Increased Steady-State Memory B Cell Subsets Among High-Risk Participants in an HIV Vaccine Trial

Influenza is a highly contagious viral respiratory disease that affects million of people worldwide each year. Annual vaccination is recommended by the World Health Organization with the goal of reducing influenza severity and limiting transmission through elicitation of antibodies targeting the hemagglutinin (HA) glycoprotein. The antibody response elicited by current seasonal influenza virus vaccines is predominantly strain-specific, but pre-existing influenza virus immunity can greatly impact the serological antibody response to vaccination. However, it remains unclear how B cell memory is shaped by recurrent annual vaccination over the course of multiple seasons, especially in high-risk elderly populations. Here, we systematically profiled the B cell response in young adult (18–34 year old) and elderly (65+ year old) vaccine recipients that received annual split inactivated influenza virus vaccination for 3 consecutive seasons. Specifically, the antibody serological and memory B-cell compartments were profiled for reactivity against current and historical influenza A virus strains. Moreover, multiparametric analysis and antibody landscape profiling revealed a transient increase in strain-specific antibodies in the elderly, but with an impaired recall response of pre-existing memory B-cells, plasmablast (PB) differentiation and long-lasting serological changes. This study thoroughly profiles and compares the immune response to recurrent influenza virus vaccination in young and elderly participants unveiling the pitfalls of current influenza virus vaccines in high-risk populations.

Complexity of the human memory B-cell compartment is determined by the versatility of clonal diversification in germinal centers

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1511270112 ◽

2015 ◽

Vol 112 (38) ◽

pp. E5281-E5289 ◽

Cited By ~ 29

Author(s):

Bettina Budeus ◽

Stefanie Schweigle de Reynoso ◽

Martina Przekopowitz ◽

Daniel Hoffmann ◽

Marc Seifert ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Cell Clone ◽

Human Memory ◽

Memory B Cells ◽

Sequencing Analysis ◽

Cell Compartment ◽

Memory B Cell ◽

Cell Clones ◽

B Cell Subsets

Our knowledge about the clonal composition and intraclonal diversity of the human memory B-cell compartment and the relationship between memory B-cell subsets is still limited, although these are central issues for our understanding of adaptive immunity. We performed a deep sequencing analysis of rearranged immunoglobulin (Ig) heavy chain genes from biological replicates, covering more than 100,000 memory B lymphocytes from two healthy adults. We reveal a highly similar B-cell receptor repertoire among the four main human IgM+ and IgG+ memory B-cell subsets. Strikingly, in both donors, 45% of sequences could be assigned to expanded clones, demonstrating that the human memory B-cell compartment is characterized by many, often very large, B-cell clones. Twenty percent of the clones consisted of class switched and IgM+(IgD+) members, a feature that correlated significantly with clone size. Hence, we provide strong evidence that the vast majority of Ig mutated B cells—including IgM+IgD+CD27+ B cells—are post-germinal center (GC) memory B cells. Clone members showed high intraclonal sequence diversity and high intraclonal versatility in Ig class and IgG subclass composition, with particular patterns of memory B-cell clone generation in GC reactions. In conclusion, GC produce amazingly large, complex, and diverse memory B-cell clones, equipping the human immune system with a versatile and highly diverse compartment of IgM+(IgD+) and class-switched memory B cells.

Alterations in memory B cell subsets upon immunization against Streptococcus pneumoniae in HIV-1 infected adults

HIV & AIDS Review ◽

10.1016/j.hivar.2015.05.002 ◽

2015 ◽

Vol 14 (4) ◽

pp. 143-147

Author(s):

Olga Tsachouridou ◽

Lemonia Skoura ◽

Pantelis Zebekakis ◽

Apostolia Margariti ◽

Antonios Galanos ◽

...

Keyword(s):

Streptococcus Pneumoniae ◽

B Cell ◽

Memory B Cell ◽

B Cell Subsets ◽

Hiv 1

Differential localization of memory B cell subsets

The FASEB Journal ◽

10.1096/fasebj.22.2_supplement.370 ◽

2008 ◽

Vol 22 (S2) ◽

pp. 370-370

Author(s):

Joseph Gene Dauner ◽

Craig P. Chappell ◽

Joshy Jacob

Keyword(s):

B Cell ◽

Memory B Cell ◽

Differential Localization ◽

B Cell Subsets

Human memory B cells originate from three distinct germinal center-dependent and -independent maturation pathways

Blood ◽

10.1182/blood-2011-04-345579 ◽

2011 ◽

Vol 118 (8) ◽

pp. 2150-2158 ◽

Cited By ~ 217

Author(s):

Magdalena A. Berkowska ◽

Gertjan J. A. Driessen ◽

Vasilis Bikos ◽

Christina Grosserichter-Wagener ◽

Kostas Stamatopoulos ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Germinal Center ◽

Somatic Hypermutation ◽

Phenotypic Diversity ◽

Human Memory ◽

Memory B Cells ◽

Memory B Cell ◽

Effector Cells ◽

B Cell Subsets

Abstract Multiple distinct memory B-cell subsets have been identified in humans, but it remains unclear how their phenotypic diversity corresponds to the type of responses from which they originate. Especially, the contribution of germinal center-independent responses in humans remains controversial. We defined 6 memory B-cell subsets based on their antigen-experienced phenotype and differential expression of CD27 and IgH isotypes. Molecular characterization of their replication history, Ig somatic hypermutation, and class-switch profiles demonstrated their origin from 3 different pathways. CD27−IgG+ and CD27+IgM+ B cells are derived from primary germinal center reactions, and CD27+IgA+ and CD27+IgG+ B cells are from consecutive germinal center responses (pathway 1). In contrast, natural effector and CD27−IgA+ memory B cells have limited proliferation and are also present in CD40L-deficient patients, reflecting a germinal center-independent origin. Natural effector cells at least in part originate from systemic responses in the splenic marginal zone (pathway 2). CD27−IgA+ cells share low replication history and dominant Igλ and IgA2 use with gut lamina propria IgA+ B cells, suggesting their common origin from local germinal center-independent responses (pathway 3). Our findings shed light on human germinal center-dependent and -independent B-cell memory formation and provide new opportunities to study these processes in immunologic diseases.

Alterations of naïve and memory B-cell subsets are associated with risk of rejection and infection in heart recipients

Transplant International ◽

10.1111/tri.12131 ◽

2013 ◽

Vol 26 (8) ◽

pp. 800-812 ◽

Cited By ~ 11

Author(s):

Nallibe Lanio ◽

Elizabeth Sarmiento ◽

Antonio Gallego ◽

Leticia Calahorra ◽

María Jaramillo ◽

...

Keyword(s):

B Cell ◽

Memory B Cell ◽

B Cell Subsets

Erratum to: TLR1/2, TLR7, and TLR9 Signals Directly Activate Human Peripheral Blood Naive and Memory B Cell Subsets to Produce Cytokines, Chemokines, and Hematopoietic Growth Factors

Journal of Clinical Immunology ◽

10.1007/s10875-010-9471-9 ◽

2010 ◽

Vol 31 (1) ◽

pp. 136-136 ◽

Cited By ~ 2

Author(s):

Sudhanshu Agrawal ◽

Sudhir Gupta

Keyword(s):

Growth Factors ◽

B Cell ◽

Peripheral Blood ◽

Human Peripheral Blood ◽

Hematopoietic Growth Factors ◽

Memory B Cell ◽

B Cell Subsets

Optimisation of ex vivo memory B cell expansion/differentiation for interrogation of rare peripheral memory B cell subset responses

Wellcome Open Research ◽

10.12688/wellcomeopenres.11386.2 ◽

2018 ◽

Vol 2 ◽

pp. 97 ◽

Cited By ~ 1

Author(s):

Luke Muir ◽

Paul F. McKay ◽

Velislava N. Petrova ◽

Oleksiy V. Klymenko ◽

Sven Kratochvil ◽

...

Keyword(s):

Cell Culture ◽

B Cells ◽

B Cell ◽

Cell Expansion ◽

Ex Vivo ◽

Cell Subset ◽

Human Memory ◽

Memory B Cells ◽

Memory B Cell ◽

B Cell Subsets

Background:Human memory B cells play a vital role in the long-term protection of the host from pathogenic re-challenge. In recent years the importance of a number of different memory B cell subsets that can be formed in response to vaccination or infection has started to become clear. To study memory B cell responses, cells can be culturedex vivo,allowing for an increase in cell number and activation of these quiescent cells, providing sufficient quantities of each memory subset to enable full investigation of functionality. However, despite numerous papers being published demonstrating bulk memory B cell culture, we could find no literature on optimised conditions for the study of memory B cell subsets, such as IgM+memory B cells.Methods:Following a literature review, we carried out a large screen of memory B cell expansion conditions to identify the combination that induced the highest levels of memory B cell expansion. We subsequently used a novel Design of Experiments approach to finely tune the optimal memory B cell expansion and differentiation conditions for human memory B cell subsets. Finally, we characterised the resultant memory B cell subpopulations by IgH sequencing and flow cytometry.Results:The application of specific optimised conditions induce multiple rounds of memory B cell proliferation equally across Ig isotypes, differentiation of memory B cells to antibody secreting cells, and importantly do not alter the Ig genotype of the stimulated cells. Conclusions:Overall, our data identify a memory B cell culture system that offers a robust platform for investigating the functionality of rare memory B cell subsets to infection and/or vaccination.