Immunoglobulin heavy chain expression shapes the B cell receptor repertoire in human B cell development

Meffre, Eric; Milili, Michèle; Blanco-Betancourt, Carla; Antunes, Henedina; Nussenzweig, Michel C.; Schiff, Claudine

doi:10.1172/jci13051

Cited by 136 publications

(65 citation statements)

References 82 publications

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“…This can be abrogated, without loss of specificity, by changing amino acids at the edge of the CDR3 156. In addition to decreasing hydrophobicity through early B cell development,84, 150, 157 we have seen a decreased hydrophobicity in memory cells compared to naïve cells,82 which would be consistent with tolerance selection during an immune response.…”

Section: Cdr3 Characteristicssupporting

confidence: 56%

Immunoglobulin gene analysis as a tool for investigating human immune responses

Dunn-Walters

Townsend

Sinclair

et al. 2018

Immunological Reviews

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SummaryThe human immunoglobulin repertoire is a hugely diverse set of sequences that are formed by processes of gene rearrangement, heavy and light chain gene assortment, class switching and somatic hypermutation. Early B cell development produces diverse IgM and IgD B cell receptors on the B cell surface, resulting in a repertoire that can bind many foreign antigens but which has had self‐reactive B cells removed. Later antigen‐dependent development processes adjust the antigen affinity of the receptor by somatic hypermutation. The effector mechanism of the antibody is also adjusted, by switching the class of the antibody from IgM to one of seven other classes depending on the required function. There are many instances in human biology where positive and negative selection forces can act to shape the immunoglobulin repertoire and therefore repertoire analysis can provide useful information on infection control, vaccination efficacy, autoimmune diseases, and cancer. It can also be used to identify antigen‐specific sequences that may be of use in therapeutics. The juxtaposition of lymphocyte development and numerical evaluation of immune repertoires has resulted in the growth of a new sub‐speciality in immunology where immunologists and computer scientists/physicists collaborate to assess immune repertoires and develop models of immune action.

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Section: Cdr3 Characteristicssupporting

confidence: 56%

Immunoglobulin gene analysis as a tool for investigating human immune responses

Dunn-Walters

Townsend

Sinclair

et al. 2018

Immunological Reviews

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“…1). Longer CDR3 lengths have been associated with both auto‐ and polyreactivity 48. Interestingly, patients with SLE display significantly shorter CDR3 lengths in B‐cells from peripheral blood46 than controls.…”

Section: Slementioning

confidence: 99%

Antibody repertoire analysis in polygenic autoimmune diseases

2018

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SummaryHigh‐throughput sequencing of the DNA/RNA encoding antibody heavy‐ and light‐chains is rapidly transforming the field of adaptive immunity. It can address key questions, including: (i) how the B‐cell repertoire differs in health and disease; and (ii) if it does differ, the point(s) in B‐cell development at which this occurs. The advent of technologies, such as whole‐genome sequencing, offers the chance to link abnormalities in the B‐cell antibody repertoire to specific genomic variants and polymorphisms. Here, we discuss the current research using B‐cell antibody repertoire sequencing in three polygenic autoimmune diseases where there is good evidence for a pathological role for B‐cells, namely systemic lupus erythematosus, multiple sclerosis and rheumatoid arthritis. These autoimmune diseases exhibit significantly skewed B‐cell receptor repertoires compared with healthy controls. Interestingly, some common repertoire defects are shared between diseases, such as elevated IGHV4‐34 gene usage. B‐cell clones have effectively been characterized and tracked between different tissues and blood in autoimmune disease. It has been hypothesized that these differences may signify differences in B‐cell tolerance; however, the mechanisms and implications of these defects are not clear.

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“…In addition to autoreactivity, bnAbs usually have a high degree of somatic mutation and/or long heavy‐chain complementarity determining region 3 (HCDR3) loops,85 and no reported bnAb lacks all three characteristics. Autoreactivity, long HCDR3 loops, and high levels of somatic hypermutation are also associated with antibodies made by B cells that are deleted by central and peripheral tolerance controls 86, 87. Furthermore, studies of antibody knock‐in mice (engineered to have B cells with the potential to express immunoglobulins (Igs) composed of the variable region heavy (V H ) and variable region light (V L ) chains of mature bnAbs or their germline precursors) have demonstrated that B cells expressing many different bnAbs or bnAb precursors are under strong tolerance control,88, 89, 90, 91, 92, 93 although this does not hold for all bnAbs studied 89…”

Section: Development Of Broadly Neutralizing Antibodies In Hiv‐1 Infementioning

confidence: 99%

Immunologic characteristics of HIV‐infected individuals who make broadly neutralizing antibodies

Borrow

Moody

2017

Immunological Reviews

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SummaryInduction of broadly neutralizing antibodies (bnAbs) capable of inhibiting infection with diverse variants of human immunodeficiency virus type 1 (HIV‐1) is a key, as‐yet‐unachieved goal of prophylactic HIV‐1 vaccine strategies. However, some HIV‐infected individuals develop bnAbs after approximately 2‐4 years of infection, enabling analysis of features of these antibodies and the immunological environment that enables their induction. Distinct subsets of CD4+ T cells play opposing roles in the regulation of humoral responses: T follicular helper (Tfh) cells support germinal center formation and provide help for affinity maturation and the development of memory B cells and plasma cells, while regulatory CD4+ (Treg) cells including T follicular regulatory (Tfr) cells inhibit the germinal center reaction to limit autoantibody production. BnAbs exhibit high somatic mutation frequencies, long third heavy‐chain complementarity determining regions, and/or autoreactivity, suggesting that bnAb generation is likely to be highly dependent on the activity of CD4+ Tfh cells, and may be constrained by host tolerance controls. This review discusses what is known about the immunological environment during HIV‐1 infection, in particular alterations in CD4+ Tfh, Treg, and Tfr populations and autoantibody generation, and how this is related to bnAb development, and considers the implications for HIV‐1 vaccine design.

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Immunoglobulin heavy chain expression shapes the B cell receptor repertoire in human B cell development

Cited by 136 publications

References 82 publications

Immunoglobulin gene analysis as a tool for investigating human immune responses

Immunoglobulin gene analysis as a tool for investigating human immune responses

Antibody repertoire analysis in polygenic autoimmune diseases

Immunologic characteristics of HIV‐infected individuals who make broadly neutralizing antibodies

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