Public Immunity: Evolutionary Spandrels for Pathway-Amplifying Protective Antibodies

Humoral immunity is seeded by affinity between the B cell receptor (BCR) and cognate antigen. While the BCR is a chimeric display of diverse antigen engagement solutions, we discuss its functional activity as an ‘innate-like’ immune receptor, wherein genetically hardwired antigen complementarity can serve as reproducible templates for pathway-amplifying otherwise immunologically recessive antibody responses. We propose that the capacity for germline reactivity to new antigen emerged as a set of evolutionary spandrels or coupled traits, which can now be exploited by rational vaccine design to focus humoral immunity upon conventionally immune-subdominant antibody targets. Accordingly, we suggest that evolutionary spandrels account for the necessary but unanticipated antigen reactivity of the germline antibody repertoire.

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PTIP chromatin regulator controls development and activation of B cell subsets to license humoral immunity in mice

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1707938114 ◽

2017 ◽

Vol 114 (44) ◽

pp. E9328-E9337 ◽

Cited By ~ 4

Author(s):

Dan Su ◽

Stijn Vanhee ◽

Rebeca Soria ◽

Elin Jaensson Gyllenbäck ◽

Linda M. Starnes ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Humoral Immunity ◽

Cell Activation ◽

Cell Receptor ◽

B Cell Receptor ◽

Transactivation Domain ◽

B Cell Activation ◽

Chromatin Regulator ◽

B Cell Subsets

B cell receptor signaling and downstream NF-κB activity are crucial for the maturation and functionality of all major B cell subsets, yet the molecular players in these signaling events are not fully understood. Here we use several genetically modified mouse models to demonstrate that expression of the multifunctional BRCT (BRCA1 C-terminal) domain-containing PTIP (Pax transactivation domain-interacting protein) chromatin regulator is controlled by B cell activation and potentiates steady-state and postimmune antibody production in vivo. By examining the effects of PTIP deficiency in mice at various ages during ontogeny, we demonstrate that PTIP promotes bone marrow B cell development as well as the neonatal establishment and subsequent long-term maintenance of self-reactive B-1 B cells. Furthermore, we find that PTIP is required for B cell receptor- and T:B interaction-induced proliferation, differentiation of follicular B cells during germinal center formation, and normal signaling through the classical NF-κB pathway. Together with the previously identified role for PTIP in promoting sterile transcription at the Igh locus, the present results establish PTIP as a licensing factor for humoral immunity that acts at several junctures of B lineage maturation and effector cell differentiation by controlling B cell activation.

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IL-7 Enables Antibody Responses to Bacterial Polysaccharides by Promoting B Cell Receptor Diversity

The Journal of Immunology ◽

10.4049/jimmunol.1800162 ◽

2018 ◽

Vol 201 (4) ◽

pp. 1229-1240 ◽

Cited By ~ 2

Author(s):

Gregory S. Dickinson ◽

Eric A. Levenson ◽

Justin A. Walker ◽

John F. Kearney ◽

Kishore R. Alugupalli

Keyword(s):

B Cell ◽

Cell Receptor ◽

B Cell Receptor ◽

Antibody Responses

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B Cell–Intrinsic STING Signaling Triggers Cell Activation, Synergizes with B Cell Receptor Signals, and Promotes Antibody Responses

The Journal of Immunology ◽

10.4049/jimmunol.1701405 ◽

2018 ◽

Vol 201 (9) ◽

pp. 2641-2653 ◽

Cited By ~ 12

Author(s):

Melissa M. Walker ◽

Bergren W. Crute ◽

John C. Cambier ◽

Andrew Getahun

Keyword(s):

B Cell ◽

Cell Activation ◽

Cell Receptor ◽

B Cell Receptor ◽

Antibody Responses

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Exploiting B Cell Receptor Analyses to Inform on HIV-1 Vaccination Strategies

Vaccines ◽

10.3390/vaccines8010013 ◽

2020 ◽

Vol 8 (1) ◽

pp. 13 ◽

Cited By ~ 4

Author(s):

Christoph Kreer ◽

Henning Gruell ◽

Thierry Mora ◽

Aleksandra M. Walczak ◽

Florian Klein

Keyword(s):

B Cell ◽

Cell Receptor ◽

B Cell Receptor ◽

Antibody Repertoire ◽

Human Antibody ◽

Malignant Cells ◽

Vaccination Strategies ◽

Receptor Repertoire ◽

Hiv 1 ◽

Cell Receptor Repertoire

The human antibody repertoire is generated by the recombination of different gene segments as well as by processes of somatic mutation. Together these mechanisms result in a tremendous diversity of antibodies that are able to combat various pathogens including viruses and bacteria, or malignant cells. In this review, we summarize the opportunities and challenges that are associated with the analyses of the B cell receptor repertoire and the antigen-specific B cell response. We will discuss how recent advances have increased our understanding of the antibody response and how repertoire analyses can be exploited to inform on vaccine strategies, particularly against HIV-1.

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B cell receptor-mediated uptake of CD1d-restricted antigen augments antibody responses by recruiting invariant NKT cell help in vivo

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0802968105 ◽

2008 ◽

Vol 105 (24) ◽

pp. 8345-8350 ◽

Cited By ~ 145

Author(s):

P. Barral ◽

J. Eckl-Dorna ◽

N. E. Harwood ◽

C. De Santo ◽

M. Salio ◽

...

Keyword(s):

B Cell ◽

Cell Receptor ◽

B Cell Receptor ◽

Antibody Responses ◽

Nkt Cell ◽

Invariant Nkt Cell

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Antibody-Mediated Coengagement of FcγRIIb and B Cell Receptor Complex Suppresses Humoral Immunity in Systemic Lupus Erythematosus

The Journal of Immunology ◽

10.4049/jimmunol.1003412 ◽

2011 ◽

Vol 186 (7) ◽

pp. 4223-4233 ◽

Cited By ~ 88

Author(s):

Holly M. Horton ◽

Seung Y. Chu ◽

Elizabeth C. Ortiz ◽

Erik Pong ◽

Saso Cemerski ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

B Cell ◽

Humoral Immunity ◽

Lupus Erythematosus ◽

Cell Receptor ◽

B Cell Receptor ◽

Receptor Complex ◽

Systemic Lupus

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Distorted antibody repertoire developed in the absence of pre-B cell receptor formation

Biochemical and Biophysical Research Communications ◽

10.1016/j.bbrc.2017.11.171 ◽

2018 ◽

Vol 495 (1) ◽

pp. 1411-1417 ◽

Cited By ~ 2

Author(s):

Lin Sun ◽

Naoko Kono ◽

Takeyuki Shimizu ◽

Hiroyuki Toh ◽

Hanbing Xue ◽

...

Keyword(s):

B Cell ◽

Cell Receptor ◽

B Cell Receptor ◽

Antibody Repertoire

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Using B cell receptor lineage structures to predict affinity

PLoS Computational Biology ◽

10.1371/journal.pcbi.1008391 ◽

2020 ◽

Vol 16 (11) ◽

pp. e1008391

Author(s):

Duncan K. Ralph ◽

Frederick A. Matsen

Keyword(s):

B Cell ◽

Real Data ◽

Cell Receptor ◽

B Cell Receptor ◽

Evolutionary Information ◽

Additional Source ◽

Link Type ◽

The Family ◽

Cognate Antigen ◽

Generation Sequencing

We are frequently faced with a large collection of antibodies, and want to select those with highest affinity for their cognate antigen. When developing a first-line therapeutic for a novel pathogen, for instance, we might look for such antibodies in patients that have recovered. There exist effective experimental methods of accomplishing this, such as cell sorting and baiting; however they are time consuming and expensive. Next generation sequencing of B cell receptor (BCR) repertoires offers an additional source of sequences that could be tapped if we had a reliable method of selecting those coding for the best antibodies. In this paper we introduce a method that uses evolutionary information from the family of related sequences that share a naive ancestor to predict the affinity of each resulting antibody for its antigen. When combined with information on the identity of the antigen, this method should provide a source of effective new antibodies. We also introduce a method for a related task: given an antibody of interest and its inferred ancestral lineage, which branches in the tree are likely to harbor key affinity-increasing mutations? We evaluate the performance of these methods on a wide variety of simulated samples, as well as two real data samples. These methods are implemented as part of continuing development of the partis BCR inference package, available at https://github.com/psathyrella/partis. Comments Please post comments or questions on this paper as new issues at https://git.io/Jvxkn.

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Dynamics of the Human Antibody Repertoire following B-cell Depletion in Systemic Sclerosis

10.1101/139758 ◽

2017 ◽

Cited By ~ 2

Author(s):

Charles F. A. de Bourcy ◽

Cornelia L. Dekker ◽

Mark M. Davis ◽

Mark R. Nicolls ◽

Stephen R. Quake

Keyword(s):

Systemic Sclerosis ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

B Cell ◽

Cell Receptor ◽

B Cell Receptor ◽

Cell Depletion ◽

Antibody Repertoire ◽

B Cell Depletion ◽

Pulmonary Arterial

AbstractSystemic sclerosis with pulmonary arterial hypertension (SSc-PAH) is a debilitating and frequently lethal disease of unknown cause lacking effective treatment options. Lymphocyte anomalies and autoantibodies observed in systemic sclerosis have suggested an autoimmune character. Here we study the clonal structure of the B-cell repertoire in SSc-PAH using immunoglobulin heavy-chain sequencing before and after B-cell depletion. We found SSc-PAH to be associated with anomalies in B-cell development, namely altered VDJ rearrangement frequencies (reduced IGHV2-5 segment usage) and an increased somatic mutation-fixation probability in expanded B-cell lineages. SSc-PAH was also characterized by anomalies in B-cell homeostasis, namely an expanded IgD+proportion with reduced mutation loads and an expanded proportion of highly antibody-secreting cells. Disease signatures pertaining to IGHV2-5 segment usage, IgD proportions and mutation loads were temporarily reversed after B-cell depletion. Analyzing the time course of B-cell depletion, we find that the kinetics of naïve replenishment are predictable from baseline measurements alone, that release of plasma cells into the periphery can precede naïve replenishment and that modes of B-cell receptor diversity are highly elastic. Our findings shed light on the humoral immune basis of SSc-PAH and provide insights into the effect of B-cell depletion on the antibody repertoire.AbbreviationsSSc-PAHSystemic sclerosis with pulmonary arterial hypertensionIGHimmunoglobulin heavy-chainBCRB-cell receptorCDR3complementarity-determining region 3IgimmunoglobulinAAamino acid

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