene selection during VH-to-DJH recombination. We find skewing towards usage of 3’ VH genes during de novo VH-to-DJH recombination that is more severe than the fetal liver (FL) B cell repertoire, and we now show a role for IL-7R signalling in DH-to-JH recombination. Transcriptome and accessibility analyses suggests reduced expression of B lineage-specific transcription factors (TFs) and their targets, and loss of DH and VH antisense transcription in IL-7Rα-/- B cells. These results refute models suggesting that IL-7R signalling is only required for survival and proliferation, and demonstrate a pivotal role in shaping the Igh repertoire by activating underpinning epigenetic mechanisms.

Longitudinal analysis of the antibody repertoire of a Zika virus-infected patient revealed dynamic changes in antibody response

ABSTRACT The Zika virus (ZIKV) is a mosquito-borne flavivirus that causes neonatal abnormalities and other disorders. Antibodies to the ZIKV envelope (E) protein can block infection. In this study, next-generation sequencing (NGS) of immunoglobulin heavy chain (IgH) mRNA transcripts was combined with single-cell PCR cloning of E-binding monoclonal antibodies for analysing antibody response in a patient from the early stages of infection to more than one year after the clearance of the virus. The patient's IgH repertoire 14 and 64 days after symptom onset showed dramatic dominant clonal expansion but low clonal diversity. IgH repertoire 6 months after disease-free status had few dominant clones but increased diversity. E-binding antibodies appeared abundantly in the repertoire during the early stages of infection but quickly declined after clearance of the virus. Certain VH genes such as VH5-10-1 and VH4-39 appeared to be preferentially enlisted for a rapid antibody response to ZIKV infection. Most of these antibodies require relatively few somatic hypermutations to acquire the ability to bind to the E protein, pointing to a possible mechanism for rapid defence against ZIKV infection. This study provides a unique and holistic view of the dynamic changes and characteristics of the antibody response to ZIKV infection.

Analysis of Factors Predictive of Risk of Transformation and Time to Transformation in Patients (pts) with Mantle Cell Lymphoma - Cohort Study of 369 Patients

Analysis of Factors Predictive of Risk of Transformation and Time to Transformation in Patients (pts) with Mantle Cell Lymphoma - Cohort Study of 369 Patients