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/jci200113051

Cited by 61 publications

(75 citation statements)

References 70 publications

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“…We have also reported the case of a girl, referred to as the Igl -/-patient [7,12], in whom we identified a cytosine insertion at the beginning of the CH1 exon of the IGHM gene, resulting in a stop codon at position 48, and in the absence of Igl chain expression. The patient reported in this paper, designated as the Igl D case [8], with a large 165 to 265 kb homologous deletion of the IGH locus encompassing the IGHM gene, represents a new case of Igl defect. Altogether we can conclude that Igl alterations account for most of the reported cases of autosomal recessive agammaglobulinemia.…”

Section: Discussionmentioning

confidence: 97%

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A new case of autosomal recessive agammaglobulinaemia with impaired pre-B cell differentiation due to a large deletion of the IGH locus

et al. 2002

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A new case of autosomal recessive agammaglobulinaemia with impaired pre-B cell differentiation due to a large deletion of the IGH locus Abstract Males with X-linked agammaglobulinaemia (XLA) due to mutations in the Bruton tyrosine kinase gene constitute the major group of congenital hypogammaglobulinaemia with absence of peripheral B cells. In these cases, blockages between the pro-B and pre-B cell stage in the bone marrow are found. The remaining male and female cases clinically similar to XLA represent a genotypically heterogeneous group of diseases. In these patients, various autosomal recessive disorders have been identified such as mutations affecting IGHM, CD79A, IGLL1 genes involved in the composition of the pre-B cell receptor (pre-BCR) or the BLNK gene implicated in pre-BCR signal transduction. In this paper, we report on a young female patient characterised by a severe non-XLA agammaglobulinaemia that represents a new case of Igl defect. We show that the B cell blockage at the pro-B to pre-B cell transition is due to a large homologous deletion in the IGH locus encompassing the IGHM gene leading to the inability to form a functional pre-BCR. The deletion extends from the beginning of the diversity (D) region to the IGHG2 gene, with all JH segments and IGHM, IGHD, IGHG3 and IGHG1 genes missing. Conclusion: alteration in Igl expression seems to be relatively frequent and could account for most of the reported cases of autosomal recessive agammaglobulinaemia.Keywords Agammaglobulinaemia AE B cell blockage AE IGH locus AE Immunoglobulin gene deletion AE Pre-B cellAbbreviations BET: ethidium bromide AE BTK: Bruton tyrosine kinase gene AE IGH: immunoglobulin heavy chain locus AE pre-BCR: pre-B cell receptor AE XLA: X-linked agammaglobulinaemia IntroductionRecurrent infections, mostly respiratory, with pyogenic bacteria are the predominant manifestations of children suffering antibody deficiencies. In some of these patients, early B cell development in the bone marrow is arrested and hypogammaglobulinaemia results from the absence of peripheral B cells. In these cases, chronic diarrhoea could also be observed and constitutes a serious clinical problem. This occurs in X-linked agammaglobulinaemia (XLA), also known as Bruton disease, characterised by defects in the Bruton tyrosine kinase gene (BTK) [13,14] that encodes the cytoplasmic tyrosine kinase btk, involved in signal transduction. In these cases, B cell development is blocked in the bone marrow at the pre-B cell stage, resulting in the accumulation of CD34+ CD19+ pro-B cells and in the presence of variable numbers of CD34-CD19+ pre-B cells. Females with a phenotype indistinguishable from XLA have also been described and Conley et al. [2] have estimated that these immunodeficiencies represent 10% of patients with congenital hypogammaglobulinaemia. The defects behind such autosomal recessive disorders have been recently identified and shown to affect predominantly the pre-B cell receptor (pre-BCR), which is an absolute prerequisite for pro-B to pre-B cell ...

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Section: Discussionmentioning

confidence: 97%

“…These observations also emphasise the requirement of signalling via a functional pre-BCR to ensure normal early B cell differentiation. Moreover, the absence of Igl chains in Igl -/-and Igl D patients, has provided an opportunity to elucidate the role of Igl in selecting the antibody repertoire in humans [8].…”

Section: Discussionmentioning

confidence: 99%

A new case of autosomal recessive agammaglobulinaemia with impaired pre-B cell differentiation due to a large deletion of the IGH locus

et al. 2002

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“…Recombined IGH, IGK, and IGL genes were PCR-amplified as described previously using V H -leader, V , and V consensus forward primers with corresponding C H , C , and C reverse primers. [14][15][16] PCR products were cloned into TA cloning vector (Life Technologies) and sequenced using M13 forward and reverse primers. Sequences were analyzed with IgBLAST (http://www.ncbi.nlm.nih.gov/ igblast/) and JOINSOLVER (http://joinsolver.niaid.nih.gov) programs, as described previously.…”

Section: Ig Gene Sequence Analysismentioning

confidence: 99%

Humans with chronic granulomatous disease maintain humoral immunologic memory despite low frequencies of circulating memory B cells

Moir¹,

Ravin²,

Santich³

et al. 2012

Blood

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“…Under normal circumstances, these polyreactive B cells may be subjected to B cell downregulation control mechanisms such as anergy, receptor editing, and B cell deletion [14,129,130]. A corollary hypothesis is that patients with diseases associated with B cell tolerance defects such as systemic lupus erythematosus (SLE) may be able to make a more salutary B cell response when infected with HIV-1.…”

Section: Antibody Escape and Evasion Mechanisms Of Hiv-1mentioning

confidence: 99%

“…In this regard, we have recently found that 2F5 and 4E10 mAbs bind to their nominal gp41 epitopes anchored in liposomes in a two step conformational change model. This model suggests that these two mAbs initially bind and induce a conformational change in the lipid-gp41 antigen that exposes the full mAb binding site (ALAM M, HAYNES B, UNPUBLISHED DATA).Under normal circumstances, these polyreactive B cells may be subjected to B cell downregulation control mechanisms such as anergy, receptor editing, and B cell deletion [14,129,130]. A corollary hypothesis is that patients with diseases associated with B cell tolerance defects such as systemic lupus erythematosus (SLE) may be able to make a more salutary B cell response when infected with HIV-1.…”

mentioning

confidence: 99%

Aiming to induce broadly reactive neutralizing antibody responses with HIV-1 vaccine candidates

Haynes¹,

Montefiori²

2006

Expert Review of Vaccines

103

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Neutralizing antibody induction is a key feature of many effective vaccines and is the only immune response that has proven to be capable of completely blocking AIDS virus infection in animal models. Unfortunately, the extensive genetic variability and complex immune-evasion strategies of HIV-1 have thwarted all attempts to date at eliciting an effective neutralizing antibody response with candidate HIV-1 vaccine immunogens. Recent advances in our understanding of how these evasion strategies operate, coupled with growing progress in unravelling the structure and immunobiology of the viral envelope glycoproteins, are contributing to novel immunogen designs to overcome the many barriers to inducing protective antibodies against HIV-1. Keywordsantiretroviral therapy; HIV-1; host cell fusion; immunogen; neutralizing antibody induction Development of a safe, practical and effective HIV-1 vaccine is one of the highest priorities of the global scientific community [1,2]. Although antiretroviral therapy (ART) has dramatically prolonged the lives of HIV-1 infected patients, ART is not yet routinely available in developing countries, and the global rate of spread of HIV-1 continues unabated. If no effective AIDS vaccine is developed by 2010, the number of people infected world-wide with HIV-1 could exceed 60 million [3].In spite of more than 20 years of research, the types of immune responses needed to protect an immunized individual from HIV-1 infection are not known. Its is known that CD8 + cytotoxic T-cell responses can control HIV-1 replication to varying degrees in acute HIV-1 infection (AHI) [4,5], and when induced by immunogens, can control viral set point after simian immunodeficiancy virus (SIV) or simian HIV (SHIV) challenges in non-human primates [4]. Strong proliferative CD4 + T-cell responses to HIV-1 proteins have been demonstrated to correlate well with immune control of HIV-1 viral load [5]. Therefore, it is highly desirable for an HIV-1 vaccine co induce robust CD4 + and CD8 + T-cell responses in order to control virus replication and reduce the likelihood of subsequent transmission [4][5][6][7]. The potential for complete ('sterilizing') immunity from HIV-1 infection may depend on the presence of pre-existing neutralizing antibodies. We know that neutralizing antibodies can prevent the acquisition of AIDS virus infection after intravenous, vaginal, rectal and oral virus challenge in nonhuman primates [8][9][10][11][12]. This level of protection is highly attractive for a vaccine against a virus, such as HIV-1, which integrates genetically and forms latent viral reservoirs soon after infection. However, the diversity of transmitted HIV-1 genetic variants and the relative resistance of the majority of HIV-1 primary isolates to most types of inducible neutralizing antibodies have posed major hurdles to current vaccine efforts. Furthermore, the few rare broadly reactive neutralizing monoclonal antibodies (mAbs) that have been isolated from HIV-1 infected patients represent species of antibodies that...

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

Cited by 61 publications

References 70 publications

A new case of autosomal recessive agammaglobulinaemia with impaired pre-B cell differentiation due to a large deletion of the IGH locus

A new case of autosomal recessive agammaglobulinaemia with impaired pre-B cell differentiation due to a large deletion of the IGH locus

Humans with chronic granulomatous disease maintain humoral immunologic memory despite low frequencies of circulating memory B cells

Aiming to induce broadly reactive neutralizing antibody responses with HIV-1 vaccine candidates

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